BR112017009326B1 - ORAL DOSAGE FORM OF A DRUG TO REDUCE BLOOD GLUCOSE LEVEL, AND, KIT - Google Patents

Abstract

ORAL DOSAGE FORM OF A DRUG TO REDUCE BLOOD GLUCOSE LEVEL, AND, KIT. The description refers to dosage forms and combinations of dosage forms useful for effective oral administration of drugs, which are otherwise unsuitable for oral administration, due to acid and/or protease-mediated degradation. Dosage forms include a self-microemulsifying drug delivery system (SMEDDS) with which the drug is combined and an antacid. When coadministered to a mammal, the dosage form(s) may prevent degradation of the drug by strong acid and digestive enzymes normally present in the gastric environment and may improve absorption of the water-soluble drug in the gastrointestinal (GI) tract. The dosage forms can be used to effectively administer insulin orally, for example, as a powder that can be stored for prolonged periods and reconstituted with water or other fluid shortly before administration.

Description

BASICS OF THE INVENTION

[001] The invention generally relates to the field of oral administration of drugs, such as human insulin, which are unstable in the gastrointestinal (GI) tract or poorly absorbed from it.

[002] Many drugs are ineffective when administered orally due to drug instability in the GI tract and low permeability across GI surfaces. Protein-digesting enzymes, such as pepsin and strong acids, may further contribute to the instability of peptide and protein drugs in the stomach, which may further inhibit the stability and efficacy of such drugs. Furthermore, drugs with low lipophilicity and/or high molecular weight tend not to be easily absorbed through epithelial layers in the GI tract.

[003] Several strategies have been reported to improve the stability and bioavailability of orally administered active agents. Specifically, drug uptake in carriers such as liposomes, micelles, nanoparticles, water-in-oil (w/o) or water-in-oil-in-water (w/o/w) emulsions or in microemulsions or in enteric-coated capsules has been suggested. to protect active compounds from exposure to unfavorable chemical environments (e.g. low pH or digestive enzymes). Such approaches may have disadvantages such as low drug stability, low drug loading, ineffectiveness, complex processing requirements, and high cost.

[004] United States Patent 6,191,105 describes the preparation of microemulsion w/o insulin formulations. The w/o emulsion may be unstable due to the phase transition that occurs after oral dispensing, with the consequence of exposing the drug directly to the harsh GI environment.

[005] United States Patent 6,277,413 describes w/o/w emulsions in which water-soluble drugs were incorporated into the internal aqueous phase. These emulsions showed low drug loading.

[006] United States Patent 5,552,156 describes the use of liposomes and micelles as drug carriers. The preparation of such formulations was complex and expensive.

[007] Australian Patent 2004305395 describes water-soluble drug nanoparticle compositions for oral administration and preparation. The preparation method of the compositions involves freeze-drying the nanoparticle, which may increase the preparation cost.

[008] United States Patent Application Serial Number 13/561,105 describes enteric-coated capsules containing cationic nanoparticles to prevent acidic degradation of active substances such as insulin. The process described for the preparation of the capsules was complex, including lyophilization and the preparation of enteric-coated capsules.

[009] United States Patent Application Serial Number 13/521,377 describes compositions for oral administration of insulin peptides that use self-microemulsifying drug delivery systems (SMEDDS) in an enteric-coated soft capsule. The insulin peptide in the SMEDDS formulation is still unstable (degraded or inactivated) in the acidic environment of the stomach. In order to overcome stability, the insulin peptide in SMEDDS is placed in an enteric-coated carrier to protect the active compounds from cleavage or other degradation in the stomach. However, the enteric-coated carrier has an undesirably delayed onset of action when administered orally. Furthermore, gastric emptying time differs between humans, and this will affect the timing of insulin release from the formulation and corresponding absorption through the intestines. Such variations induce large variations in insulin absorption, potentially leading to out-of-control blood sugar levels.

[0010] SMEDDS in liquid dosage forms has limitations such as incompatibility of the excipient capsule (see, for example, Mu et al., 2013, Int. J. Pharm. 453(1):215-224 and Kallakunta et al. , 2012, Powd. Technol. 221:375-382).

[0011] United States patent application publication publication number 2011/0293714 describes compositions that include a polar organic solvent and a lipophilic component and that are used for oral administration of derivatized insulin peptides. A high oral dose (840 IU/kg) of such compositions should be used to reduce blood glucose.

[0012] United States Patent application publication number 2009/0176691 describes monophasic formulations that include a buffering agent and a protein active agent in a free form. These monophasic formulations are intended to be administered orally, with the buffering agent causing the pH of the stomach and/or intestines to be buffered in the pH range 4-8 following oral administration.

[0013] At least some of the technologies described by others yield compositions that effect absorption of drugs (e.g., insulin) after oral administration (e.g., Wong, 2010, J. Drug Target. 18(2):79-92; Arbit et al., 2009, Diabetes Sci. Technol. 3(3):562-567). However, applicants believe that oral formulations have not been designed that have a rapid onset, high bioavailability and, optionally, a short duration of activity, as would be of particular use for drugs such as insulins. Conventional oral insulin formulations have a slow onset time (more than 1.5 hours) and a long effective duration (more than 5 hours). It would be beneficial for clinicians and patients to have access to rapid-acting (onset within 15 minutes) and short-acting (less than 5 hours) drugs such as insulin to provide effective metabolic control using a convenient orally administered dosage form.

[0014] The present description describes compositions that overcome at least some deficiencies of previous compositions and provide fast-acting, short-acting drug compositions, even for drugs that are unstable or poorly bioavailable when administered orally using conventional formulations.

BRIEF SUMMARY OF DESCRIPTION

[0015] The description refers to a dosage form for oral administration of a hydrophilic drug to the bloodstream of a mammal. The dosage form includes a bolus of an antacid sufficient to increase the gastric pH of the mammal to at least about 3 (preferably at least about 3.4) after ingestion of the dosage form (e.g., the bolus may be capable of neutralize 1 to 7 milliequivalents of stomach acids). The dosage form also includes a substantially homogeneous combination of a therapeutically effective amount of the drug and a surfactant system. The surfactant system includes a nonionic surfactant.

[0016] The identity and amount of the surfactant system are selected to be sufficient to induce spontaneous emulsification upon contact between the combination and an aqueous medium under conditions of gentle mechanical agitation, such as conditions occurring in the mammalian stomach or in a container (e.g., a small cup) in which the combination is stirred with a small amount of aqueous medium before administration. By way of example, the identity and amount of the surfactant system can be selected to be sufficient to induce spontaneous emulsification upon contact between the combination and a nine-fold excess of distilled water under conditions of mechanical agitation characteristic of the mammalian stomach. (The precise objective standard selected is not critical; the surfactant system may be selected to be sufficient to induce spontaneous emulsification upon contact with a four- or two-fold excess of distilled water or USP simulated gastric fluid, for example). Preferably, the identity and amount of the surfactant system are selected so that the average size of the emulsion droplets formed upon contact between the combination and the aqueous medium is no greater than about 2000 nanometers (or less, such as preferably no greater than at about 800, 500 or 300 nanometers).

[0017] In dosage form, the cake can be included in the substantially homogeneous combination. Alternatively, the cake and combination may be present in distinct portions of the dosage form, such as in the form of distinct solids, powders or liquids.

[0018] The dosage form is useful for administering a variety of hydrophilic drugs, including drugs that are normally poorly bioavailable when administered orally. Examples of such drugs include insulin peptides (e.g., anthropotherapeutic insulins such as isolated or synthesized human insulin peptides), growth hormones, gentamicin, gemcitabine, penicillins, and vancomycin.

[0019] The dosage form may be provided in the form of a kit that includes the dosage form and an amount of the aqueous medium sufficient to dissolve or suspend the antacid bolus and to emulsify the combination. Alternatively, it may be provided in the form of a kit that includes a first dosage form including the antacid bolus and a second dosage form including the substantially homogeneous combination of the drug and the surfactant system.

[0020] The description further relates to a method for oral administration of a hydrophilic drug to the bloodstream of a mammal. The method is carried out by combining a therapeutically effective amount of the drug and the surfactant system described herein, mixing the combination, the aqueous medium and a bolus of an antacid sufficient to increase the gastric pH of the mammal to at least about 3 to produce an emulsified mixture; and then oral administration of the emulsified mixture to the mammal.

[0021] In an alternative method, the drug and the surfactant system are combined to yield a combination, the antacid bolus is administered orally to the mammal, and the combination is administered orally to the mammal sufficiently close in time to the administration of the bolus so that the The mammal's gastric pH remains at least about 3 while the combination is administered.

BRIEF SUMMARY OF THE VARIOUS VIEWS OF THE DRAWINGS

[0022] Figure 1 is a graph of blood glucose levels over time, calculated as a percentage of initial blood glucose values, for streptozotocin (STZ)-induced diabetic mice that were orally administered 200 IU/kg insulin in a 3.78% w/v aqueous solution of sodium bicarbonate (NaHCO3) (filled circles), in phosphate buffered saline (PBS) (open circles), or in Formulation 1 suspended in a NaHCO3 solution (concentration final at 3.78%; triangles). Data shown are means and standard deviations for groups of 8 mice each.

[0023] Figure 2 is a graph of blood glucose levels over time, calculated as a percentage of initial blood glucose values, for STZ-induced diabetic mice that were orally administered 200 IU/kg insulin in Formulation 1 suspended in NaHCO3 solutions of varying final concentration. The final NaHCO3 concentrations were: 0.90% (filled circles), 1.80% (open circles), 2.70% (filled triangles) and 3.78% (open triangles). Data shown are means and standard deviations for groups of 8 mice each.

[0024] Figure 3 is a graph of blood glucose levels over time, calculated as a percentage of initial blood glucose values, for dogs that were orally administered 150 IU/kg of insulin in Formulation 1 suspended in a solution of NaHCO3 (final concentration at 3.78%; open circles) or for untreated control dogs (filled circles). Data shown are means and standard deviations for groups of two beagle dogs each.

[0025] Figure 4 is a graph of blood glucose levels over time, calculated as a percentage of initial blood glucose values, for STZ-induced diabetic mice that were orally administered 200 IU/kg insulin in Formulation 2 suspended in a NaHCO3 solution (final concentration 3.78%). Data shown are means and standard deviations for groups of 8 mice each.

[0026] Figure 5 is a graph of blood glucose levels over time, calculated as a percentage of initial blood glucose values, for STZ-induced diabetic mice that were orally administered 200 IU/kg insulin at the Formulation 3 suspended in a NaHCO3 solution (final concentration 3.78%). Data shown are means and standard deviations for groups of 8 mice each.

[0027] Figure 6, which consists of Figures 6A and 6B, is a pair of graphs of blood glucose levels over time, calculated as a percentage of initial blood glucose values, (Fig. 6A) and plasma concentration of insulin over time (Fig. 6B) for Wistar rats that were orally administered 200 IU/kg of insulin in Formulation 4 suspended in 3.00% NaHCO3. Data shown are means and standard deviations for groups of 3 mice each. Comparison data are also shown for rats administered free insulin suspended in a 3% NaHCO3 solution.

[0028] Figures 7 and 8 are graphs of blood glucose levels over time, calculated as a percentage of initial blood glucose values, for STZ-induced diabetic mice that were orally administered 50 IU/kg of insulin in the Formulation 5, which included 8% NaHCO3 (Fig. 7) or 50 IU/kg insulin in Formulation 6, which included 2.1% NaHCO3a and 0.9% MgOH2 (Fig. 8).

[0029] Figure 9, consisting of Figures 9A and 9B, is a pair of graphs of blood glucose levels over time, calculated as a percentage of initial blood glucose values, (Fig. 9A) and plasma concentration of insulin over time (Fig. 9B) for STZ-induced diabetic Wistar rats that were orally administered 200 IU/kg insulin in Formulation 4. Data shown are means and standard deviations for groups of 3 rats each.

[0030] Figure 10 is a graph of blood glucose levels over time, calculated as a percentage of initial blood glucose values, for STZ-induced diabetic Wistar rats that were orally administered 200 IU/kg insulin suspension after dispersing Formulation 7 in water.

[0031] Figure 11 is a graph of blood glucose levels over time, calculated as a percentage of initial blood glucose values, for STZ-induced diabetic mice that were orally administered 200 IU/kg insulin suspension after dispersion of Formulation 8 in water.

[0032] Figure 12 is a graph of plasma insulin concentration over time for STZ-induced diabetic Wistar rats that were orally administered 116 IU/kg of insulin in Formulation 9. Data shown are means and standard deviations for groups of 5 mice each.

[0033] Figure 13 is a graph of blood glucose levels over time, calculated as a percentage of initial blood glucose values, for streptozotocin (STZ)-induced diabetic mice that were orally administered 200 IU/kg insulin in a 3.78% w/v aqueous solution of sodium bicarbonate (NaHCO3) that was freshly prepared (filled squares) or that had been stored at 5 degrees Celsius for three months before administration (filled circles).

[0034] Figure 14 is a graph of blood glucose levels over time, calculated as a percentage of initial blood glucose values, for STZ-induced diabetic mice that were orally administered 200 IU/kg of an insulin solution free (filled squares) or rapid-acting oral formulation insulin described in an example here (filled circles).

[0035] Figure 15 is a plasma insulin concentration over time for Beagle dogs administered orally 25 IU/kg insulin in Formulation 8 and free insulin with 0.5 IU/kg subcutaneous (SC) injection . Data shown are means and standard deviations for groups of three beagle dogs each.

DETAILED DESCRIPTION

[0036] This description refers to oral formulations and dosage forms for drugs (especially hydrophilic drugs) that are unstable in acidic solutions, that are susceptible to digestion by pepsin or other gastric protease/peptidase, that have low gastrointestinal permeability, that have an undesirably delayed onset of action when administered orally, which have an undesirably long duration of action when administered orally, or any combination thereof (collectively, “gastrically unsuitable drugs”). Oral formulations include both i) a self-(micro)emulsifying drug delivery system (SMEDDS) that includes the drug and ii) a bolus of an antacid that is sufficient to increase gastric pH to at least about 3, and preferably to 3.4 or greater, following oral administration of the formulation to an individual, such as a human or other mammal.

[0037] SMEDDS technology is known and understood (see, for example, Khan et al. 2012, J. Pharmacy Alt. Med. 1:13-19; U.S. patent application publication no. 2003/0022944; publication of U.S. Patent Application No. 2010/0273730). SMEDDS are isotropic mixtures of one or more relatively hydrophobic solvents, one or more surfactants, and drug that exhibit the ability to form fine microemulsions (e.g., micelles or liposomes) upon gentle agitation after dilution in (e.g., contact with) a phase aqueous. Enhancement of the bioavailability of hydrophobic and hydrophilic drugs through incorporation of such drugs into SMEDDS formulations has been described by others. However, simply incorporating into a SMEDDS a drug that exhibits undesirable bioavailability or pharmacokinetics when administered orally often does not reliably confer adequate bioavailability or pharmacokinetics for pharmaceutical purposes. This is particularly so for drugs that are sensitive to (i.e., degraded, cleaved, or inactivated by) acidic conditions in the stomach or to the action of one or more proteases or peptidases (e.g., pepsin) that normally occur in the stomach.

[0038] Described herein is a formulation that includes both a drug-containing SMEDDS composition and an antacid bolus. These two components can be co-administered orally to a mammalian subject (or administered orally to the subject sufficiently close together in time when the antacid effect of the bolus overlaps the period in which the drug-containing SMEDDS composition resides in the stomach) to effectively dispense the drug. through the gastrointestinal barrier and reduce or eliminate the degradation of the drug by gastric acid and/or enzymes.

[0039] The subject matter described herein includes dosage forms for oral administration to a mammal (e.g., a human), a drug (preferably a hydrophilic drug) that is poorly gastroavailable when the drug is administered orally to the mammal in a simple form of immediate release, (e.g., a tablet, capsule, collection of granules, or solution). The dosage form includes a bolus of an antacid sufficient to increase the animal's gastric pH to at least about 3 after ingestion of the dosage form. The dosage form also includes (as an additional part of a unit dosage form or as an additional part of a multipart dosage form) a combination (preferably a substantially homogeneous combination) of i) a therapeutically effective amount of the drug, ii) optionally, a polyol solvent, and iii) a surfactant system that includes a non-ionic surfactant. A composition is “substantially homogeneous” when it is well mixed or blended so that it appears to an ordinary pharmacist to have a visually uniform composition (i.e., even though the composition includes visually distinguishable components, those components appear to be evenly distributed throughout the composition ). The identities and amounts of the drug, any polyol solvent, and the surfactant system are selected so that when the combination is placed in contact with an aqueous phase under conditions of gentle mechanical agitation, the combination emulsifies spontaneously. Thus, for example, when the combination is stirred in a glass of water (or other aqueous liquid, such as a drink) before oral administration, or when the combination comes into contact with the aqueous contents of the stomach, the combination emulsifies, producing a drug-containing emulsion in the mammal's GI tract. Since the antacid bolus reduces acidity in the stomach and consequently reduces the activity of gastric proteolytic enzymes, the stability of the drug in the emulsion is increased and uptake of the drug by the mammal (i.e., into the mammal's bloodstream) is also enhanced. .

[0040] The formulations described here can prevent the degradation of the drug in the presence of strong acid and digestive enzymes normally found in the gastric environment of mammals. The formulations can also improve drug absorption in the GI tract. Such formulations can enhance the rate of drug uptake and can optionally limit the duration of drug action (e.g., by including a limited amount of antacid). In the context of some drugs, such as insulin, a rapid onset of action (within 15 to 30 minutes after insulin administration, for example) and a relatively short duration of action (falling to less than 25% of maximum activity below 5 hours, and preferably less than about 4 hours, after administration of insulin, for example) are desirable. In this way, the orally administered insulin-containing formulations described herein can mimic the relative immediacy and short duration of action characteristics of subcutaneously injected insulin, for example. In other embodiments, the drug may be included in a composition from which the drug will be released over an extended period of time (e.g., 0 to 24 hours, such as by selecting formulation components from which the drug transfers to watery gastrointestinal fluids only slowly).

[0041] The components of the compositions and methods described here are described below in greater detail.

[0042] The compositions described here for oral administration of drugs that are normally poorly absorbed from the GI tract have two main components, which can be combined in a unit dosage form, packaged as a kit including two or more components, or provided separately to a doctor or patient for combined use. The two primary components of the compositions are a “SMEDDS composition” (i.e., a combination of a microemulsion concentrate and a drug that may optionally be homogeneous) and an antacid bolus. The antacid bolus is administered to a mammalian patient, such as a human, to increase the pH of the stomach (and, optionally, other portions of the GI tract). The SMEDDS composition includes the drug and spontaneously emulsifies upon contact with an aqueous medium to yield droplets (e.g., micelles) that include or contain the drug and that facilitate drug delivery across cellular layers (e.g., gastric or epithelial epithelium). small intestine) along the GI tract. Drug administered through these cell layers can enter the systemic blood circulation and be dispensed throughout the body.

[0043] The SMEDDS composition and the antacid bolus components can be administered to an individual in a dosage form in which the two components are combined. By way of example, they may be administered in a dosage form that includes a liquid in which both components are suspended or dissolved, one that includes separate powder forms of the two components that are mixed, or one that includes an adsorbent (e.g. example, an insoluble mineral powder, such as silica particles) on which one or both components are adsorbed. Alternatively, the two components may be administered in a dosage form in which the two components occur in separate locations (e.g., a bilayer tablet or multicompartment capsule in which the two components occur in separate compartments). As another alternative, the two components may be administered in separate dosage forms, provided that the SMEDDS composition is administered during the period of time that the antacid bolus causes the gastric pH to be above about 3. The compositions In the form of liquids that are prepared before oral administration or in the form of powders they can be advantageously administered to patients who have difficulty swallowing tablets or capsules.

The composition of SMEDDS

[0044] An important part of the compositions and methods described herein relates to a drug-containing composition that emulsifies spontaneously upon contact with water or an aqueous medium to form droplets that include the drug. Since this description is directed primarily to enhancing the release of gastrically impractical drugs (e.g., relatively hydrophilic drugs) such as polypeptides (e.g., anthropotherapeutic insulins), the droplets that are formed are preferably micelles that include the drug or a fraction thereof. of the drug. These micelles are suspended in an aqueous medium and the suspension is administered to the individual. Alternatively, micelles can be formed in the GI tract by administering the SMEDDS composition, optionally (i.e., in the event that the stomach contains relatively little fluid) together with sufficient aqueous liquid (e.g., antacid bolus dissolved in water) to facilitate emulsification in the stomach. In the individual's GI tract, the micelles facilitate drug transit through the GI cell layers, preferably into the individual's bloodstream, from where they can be delivered to a desired site of action (e.g., within the blood or to a site in the body). distant from the GI tract).

[0045] The SMEDDS composition is a combination of a therapeutically effective amount of the drug to be administered and a surfactant system. The drug may be dissolved or suspended in an aqueous solution, a polyol solvent, or both, before combining it with the surfactant system. The drug may also, for example, be combined with the surfactant system in a powder form (e.g., anhydrous or hydrated powder). The surfactant system includes a nonionic surfactant. The identity and amount of surfactant system are selected such that the SMEDDS combination spontaneously emulsifies upon contacting an aqueous medium under conditions of gentle mechanical agitation, such as the SMEDDS composition being gently swirled in a container (e.g., a beaker). drink cup or unit dosage cup) after combining it with the medium. In one embodiment, the SMEDDS composition is kept discrete (e.g., in the form of a powder or granule composition contained within a capsule that is swallowed whole and subsequently dissolves within the GI tract) until shortly before or after being swallowed by an individual, and the SMEDDS composition emulsifies in the individual's gastrointestinal (GI) tract when it comes into contact with the aqueous fluid therein (e.g., in the form of a powder or granulated composition contained within a capsule swallowed whole and which subsequently dissolves within the stomach or small intestine). The combination time of the drug and the surfactant system is not critical. Where stability concerns permit, the drug may be mixed (e.g., homogeneously) with the surfactant system; Alternatively, the drug and surfactant system can be combined (e.g., by mixing a powdered drug with a liquid surfactant system) immediately before or simultaneously with combining the two with the antacid bolus.

[0046] The SMEDDS composition may also include a polyol solvent, such as glycerol, propylene glycol or a polyethylene glycol (or other polyether compound) that is liquid in its pure state at 20 degrees Celsius and atmospheric pressure. The polyol solvent can function to assist in combining the drug with the surfactant system, coating the combined drug/polyol/surfactant system on an adsorbent, or dissolving the drug in the aqueous medium, for example. The amount of the polyol that is included in the SMEDDS composition is not critical and can be readily determined empirically by one skilled in the art, depending on the intended purpose(s) of the polyol. By way of example, the SMEDDS composition may include about 0 to 80% by weight polyol before combining with the aqueous medium. In formulations that include human insulin as the drug, SMEDDS compositions that include at least about 40% by weight polyol are desirable.

[0047] An important feature of the SMEDDS composition is that at least some droplets formed after contact between them and an aqueous medium have an appropriate size for transit through or between the cell layers of the GI tract. The droplets should have a size (i.e., diameter) of no more than about 500 nanometers, preferably no more than about 300 nanometers, and preferably have a size of at least about 10 nanometers. The size of the droplets that are formed is determined by the composition of the SMEDDS composition, mainly by the surfactant system.

[0048] The formulation of self-emulsifying compositions is known in the art (see, for example, Khan et al. 2012, J. Pharmacy Alt. Med. 1:1319; U.S. patent application publication no. 2003/0022944; application publication U.S. Patent No. 2010/0273730; and others). Inherent in the formulation of self-emulsifying compositions with selected droplet size distributions are routine testing of multiple ingredient combinations and ratios, such as the identities and concentrations of surfactants used. A certain degree of empirical testing is routinely performed in selecting the identities and concentrations of the components used.

[0049] The SMEDDS composition can be prepared, packaged and/or administered to an individual as a substantially homogeneous composition, being a substantially homogeneous single-phase liquid, a substantially uniform powder or granulation (e.g., loose, compressed into a tablet or contained within a capsule), or a substantially homogeneous emulsion (e.g., w/o emulsion, or w/o/w emulsion). When in the form of an emulsion, the SMEDDS composition preferably contains the drug in the dispersed aqueous phase of the emulsion (i.e., within the aqueous phase of a w/o emulsion). In one embodiment, the SMEDDS composition is prepared, packaged and/or administered in the form of a powder or granulated mixture (optionally including the antacid bolus) that is intended to be mixed with water or other aqueous fluid (to facilitate emulsification). of the SMEDDS composition) shortly (within 24 hours, preferably within 2 hours) or immediately before oral administration.

[0050] The SMEDDS composition is useful for enhancing drug delivery across gastric and intestinal membranes, such as through the tight junctions that exist between intestinal epithelial cells. The compositions can be used to enhance the dispensing of drugs of substantially any hydrophilicity/hydrophobicity, but this description focuses particularly on relatively hydrophilic drugs, which are normally subjected to acids and enzymes that are contained in the aqueous medium of mammalian gastric fluids. Examples of such drugs include insulin peptides, growth hormones, erythropoietin, antibodies (e.g., monoclonal antibodies) and antibody fragments, gentamicin, gemcitabine, penicillins, and vancomycin.

[0051] Insulin peptides represent a particularly important class of drugs that are known to be susceptible to degradation and/or inactivation in gastric fluids. The family of gastric proteases referred to as pepsin generically is known for cleavage of insulin peptides at defined sites under acidic conditions (pH < 3.4) that normally occur in mammalian stomachs. Pepsin has maximum activity at about pH 2.0 and is substantially inactive at pH 6.5 or higher. Thus, the antacid bolus can be selected to yield a gastric pH greater than about 3, preferably greater than 3.4, and more preferably even greater (there may be negligible additional benefits in inducing gastric pH > 6.5). Insulin peptides are also known to be subject to deamidation under acidic conditions. Cleaved and/or deamidated insulin peptides exhibit less of the beneficial pharmaceutical activity of intact insulin, which likely explains the ineffectiveness of insulin for the treatment of insulin-sensitive disorders (e.g., diabetes) when insulin is administered orally. The compositions described herein protect insulin (and other drugs) from the inactivating effects of stomach acid and proteases and also facilitate the transit of insulin across GI membranes. The compositions and methods described herein therefore have particular utility for enhancing the bioavailability of insulin peptides when they are administered orally.

[0052] Numerous insulin peptides are known and this term is used here to refer to naturally occurring forms of insulin (e.g., regular, unmodified human insulin) and synthetic insulins and insulin-like peptides (e.g., those generated by modification of naturally occurring insulin or via non-biotic synthetic routes). The precise identity of the insulin peptide is not critical. Preferably, the insulin peptide is an anthrotherapeutic insulin in that it induces one or more physiological effects in a human to whom it is administered that are similar or identical to those induced by injection (e.g., intravenous, intramuscular, or subcutaneous) of insulin. naturally occurring human.

[0053] The amounts of the drug and any polyol or aqueous solvents that are incorporated into the SMEDDS composition are not critical, as long as the SMEDDS composition maintains its ability to emulsify spontaneously upon contact with an excess of aqueous fluid. The SMEDDS composition must include at least enough of the drug to have a desired pharmaceutical effect on a subject when a unit dose of the SMEDDS composition is administered to the subject. The aqueous solution must be selected to be compatible with (i.e., not cause significant degradation or inactivation of) the drug during the period and conditions of anticipated storage between manufacture and administration of the SMEDDS composition. Appropriate amounts of the aqueous solution can improve the processability of the SMEDDS composition during its manufacture and will typically not exceed about 30% (w/w) of the SMEDDS composition and, preferably, will make up 20%, 10% or less of the composition of SMEDDS. The SMEDDS composition can be made in bulk and dispensed in aliquots in unit dosage forms suitable for administration to individual subjects; in such cases, the bulk SMEDDS composition will include multiples of an effective dose of the drug, while each unit dose will include a single effective dose. By way of example, a bulk SMEDDS composition may be prepared and packaged in a compartment of several double-compartment individual dosage forms (e.g., capsules).

[0054] The SMEDDS composition may include a polyol solvent, such as one or more of glycerol, propylene glycol and polyethylene glycols (PEG). Other similar compounds (e.g. other polyethers) may also be used. Polyol solvents can facilitate the dissolution or suspension of drugs (e.g., insulin) in the other components of the SMEDDS composition, thereby enhancing the drug uptake-inducing effect of the SMEDDS composition. When a polyol solvent is included, the SMEDDS composition preferably includes at least about 5% (w/w) of the polyol solvent(s), and preferably no more than about 50% (w/w). In some SMEDDS compositions, the appropriate polyol(ol) content of the composition is in the range of about 20 to 30% (w/w) of the composition.

[0055] The SMEDDS composition includes a surfactant system that, in combination with the drug and any aqueous solvent or polyol included, makes the SMEDDS composition spontaneously emulsifying in contact with an aqueous medium. A precise degree or rate of emulsification is not necessary, but it is preferred that substantially the entire SMEDDS composition emulsify within one hour when it is combined with a nine-fold excess of distilled water at 20 degrees Celsius under gentle stirring (i.e., nine parts of water and one part of the SMEDDS composition stirred in a temperature-controlled beaker with a rotating stir bar at 10 revolutions per minute). The surfactant system includes at least one nonionic surfactant, and preferably includes at least one surfactant selected from the group consisting of polyglycolized glycerides having at least one acyl moiety and propylene glycol esters of fatty acids. A polyglycolized glyceride, as used herein, refers to a mixture of monoglycerides, diglycerides and triglycerides with polyethylene glycol (PEG) monofatty acid esters and/or fatty diacid esters, having hydrophilic lipophilic balance (HLB) values between and including 4 and 19. The acyl moiety(s) is/are a straight or branched chain alkane or alkene compound (preferably no longer having two alkenyl bonds) including from 8 to 18 carbon atoms. Preferred acyl moieties include -CO- (CH2)7CH3, -CO-(CH2)9CH3, -CO-(CH2)11CH3, -CO-(CH2)13CH3, -CO- (CH2)7-CH=CH-(CH2 )7CH3, and -CO-(CH2)7-CH=CH-CH2-CH=CH- (CH2)4CH3. Examples of polyglycolized glycerides include oleoyl polyoxylglycerides (oleoyl-polyoxyl-6 glycerides such as Labrafil® M-1944CS), linoleoyl polyoxylglycerides (linoleoyl polyoxyl-6 glycerides such as Labrafil® M-2125CS), caprylocaproyl polyoxylglycerides (PEG-6 caprylic glycerides/ caprics such as SOFTIGEN® 767), caprylocaproyl polyoxyl-8 glycerides (e.g. Labrasol®), lauroyl polyvinyloxylglycerides (Gelucire® 44/14) and combinations thereof.

[0056] Propylene glycol fatty acid esters, as used herein, refer to a mixture of propylene glycol mono- and diesters of saturated and unsaturated fatty acids, preferably derived from edible oils and fats, which can be produced by direct esterification of propylene glycol with fatty acids or by transesterification of propylene glycol with oils or fats. When prepared by transesterification, the product may contain residual mono- and diglycerides and glycerol, a process that can be followed by molecular distillation to separate the monoesters. Examples of propylene glycol fatty acid esters include propylene glycol monocaprylate, propylene glycol dilaurate, propylene glycol monolaurate, propylene glycol dicaprylocaprate, propylene glycol laurate, propylene glycol caprylate.

[0057] The surfactant system may additionally include an additional surfactant (or more than one), such as one selected from the group consisting of polysorbate, poloxamers, polyoxyethylene castor oil derivatives, polyoxyethylene alkyl ethers, sorbitan fatty acid esters , glyceryl monooleate, glyceryl monolinoleate, medium chain triglycerides, polyglyceryl oleate, lauroyl polyoxylglyceride, stearoyl polyoxylglycerides and combinations thereof.

[0058] The formulation of self-emulsifying compositions is known in the art, including the selection of the identity(ies) and the concentration of surfactant(s) included in such compositions. The identity and concentration of the surfactant(s) included in the surfactant system are not critical, except that they are selected so as to give the SMEDDS composition the ability to emulsify spontaneously upon contact with an aqueous medium (optionally, with gentle agitation). Preferably, the surfactant system represents about 5 to 90% (w/w) of the SMEDDS composition, more preferably, at least about 20%, at least about 30%, at least about 40%, at least about 50%, and even more preferably at least about 60% (e.g., 20 to 70%, 40 to 70% or 50 to 70% w/w). As is known in the art, combinations of surfactants are suitable for imparting spontaneous emulsifying capacity to drug-containing formulations and such combinations are suitable for the surfactant system described herein. Surfactant combinations can be selected, for example, with reference to their hydrophilic-lipophilic balance (HLB) value (see, for example, U.S. patent application publication Nos. 2003/0022944 and 2010/0273730). When HLB values are used to select a surfactant system, HLB values in the range of about 8 to 19 are considered appropriate for the compositions described herein.

[0059] The composition of SMEDDS can be made by combining its components in any order that is effective to yield a composition that emulsifies spontaneously upon contact with an aqueous medium. In a suitable method, the drug is dissolved or suspended in an aqueous solution, and this solution/suspension is then combined with a polyol solvent(s) to form a substantially homogeneous single-phase mixture. The surfactant(s) of the surfactant system are added (individually or after a prior combination of surfactants) to this mixture. Depending on the surfactant system selected, gentle stirring, rocking, or other shaking may yield a second substantially homogeneous single-phase mixture (e.g., if little or no aqueous solvent or polyol is included) or a multiphase mixture, such as a w/o emulsion or w emulsion. /o/w (especially if relatively large amounts of aqueous solvent(s) are included).

[0060] The SMEDDS composition can be associated with an adsorbent. Adsorbents are solid compositions, most often used in the form of fine powders that act primarily as excipients to facilitate the manipulation of the compositions of the drug compositions described herein. Because adsorbents tend to be free-flowing powders or other easily manipulated substances, the clumping, adsorption, drying, or adhesion of a component on or into an adsorbent facilitates manipulation of that component. The use of adsorbents is well known in pharmaceutical techniques. Examples of suitable adsorbents include silica (e.g., silica powders such as fumed silica) and other mineral powders that are substantially insoluble in water, celluloses (e.g., microcrystalline cellulose powders) and starches.

[0061] By way of example, the SMEDDS composition (including the drug) can be solidified into microcrystalline cellulose granules (for example, by contacting the granules with a SMEDDS composition including a volatile solvent and then evaporating some or all of the solvent) and the granules coated with SMEDDS composition can be combined with a powdered antacid to yield the dosage form. Alternatively, the antacid can also be solidified onto the granules (e.g. as an outer layer). As yet another alternative, the SMEDDS composition (not yet including the drug) can be coated on the granules, and the powdered drug and powdered antacid can be mixed with the granules. One skilled in the art in this field recognizes that many known configurations of adsorbents and the other components of the drug compositions described herein can be used without departing from the subject matter described herein.

[0062] The SMEDDS composition can be stored (preferably at a controlled temperature, such as less than 20 degrees Celsius and preferably above the freezing point of any aqueous phase present therein, such as 4-5 degrees Celsius) as a substantially homogeneous mixture (whether emulsified or not) or may be combined with an aqueous medium (e.g., water or an aqueous solution/suspension of an antacid) to form an emulsion before storage. Dry or low moisture compositions are known to exhibit superior storage properties under a wide range of conditions. The dosage forms described herein in which one or more components are present in the form of a dry powder (e.g., coated or adhered to an adsorbent) can thus withstand more stringent storage conditions, such as storage at a controlled temperature (e.g. , less than 30 degrees Celsius and above 0 degrees Celsius) for long periods.

[0063] The SMEDDS composition can be administered directly to an individual (i.e., such that it spontaneously emulsifies upon contact with the individual's aqueous stomach fluid) or can be contacted with an aqueous medium (e.g., a glass of water, a glass of water in which the antacid bolus described herein has been dissolved, or a flavored beverage) prior to administration of the medium to the subject (i.e., so that the SMEDDS composition will fully or partially emulsify in the medium prior to administration. its administration to the individual).

The antacid cake

[0064] The compositions and methods described herein involve a bolus of one or more antacids that is sufficient to raise the gastric pH of the animal to which the bolus is administered to at least about 3 (i.e., preferably no more than 3 5 minutes later) oral administration of the bolus. The identity of the antacid is not critical, and suitable examples include sodium bicarbonate, magnesium hydroxide, calcium carbonate and aluminum hydroxide. Other suitable antacids are described in U.S. Patent Application Publication No. 2014/0127296, for example. In an alternative embodiment, the antacid is provided in a form that is not released as a single bolus after oral administration, but instead releases antacid over a prolonged period of time (e.g., 2 to 24 hours) after oral administration. Extended-release antacid preparations are known.

[0065] The selection of a suitable antacid (or combination of antacids) and adequate amounts thereof to achieve a gastric pH of not less than about 3 (preferably not less than 3.4) is within the knowledge of one of ordinary skill in this field. and takes into account the amount of acid expected to be present in an individual's stomach. By way of example, a fasting human would normally be expected to have about 1 to 7 milliequivalents (mEq) of stomach acids within the stomach. One skilled in the art in this field is able to calculate amounts of antacids necessary to achieve a desired pH in an individual's stomach for a desired period of time.

[0066] The form in which the antacid bolus is packaged and/or administered to an individual is not critical. Liquids are relatively bulky and present difficulties in packaging and storage, but they are relatively simple to administer. Solids are more compact and generally shelf-stable, but require hydration and dissolution before administration or within the patient after administration.

[0067] The amount of antacid in the bolus will affect the duration in which gastric pH is raised above 3. Generally speaking, large amounts of antacids will result in a longer duration, at least to a point. When a relatively short duration of action is desired for the drug, including in the dosage form, just enough antacid to increase gastric pH during the desired period of time can serve to limit the duration of action of the drug by allowing gastric secretions that exceed the pH-raising effect of the antacid to degrade or inactivate the drug.

[0068] A pharmaceutical agent effective for reducing gastric acid secretion can be administered with (or overlapping in time with) the compositions described herein if prolonged protection of the drug against the effects of stomach acid is desired.

The dosage form

[0069] The precise manner or nature of the dosage form in which the compositions described herein are administered to an individual is not critical. Any of a wide variety of known dosage forms can be used, including tablets, capsules, liquid carriers, and multilayer or multicompartment dosage forms. Other contemplated dosage forms include powders, granules and dosage cups with a solid material contained or affixed thereto, each of which may be combined with an aqueous fluid prior to administration to emulsify the SMEDDS composition, suspend or dissolve the antacid, or both. What is important is that the drug is released from the dosage form containing the SMEDDS composition over a period of time that overlaps the period of time for which the antacid bolus increases gastric pH above about 3.

[0070] In one embodiment, the compositions described herein are packaged as powder unit dosage forms in which a unit dose of solid SMEDDS composition (e.g., powder SMEDDS composition or an adsorbent with the SMEDDS compositions adsorbed onto the same or dried on the same) is combined with unit dosages of the drug (in solid form) and antacid (also in solid form). The solid components of the dosage form are combined with an aliquot of aqueous fluid (provided by the individual or included separately with the solid dosage form) to form a dispersion, emulsion or (preferably) nanoemulsion suspended in the aqueous fluid before administering the suspension to a patient.

[0071] In another embodiment, the compositions described here are packaged as unit dose forms in which a unit dose of the SMEDDS composition was emulsified by contact with an aqueous medium in which a unit dose of the antacid bolus was dissolved; the emulsion is administered orally to the subject (e.g., by pouring or squeezing the contents of the unit dosage form into the subject's mouth or by the subject swallowing the entire dosage form, such as in the form of a capsule).

[0072] In another embodiment, the compositions are used by physicians and/or patients in the form of a kit that contains the unit dose of the antacid packaged separately (e.g., as a tablet or liquid) from the unit dose of the SMEDDS composition ( for example, provided within a capsule); the complete dosage form is administered to the patient by administering the unit dose of the antacid and the unit dose of the SMEDDS composition to the patient.

[0073] In yet another embodiment, the unit dose of the antacid and the unit dose of the SMEDDS composition are packaged in separate compartments or layers of a single dosage form (e.g., a multi-compartment container, a coated or bilayer tablet or a coated capsule or multicompartment), such that ingestion of the entire dosage form by an individual will lead to release of the antacid bolus from its compartment (i.e., increasing gastric pH to >3) and release of the SMEDDS composition of its compartment (leading to the release or formation of a drug-containing emulsion in the GI tract).

[0074] In yet another embodiment, the drug and the antacid are combined and prepared in the form of a tablet or powder and provided to the patient together with a SMEDDS composition that has already been combined with an aqueous fluid (i.e., so that is in the form of a suspended nano or microemulsion). In this embodiment, the dosage form is administered to a patient by combining (or having the patient combine) the tablet or powder with the suspended emulsion (to dissolve or suspend the drug and the antacid therein) and administering the resulting liquid to the patient.

[0075] In still other configurations, the dosage form may be a capsule that contains the SMEDDS composition and that is coated with a fast-dissolving antacid bolus. The dosage form may be poured into a glass of water to form an antacid solution (optionally flavored), and this solution may be used as a means to facilitate swallowing of the capsule by the individual or as a medium in which the capsule dissolves ( thus forming an emulsion containing drug in the medium) and the medium is then consumed by the individual.

[0076] This list of exemplary modalities is not limiting. Substantially any dosage form or method may be used to orally administer two compositions to the same individual. Administration of the SMEDDS composition must, however, be carried out during a period in which contact between the SMEDDS composition and gastric fluids occurs while the gastric pH has been raised above about 3 by administration of the antacid bolus.

Use of compositions

[0077] The compositions described herein can be used to orally administer a gastrically unavailable drug (That is, a poorly gastroavailable drug, such as a hydrophilic drug) to the bloodstream of a mammal. To achieve this, a therapeutically effective amount of the drug is dissolved or suspended in water or an aqueous solution. The dissolved or suspended drug is combined with the surfactant system described herein and, optionally, a polyol solvent. These components are gently mixed to form a substantially homogeneous SMEDDS composition, which may be a substantially single-phase liquid, a w/o emulsion (hydrophilic drugs that tend to localize in the aqueous phase), or a w/o/w emulsion (hydrophilic drugs which tend to be located in one or both aqueous phases). In another embodiment, the drug is combined with a surfactant system and an adsorbent to form a mixture in a solid form (e.g., a solid granule or powder) that is combined with an aqueous liquid (e.g., water or a suspension of the antacid bolus) before administration.

[0078] As described herein, the identities and amounts of the drug, any aqueous solvent, any polyol solvent and the surfactant system are selected such that the SMEDDS composition emulsifies spontaneously upon contacting an aqueous medium under conditions of gentle mechanical agitation. The SMEDDS composition is contacted with such an aqueous medium to create an emulsion (or to dilute the existing emulsion in the SMEDDS composition), and this emulsion may optionally be stored at reduced temperature (preferably above the freezing point of the phases). emulsion). The emulsion thus formed is administered orally to a mammal, in conjunction with (i.e., shortly before, shortly after, or simultaneously with the administration of) a bolus of an antacid sufficient to raise the gastric pH of the animal to at least about 3 ( and preferably above 3.4).

[0079] Optionally, the emulsion can be formed in the individual's stomach by administering to the individual a dosage form that releases the SMEDDS composition directly into the stomach. If not already in the form of an emulsion in dosage form, the SMEDDS composition may spontaneously form an emulsion in the subject's gastric fluids. Ingestion of water with the dosage form may increase the likelihood that the individual's gastric contents will include sufficient water to form an emulsion.

[0080] The SMEDDS composition must be administered orally to the mammal with sufficient precision at the time of bolus administration so that the animal's gastric pH remains at least about 3 while the emulsion formed from the SMEDDS composition remains at the mammal's stomach.

[0081] Diabetes and other diseases treatable by administering insulin peptides to an individual are disorders for which the compositions and methods described herein are considered particularly suitable. Effective acute treatment of insulin-sensitive disorders may require a rapid onset of action following administration of an insulin peptide and it may be desirable for the duration of action of the insulin peptide to last no more than a few hours. For these reasons, injectable insulin peptide compositions are commonly used, because insulin peptides tend to be poorly bioavailable (if at all) when administered by other routes (e.g., oral). As the discussion and examples here indicate, insulin peptides that are administered orally in one of the formulations described here can exert a very rapid onset of action (< 30 minutes) and a duration of action that lasts for 2 to 4 hours. For these reasons, the formulations described herein can be used to deliver insulin peptides regularly or on an acute basis, as needed, to individuals requiring insulin therapy. The ability for individuals to ingest formulations orally rather than by injection may also improve comfort and ease of administration by encouraging patient compliance with prescribed dosing regimens or emergency instructions.

Examples

[0082] The subject matter of this description is now described with reference to the following Examples. These Examples are provided for illustrative purposes only, and the subject matter is not limited to these Examples, but encompasses all variations that are evident as a result of the teaching provided here.

Example 1 Formulations

[0083] Formulations containing insulin are described in this Example.

[0084] Each of Formulations 1, 2 and 3 was prepared as follows.

[0085] Unmodified human insulin (28.8 IU/mg) was weighed into a 7 milliliter vial and the indicated amount of 0.05 normal HCl was added to the vial to dissolve the insulin. A polyol solvent (propylene glycol, glycerol and/or PEG 400) was added to the vial and the contents were gently shaken to combine the ingredients. Three surfactants were then added to the vial and the contents were gently shaken until a clear mixture was formed. This clear mixture was suspended in approximately 160 to 230 microliters of a 3.78% (w/w) NaHCO3 solution (a tenfold dilution), causing emulsion, prior to administration.

[0086] The formulation here designated as Formulation 1 had the following composition:

[0087] The formulation here designated as Formulation 2 had the following composition:

[0088] The formulation here designated as Formulation 3 had the following composition:

[0089] Labrasol™ is a registered trademark of Gattefosse USA and is a mixture of PEG-8 caprylic/capric glycerides with the general formula R- (CH2-CH2O)8-R, where each -R is either -CO- (CH2)6-CH3 or -CO-(CH2)8-CH3. Lauroglycol™ FCC is a registered trademark of Gattefosse USA and is a propylene glycol monolaurate (C15H30O3). Tween™ 80 is a registered trademark of Sigma-Aldrich Chemical Company and is a mixture of polyoxyethylene (20) sorbitan monooleates. Softigen™ 767 is a registered trademark of Sasol Olefins & Surfactants GmbH and is a mixture of PEG-6 Caprylic/Capric Glycerides with the general formula R-(CH2- CH2O)6-R, where each -R is or -CO -(CH2)6-CH3 or -CO-(CH2)8-CH3. Cremophor™ RH40 is a registered trademark of BASF Group and hydrogenated castor oil surfactants. The main constituent of Cremophor TM RH 40 is glycerol polyethylene glycol hydroxystearate, which, together with glycerol polyglycol esters of fatty acids, forms the hydrophobic part of the product. The hydrophilic part consists of polyethylene glycols and glycerol ethoxylate, with the formula C57H110O9(CH2CH2O)n. Labrafil™ 1944CS is a registered trademark of Gattefosse USA and has the general structure HO-(CH2-CH2O)6-CO-(CH2)7- CH=CH-(CH2)7-CH3.

[0090] Surfactants also considered acceptable but not used in these experiments include Labrafil™ M-2125CS, which is a registered trademark of Gattefosse USA and has the general structure HO-(CH2-CH2O)6-CO-(CH2)7-CH =CH-CH2-CH=CH-(CH2)4-CH3, and Gelucire 44/41, which is a registered trademark of Gattefosse USA and has the general formula R-(CH2-CH2O)32- R, where each - R is either -CO-(CH2)10-CH3 or -CO-(CH2)12-CH3.

[0091] Formulation 4 was prepared by mixing, in a 20 milliliter beaker, 8 milligrams of unmodified human insulin, 300 milligrams of sodium bicarbonate, 100 milligrams of glycerol and 600 milligrams of Labrasol™. Subsequently, 8992 milligrams of water were added to the beaker and the combined ingredients were mixed by gentle stirring until a nanoemulsion was formed.

[0092] The formulation here designated as Formulation 4 had the following composition:

[0093] Formulation 5 was prepared as follows. In a 20 milliliter beaker, 8 milligrams of insulin, 800 milligrams of sodium bicarbonate, 100 milligrams of glycerol and 600 milligrams of Labrasol™ were combined and mixed. 8492 milligrams of water were added to the beaker and the contents were mixed by gentle stirring until a nanoemulsion was formed.

[0094] The formulation here designated as Formulation 5 had the following composition:

[0095] Formulation 6 was prepared as follows. In a 20 milliliter beaker, 8 milligrams of insulin, 210 milligrams of sodium bicarbonate, 90 milligrams of magnesium hydroxide, 100 milligrams of glycerol and 600 milligrams of Labrasol™ were combined and mixed. After that, 8992 milligrams of water were added to the beaker and the contents were mixed by gentle stirring until a nanoemulsion was formed.

[0096] The formulation here designated as Formulation 6 had the following composition:

[0097] Formulation 7 (a powder intended for oral administration after forming a suspension from the powder) was prepared by adding Labrasol™ drop by drop to Aerosil™ 200, contained in a mortar. After addition, this mixture was homogenized using a corresponding pestle to ensure uniform distribution. Insulin and sodium bicarbonate powder were then added to the mixture of Labrasol™ and Aerosil™ 200 and the resulting combination was mixed. The resulting powder was passed through a No. 16 sieve (nominal sieve opening 1.19 millimeters), dried at room temperature and stored until further use. Thereafter, 1.158 grams of the stored powder was combined with 9 milliliters of water prior to administration, yielding a water-based dispersion.

[0098] The formulation here designated as Formulation 7 had the following composition:

[0099] Formulation 8 (a powder intended for oral administration after forming an aqueous suspension from the powder) was prepared by adding liquid Labrasol® drop by drop to Neusilin® US2 (a granulated magnesium aluminometasilicate product sold by Fuji Chemical Industry Co., Ltd. with an average particle size of about 60 to 120 micrometers) contained in mortar. After addition, the mixture was homogenized using a corresponding pestle to ensure uniform distribution of the formulation. Insulin and sodium bicarbonate powders were then added to the Labrasol -Neusilin® US2 mixture and the resulting combination was mixed. The resulting powder was passed through a No. 16 sieve, dried at room temperature and stored until further use. Thereafter, 1.108 grams of this powder was combined with 9 milliliters of water before administration, yielding a water-based dispersion.

[00100] The formulation here designated as Formulation 8 had the following composition:

[00101] Formulation 9 (a two-part formulation) was prepared as follows. Part A components:

[00102] Part A (granules) was prepared by a wet granulation method, in which all components of Part A were weighed and passed through a No. 20 sieve. Insulin was dissolved in 0.05 N HCl and then placed in mortar containing the other components of Part A. After adding insulin, the mixture was homogenized using a pestle for 100 strokes to ensure uniform distribution of the formulation and the granules were dried using a fluidized bed dryer at 25 degrees Celsius for 30 minutes. The dried granules were passed through a No. 16 sieve and stored at 4 degrees Celsius until further use. Part B Components

[00103] Part B was prepared by accurately weighing Labrasol® and glycerol and then suspending these components in water to form a dispersion.

[00104] Formulation 9 was prepared by combining part A and B shortly before oral administration (e.g., within 2 hours before oral administration).

Example 2 droplet size

[00105] An advantage of the formulations described here is that the insulin is contained in the aqueous core of droplets (which may include micelles and/or liposomes) that are formed spontaneously (optionally after gentle agitation) after contact of the formulation with water or a solution aqueous. Because the size of such droplets influences their ability to cross gastrointestinal surfaces (and therefore affects the rate and extent of bioavailability of a drug contained within liposomes), the size of droplets formed after self-emulsification of the formulations described here was analyzed. .

[00106] In separate samples, one part of each of Formulations 1, 2, 3 and 4 was combined with 500 parts of distilled water with gentle stirring and allowed to form a dispersion or emulsion. The size of the droplets thus formed was measured using a Zetasizer Nano ZS zeta potential analyzer (Malvern Instruments, Ltd.). The same instrument was used to measure the polydispersity index (PDI) for these emulsions. The calculations for the PDI parameter are defined in the standard document ISO 13321:1996 E and ISO 22412:2008. One part of Formulation 1 was combined with 500 parts of 0.1 N HCl or phosphate buffered saline (PBS) indicated that droplet sizes are generally no larger than about 2000 nanometers and other formulations described herein have sizes of droplets that are generally no larger than approximately 800 nanometers.

[00107] The results of these experiments were as follows.

[00108] The average droplet size of Formulation 1 in 0.1 N HCl was 1822 nanometers. The average droplet size of Formulation 1 in standard phosphate buffered saline was 873 nanometers.

Example 3 Acid neutralization studies

[00109] Formulation 1 was diluted ten times with a 4.2% (w/w) solution of sodium bicarbonate (i.e., one part of Formulation 1 combined with nine parts of bicarbonate solution, final concentration of 3. 78%). The pH of this diluted composition was 8.2. The pH of 0.1N HCl is 1.2.

[00110] 4.0 milliliters of 0.1 N HCl were combined with selected amounts of the diluted composition and the pH of the resulting combined solution was measured. When HCl was combined with 1.0 milliliters of the diluted composition, the resulting pH was 5.64. When HCl was combined with 1.5 milliliters of the diluted composition, the resulting pH was 6.27. When HCl was combined with 2.0 milliliters of the diluted composition, the resulting pH was 6.48. These results demonstrate the acid neutralizing effect of the Formulation/antacid combinations described herein. One of skill in the art can select an appropriate amount of antacid to neutralize anticipated amounts of stomach acid in humans and other individuals (e.g., increase gastric pH to at least 3.0, at least 3.4, or any other desired value ).

Example 4 Proteolytic studies

[00111] Pepsin is a digestive protease in the stomach that exhibits significant proteolytic activity (including insulin inactivating activity) between pH 1 and pH 3. The following experiments were carried out to investigate the effect of pH on the pepsin-mediated inactivation of insulin contained in insulin-loaded formulations described herein.

[00112] Separately, 1 milliliter of Formulation 1 was combined with 9 milliliters of standard phosphate-buffered saline to form a dispersion or an emulsion (the precise nature of the composition was not considered critical and is referred to as an “emulsion” below). . The pH of this emulsion was 6.9. The emulsion was then combined with 0.5 milliliters of simulated gastric fluid (1 gram sodium chloride, 3.5 milliliters 37% HCl in 500 milliliters water) that included 1650 units of pepsin at a pH of 1.4 or 3.4 (pH adjustment was with 0.1 N NaOH). The mixtures were then incubated at 37°C. After 5, 30, or 90 minutes, the incubation was terminated in aliquots of the mixtures by addition of 0.1 N NaOH (to shift the pH to the range of about 6 to 6.5 and thus stop pepsin activity). .

[00113] Pepsin-mediated cleavage of insulin was assessed in each of the aliquots using HPLC detecting expected insulin cleavage products. No intact insulin was observed in aliquots incubated at pH 1.4 for 5, 30, or 90 minutes, suggesting that rapid proteolytic cleavage of insulin occurred. Essentially all insulin remained intact in aliquots that had been incubated for 30 and 90 minutes of incubation at pH 3.4 (insulin was not evaluated in an aliquot incubated for only 5 minutes at pH 3.4), suggesting that a pH of 3.4 rendered pepsin sufficiently inactive to maintain insulin in uncleaved form during these periods. These results also suggest that increasing an individual's gastric pH to pH 3.4 (or at least to 3.0) allows insulin to remain intact in the gastric space when administered orally in the formulations described here.

Example 5 In vitro intestinal permeability studies

[00114] The experiments described in this example demonstrated that insulin can be transported through monolayers of Caco-2 cells, which are known to resemble layers of enterocyte cells that line the small intestine. These experiments were therefore considered indicative of the ability of the formulations described here to transport hydrophilic drugs such as insulin across the intestinal lining.

[00115] Caco-2 cells were cultured at 37 ± 2 degrees Celsius in minimum essential medium (MEM) with Eagles salt and l-glutamine supplemented with 15% fetal bovine serum, with 1% non-essential amino acids and with 1% of antibiotic-antimycotic in an incubator under a 5% carbon dioxide atmosphere to simulate intestinal lining cells. Cell monolayers that showed transepithelial electrical resistance values greater than 300 Ohms per square centimeter 21 to 28 days after seeding were used for this study.

[00116] At time zero, the medium on one side of the cell monolayer was replaced with 0.5 milliliter of a solution that included one of Formulations 1, 2 or 3 or insulin not incorporated into a formulation containing SMEDDS. The solution was diluted tenfold with medium (i.e., one part insulin-containing solution and nine parts buffer) before application to the monolayer. Thirty minutes after this replacement, the insulin content on the basolateral face of the monolayer was analyzed by HPLC. The permeability coefficient (Papp) was calculated from the following equation: Papp = (dQ/dt) / (Co x area), where dQ/dt is the linear appearance rate obtained from the profile of the transported quantity of the substrate in relation to time (measured in micrograms per second); Co is an initial concentration measured in the donor compartment (measured in micrograms per milliliter) and “area” is the surface area of the cell monolayer membrane.

[00117] No trans-monolayer transport of free insulin (i.e., insulin not combined with a SMEDDS-containing composition) can be detected after 3o minutes of incubation. Papp values are determined to be: for monolayers to which diluted Formulation 1 was applied, 12x10-6 centimeters per second; for monolayers to which diluted Formulation 2 was applied, 16x10-6 centimeters per second; and for monolayers to which diluted Formulation 3 was applied, 9x10-6 centimeters per second.

[00118] These results demonstrated that administration of insulin to monolayers of Caco-2 cells cultured in diluted SMEDDS formulations described here significantly enhanced insulin transport across the monolayer. Because Caco-2 cell monolayers form tight junctions and are believed to be an appropriate model of the enterocyte cell layers that line the small intestine, the results of these experiments are indicative of the ability of the formulations described here to transport hydrophilic drugs. , such as insulin, through the intestinal lining.

Example 6 IN VIVO Hypoglycemic Study With Insulin Containing SMEDDS Combined With Antacids After Oral Administration in Diabetic Mice, Normal Rats and Healthy Beagle Dogs

[00119] Diabetes was induced in male C57BL/6JNarl mice (8 weeks old, about 20 grams body weight) by two tail vein injections of streptozotocin (STZ) (first: 75 mg/kg, second: 150 mg/kg). The induction of diabetes in mice was verified by measuring the glucose concentration in a blood sample that was obtained from the tail vein. Blood glucose levels in mice greater than 300 mg/dL were considered confirmation of the induction of diabetes and mice exhibiting such levels (“STZ-induced diabetic mice”) were used in the experiments described in this Example.

[00120] A composition containing 200 IU/kg insulin was administered by oral gavage to each of eight STZ-induced diabetic mice in three groups (i.e., 24 mice in total). A first group received unmodified free insulin suspended in about 160 to 230 microliters (depending on the animal's weight) of a 3.78% (w/w) NaHCO3 antacid solution. A second group each received insulin in the form of Formulation 1 suspended in about 160 to 230 microliters of phosphate-buffered saline (PBS). A second group received insulin in the form of Formulation 1 suspended in about 160 to 230 microliters of a 3.78% (w/w) NaHCO3 antacid solution (i.e., a tenfold dilution of Formulation 1). Gastric pH was expected to increase above 3.4 within a short time (i.e., within 0 to 3 minutes) after gavage for the first and third groups, and no substantial change in gastric pH was expected after gavage in the second group.

[00121] Blood samples were taken from each mouse after gavage, and blood glucose levels in these samples were determined. The results of these blood glucose determinations are shown in Figure 1.

[00122] The STZ-induced diabetic mice in the third group (to which the insulin in Formulation 1 along with the antacid were administered) showed a substantial drop in blood glucose level, beginning just 15 minutes after oral gavage and lasting no longer than that about 4 hours. During the first 15 minutes after administration, the blood glucose level decreased by approximately 10% compared to time zero. Blood glucose levels of STZ-induced diabetic mice in the first (free insulin + antacid) and second (insulin in Formulation 1 without antacid) diabetic mice did not vary significantly over the remaining study period.

[00123] An approximately proportional dose-response was observed in groups of STZ-induced diabetic mice to which 50, 100 and 200 IU/kg of insulin were administered orally separately in Formulation 4 diluted with 3% NaHCO3 as described here . Of these mice, those that received 50 IU/kg of insulin showed a maximum 11% reduction in blood glucose levels 30 minutes after administration, relative to baseline levels; those who received 100 IU/kg of insulin showed a maximum reduction of approximately 25% in blood glucose levels after administration; those who received 200 IU/kg of insulin showed a maximum reduction of approximately 45% in blood glucose levels after administration.

[00124] Similar results were observed in STZ-induced diabetic mice to which a ten-fold dilution of Formulation 2 in 3.78% NaHCO3 was administered by oral gavage, as shown in Figure 4 (200 IU/kg insulin) . Similar results were also observed when 50 IU/kg insulin was administered by oral gavage to STZ-induced diabetic mice in the form of Formulation 5 along with 8% NaHCO3 (see Figure 7) or Formulation 6, which included 2.1 NaHCO3. % and 0.9% Mg(OH)2 (see Figure 8). For STZ-induced diabetic mice to which 200 IU/kg insulin in Formulation 3 (a ten-fold dilution in 3.78% NaHCO3) was administered orally, a decrease in blood glucose level was also observed, although the decrease was relatively light (see Figure 5). On the other hand, for STZ-induced diabetic Wistar rats that were orally administered 200 IU/kg of insulin in Formulation 4, a similar profile of decreased blood glucose level was observed (see Fig. 9A), as well as levels elevated levels of insulin in the blood (see Fig. 9B).

[00125] Formulations 7 and 8 were also effective in rapidly lowering the blood glucose level in STZ-induced diabetic Wistar rats or STZ-induced diabetic rats after administration, as shown in Figs. 10 and 11. Furthermore, insulin (116 IU/kg) in Formulation 9 administered to STZ-induced diabetic Wistar rats induced an increase in blood insulin concentration (see Fig. 12), indicating effective insulin absorption from this formulation. .

[00126] Results of experiments in which the NaHCO3 content of the composition administered to STZ-induced diabetic rats by oral gavage was varied are shown in Figure 2. In the composition range, NaHCO3 concentrations ranged from 1.80 to 3.78 % (w/w), there was little difference in blood glucose levels, and some difference was observable in blood glucose levels obtained when the NaHCO3 concentration was reduced to 0.90% (w/w). These results suggest that an amount of antacid sufficient to reduce gastric pH to 3.4 (or at least to about 3) shortly after oral administration is beneficial for the bioavailability of insulin via the oral route. Decreasing the antacid bolus that is administered in conjunction with insulin may limit overall bioavailability and reduce the duration of insulin action. Therefore, the use of antacids of different amounts in the formulation can titrate (or adjust) the duration of insulin action.

[00127] As illustrated in Figure 13, the potency of orally administering Formulation 1 mixed with antacid to STZ-induced diabetic mice was unchanged if the composition was stored for three months at 5 degrees Celsius prior to administration (relative to the freshly prepared composition ). These data illustrate that the compositions described here are suitable for storage.

[00128] When unmodified insulin (150 IU/kg) was administered to healthy beagle dogs via oral gavage in a ten-fold dilution of Formulation 1 in 3.78% NaHCO3 (total volume of 50 milliliters), similar results were observed , as indicated in Figure 3. In Figure 3, a rapid onset of insulin action is illustrated by a drop in blood glucose levels in treated dogs (open circles) 15 minutes after administration, relative to untreated dogs (filled circles ). The duration of action in dogs (no more than about 1 hour) appears to have been shorter in dogs than in mice, potentially due to the greater production of gastric acid in dogs relative to mice.

[00129] When unmodified insulin (200 IU/kg) was administered to normal Wistar rats via oral gavage in Formulation 4 in 3% NaHCO3 (total volume of 2.5 to 3.3 milliliters), results similar to those observed are obtained for mice and dogs, as illustrated in Figure 6A. Figure 6B shows the insulin levels measured in these mice, confirming that the blood glucose lowering effect is attributable to elevated blood insulin levels.

[00130] One of the two insulin formulations was administered to beagle dogs to measure the concentration of insulin in the blood. The first formulation was Formulation 8, as described herein, and was administered in the amount of 25 IU per kilogram orally after suspension in liquid. The second formulation was regular insulin, administered subcutaneously (SC) in an aqueous suspension in an amount of 0.5 IU per kilogram. Blood samples were obtained from dogs that received the formulations at time 0 (i.e., immediately before administration) and at 15, 30, 60, 90, 120, 150, 180 and 240 minutes after administration. The results of these studies are shown in Figure 15.

[00131] Taken together, the data shown in the Examples described herein demonstrate that formulating insulin into a composition containing SMEDDS and combining with an antacid bolus sufficient to increase gastric pH above about 3.0 rapidly renders insulin ( i.e., within 15 to 30 minutes or less) available in mammalian individuals and can result in insulin having a duration of action of approximately 2 to 4 hours. These data demonstrate that the formulations described herein can be effectively used to administer hydrophilic drugs that are sensitive to the acidic and/or proteolytic environment of the stomach and that such formulations can be selected to yield a rapid onset and limited duration of action of drugs so dispensed.

Example 7

[00132] A fast-acting oral insulin formulation was developed using nanoemulsion solutions containing unmodified insulin (regular insulin). The rapid-acting oral insulin formulation begins to produce its physiological effects within 15 minutes of oral administration and peak blood insulin levels occur at 30 minutes. The duration of the activity was less than 3 hours. Furthermore, the glycodynamic responses of the oral insulin formulation were proportional to the administered dose. Stability studies showed that the potency and pharmacological action for this insulin formulation were stable after storage at 5 degrees Celsius for three months.

[00133] Insulin is generally administered parenterally because of proteolytic degradation and low permeability in the gastrointestinal tract. Injections are often painful and can lead to poor patient compliance. In contrast to inconveniences and discomfort of injected administration, the oral route of drugs is a comfortable and convenient route of administration. Many strategies such as liposomes, nanoparticles, microemulsion, or enteric-coated capsules have been reported to improve oral insulin delivery. At least some of these platforms provide effective insulin absorption (Wong, 2010, J. Drug Target. 18(2):79-92; Arbit et al., 2009, J. Diabetes Sci. Technol. 3(3):562- 567). However, none of these oral formulations were fast-acting and short-lived.

[00134] Current experimental oral insulin formulations have a slow onset time (more than 1.5 hours) and a long effective duration (more than 5 hours). The rapid action (onset within 15 minutes) and short duration (less than 5 hours) of orally administered insulin, with effects analogous to insulin administered by intravenous injection, would provide greater metabolic control (Mannucci et al., 2009, Diabetes Obes. Metab. 11(1):53-59). This is because adequate timing of insulin administration results in postprandial carbohydrate absorption matching. Therefore, the purpose of the experiments described in this example was to develop a fast-acting, short-acting oral insulin formulation for oral administration, to provide better metabolic control for patients with diabetes.

[00135] A fast-acting oral formulation including regular (i.e., unmodified) insulin (“formulation insulin”) was used in the studies described in this example. An IN VIVO hypoglycemia study was performed to investigate free insulin and oral gavage formulation insulin in streptozotocin-induced diabetic mice (200 IU/kg) and healthy beagle dogs (150 IU/kg). Dose proportionality (doses of 50, 100 and 200 IU/kg) on glycodynamic responses was also investigated in streptozotocin-induced diabetic mice.

[00136] The stability of the rapid-acting oral insulin formulation was also investigated in this study. Insulin formulation samples were stored in closed glass screw-top vials at 5 degrees Celsius for three months. The drug remaining in the formulation was analyzed, and IN VIVO potency was also assessed by administering insulin formulation to streptozotocin-induced diabetic mice and blood glucose medication with a glucometer.

[00137] The results obtained in these studies are now described.

[00138] Blood glucose levels of streptozotocin-induced diabetic mice induced by oral administration with 200 IU/kg free insulin solution and rapid-acting oral formulation insulin are shown in Figure 14. The maximum reduction (about 45% ) of the initial blood glucose value was observed 0.5 hour after oral gavage of the formulation insulin. The duration of the activity was less than three hours. No significant differences in blood glucose levels were found at any time when free insulin solution was dosed by oral gavage.

[00139] The reduction in glucose in healthy beagle dogs following treatment with rapid-acting oral insulin formulation is shown in Figure 3. The rapid-acting oral insulin formulation produced an average reduction in blood glucose level (about 25% ) 0.5 hour after administration, in relation to the control. This finding was similar to observations in hyperglycemic mice.

[00140] The following table shows the proportionality of the dose (doses of 50, 100 and 200 IU/kg) of rapid-acting oral formulation insulin on glycodynamic responses. The mean glucose reduction 0.5 hour post-dose showed a linear dose-response relationship.

[00141] The IN VITRO potency of the insulin formulations described here after storage at 5 degrees Celsius for three months was evaluated and indicated that 101.1±0.16% of insulin remained intact and available (data not shown). IN VIVO potency was assessed by administering formulation insulin to diabetic mice by oral gavage (results are shown in Figure 13). There was no significant difference between hypoglycemic profiles using freshly prepared formulation insulin and insulin from a formulation stored for three months. This result confirmed the IN VITRO potency of the formulation insulin after storage at 5 degrees Celsius for at least 3 months.

[00142] The information contained in this example indicates that the rapid-acting short-acting oral insulin formulation (“formulation insulin”) described in this example exhibits dose proportionality, using insulin doses of 50, 100 and 200 IU/kg. Both IN VITRO and IN VIVO studies showed no significant loss of potency and biological activity of insulin in a formulation stored at 5 degrees Celsius for three months.

[00143] The description of each patent, patent application and publication cited herein is incorporated herein by reference in its entirety.

[00144] Although this subject matter has been described with reference to specific embodiments, it is evident that other embodiments and variations may be conceived by others skilled in the art without departing from the true spirit and scope of the subject matter described herein. The appended claims include all equivalent embodiments and variations.

Claims (24)

1. An oral dosage form of a drug for reducing the level of glucose in the blood, characterized by the fact that it comprises an antacid sufficient to increase the gastric pH of a mammal to at least about 3 upon ingestion of the dosage form and a combination of a therapeutically effective amount of the drug and a surfactant system that includes a nonionic surfactant, such as a self-microemulsifying drug delivery system (SMEDDS), wherein the drug is a polypeptide for lowering the blood glucose level, wherein the surfactant system includes at least one polyglycolized glyceride with at least one acyl moiety and propylene glycol esters of fatty acids selected from the group consisting of oleoyl polyoxylglycerides, oleoyl polyoxyl-6 glycerides, linoleoyl polyoxylglycerides, linoleoyl polyoxyl-6 glycerides, caprylocaproyl polyoxylglycerides , PEG-6 caprylic/capric glycerides, caprylocaproyl polyoxyl-8 glycerides and lauroyl polyoxylglycerides, and wherein the identity and amount of the surfactant system is sufficient to induce spontaneous emulsification upon contact between the combination and a double, quadruple or ninefold excess upper layer of distilled water under conditions of mechanical agitation characteristic of the mammalian stomach. 2. Dosage form according to claim 1, characterized in that the combination includes the antacid. 3. Dosage form according to claim 1 or 2, characterized in that the antacid is sufficient to increase the gastric pH of the mammal to at least 3.4 after ingestion of the dosage form. 4. Dosage form according to any one of claims 1 to 3, characterized in that the combination is in the form of a first composition and the antacid is in the form of a second composition. 5. Dosage form according to claim 4, characterized by the fact that the first and second compositions are present in distinct portions of the dosage form. 6. Dosage form according to claim 4 or 5, characterized in that the first composition and the second composition are in liquid or solid form. 7. Dosage form according to any one of claims 1 to 6, characterized in that the identity and amount of the surfactant system are selected so that the average droplet size of the emulsion formed upon contact between the combination and the aqueous medium is not larger than 2000 nanometers. 8. Dosage form according to claim 7, characterized in that the average droplet size is not more than 800 nanometers. 9. Dosage form according to any one of claims 1 to 8, characterized in that the drug is a hydrophilic polypeptide drug for reducing the level of glucose in the blood. 10. Dosage form according to any one of claims 1 to 9, characterized in that the combination further comprises a polyol solvent. 11. Dosage form according to any one of claims 1 to 10, characterized in that the antacid is sufficient to raise the animal's gastric pH to at least 3 within one minute following ingestion of the dosage form. 12. Dosage form according to any one of claims 1 to 11, characterized in that the antacid is selected from the group consisting of sodium bicarbonate, magnesium hydroxide, calcium carbonate, aluminum hydroxide and combinations thereof. 13. Dosage form according to any one of claims 1 to 12, characterized in that the antacid is sufficient to neutralize at least 1 milliequivalent of stomach acids. 14. Kit, characterized by the fact that it comprises the dosage form as defined in any one of claims 1 to 13 and an aliquot of an aqueous medium in an amount sufficient to dissolve or suspend the antacid and emulsify the combination. 15. Kit, characterized in that it comprises a first dosage form comprising an antacid sufficient to increase the gastric pH of a mammal to at least 3 after ingestion of the first dosage form and a second dosage form comprising a combination of a therapeutically effective amount of a drug that is unstable or poorly absorbed in the gastrointestinal (GI) tract and a surfactant system that includes a nonionic surfactant, such as a self-microemulsifying drug delivery system (SMEDDS), wherein the drug is a polypeptide to reduce blood glucose level; wherein the surfactant system includes at least one polyglycolized glyceride with at least one acyl moiety and propylene glycol esters of fatty acids selected from the group consisting of oleoyl polyoxylglycerides, oleoyl polyoxyl-6 glycerides, linoleoyl polyoxylglycerides, linoleoyl polyoxyl-6 glycerides, caprylocaproyl polyoxylglycerides, PEG-6 caprylic/capric glycerides, caprylocaproyl polyoxyl-8 glycerides and lauroyl polyoxylglycerides, and wherein the identity and quantity of the surfactant system is sufficient to induce spontaneous emulsification upon contact between the combination and a double, quadruple or nine times higher than distilled water under conditions of mechanical agitation characteristic of the mammalian stomach. 16. Dosage form according to claim 1, characterized in that the drug is selected from the group consisting of anthrotherapeutic insulins. 17. Dosage form according to claim 1, characterized by the fact that the drug is a human insulin peptide. 18. Dosage form according to any one of claims 1 to 6, characterized in that the drug is insulin peptides; wherein the surfactant system optionally includes one or more additional surfactants; wherein the combination further comprises a polyol solvent; wherein one or more additional surfactants are selected from the group consisting of polysorbate, poloxamers, polyoxyethylene castor oil derivatives, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, glyceryl monooleate, glyceryl monolinoleate, medium chain triglycerides , polyglyceryl oleate, lauroyl polyoxyglyceride, stearoyl polyoxyglycerides and combinations thereof; wherein the polyol solvent is selected from the group consisting of glycerol, propylene glycol and polyethylene glycols; and wherein the antacid is selected from the group consisting of sodium bicarbonate, magnesium hydroxide, calcium carbonate, aluminum hydroxide and combinations thereof. 19. An oral dosage form of a drug for reducing the level of glucose in the blood, characterized in that it comprises: an antacid sufficient to increase the gastric pH of a mammal to at least 3 after ingestion of the dosage form, a systemic surfactant that includes a nonionic surfactant, such as a self-microemulsifying drug delivery system (SMEDDS), and a therapeutically effective amount of the drug, wherein the drug is a polypeptide for reducing the blood glucose level; wherein the surfactant system includes at least one polyglycolized glyceride with at least one acyl moiety and propylene glycol esters of fatty acids selected from the group consisting of oleoyl polyoxylglycerides, oleoyl polyoxyl-6 glycerides, linoleoyl polyoxylglycerides, linoleoyl polyoxyl-6 glycerides, caprylocaproyl polyoxylglycerides, PEG-6 caprylic/capric glycerides, caprylocaproyl polyoxyl-8 glycerides and lauroyl polyoxylglycerides, wherein the identity and quantity of the surfactant system is sufficient to induce spontaneous emulsification upon contact between the combination and a double, quadruple or nine excess times higher than distilled water under conditions of mechanical agitation characteristic of the mammalian stomach. 20. Dosage form according to any one of claims 1 to 6 and 19, characterized in that the drug is selected from the group consisting of insulin peptides, growth hormones, erythropoietin, monoclonal antibodies and antibody fragments ; or wherein the drug is insulin peptides; or which drug represents naturally occurring forms of insulin, synthetic insulins, or insulin-like peptides. 21. Dosage form according to any one of claims 1 to 6 and 18 to 20, characterized in that the dosage form is in a unit dosage form or a multi-compartment dosage form. 22. Dosage form according to any one of claims 1 to 6 and 18 to 20, characterized in that the dosage form includes tablets, capsules, powder, granules, solution and/or suspension 23. Dosage form according to any one of claims 1 to 6 and 18 to 20, characterized in that the dosage form is a substantially homogeneous composition. 24. Dosage form according to claim 1 or 19, characterized by the fact that the dosage form is selected from the group consisting of: (i) a dosage form comprising an insulin peptide, a caprylocaproyl polyoxyl -8 glyceride, propylene glycol, hydrochloride (HCl), a propylene glycol monolaurate and a mixture of polyoxyethylene (20) sorbitan monooleates, in combination with sodium bicarbonate (NaHCO3); (ii) a dosage form comprising an insulin peptide, a mixture of PEG-6 caprylic/capric glycerides having the general formula R-(CH2-CH2O)6-R, wherein each -R is -CO-(CH2) 6-CH3 or -CO-(CH2)8- CH3, propylene glycol, hydrochloride (HCl), a propylene glycol monolaurate and a mixture of polyoxyethylene (20) sorbitan monooleates, in combination with sodium bicarbonate (NaHCO3); (iii) a dosage form comprising an insulin peptide, a polyglycolyzed glyceride, glycerol, a polyethylene glycol, hydrochloride (HCl), a hydrogenated castor oil surfactant and a mixture of polyoxyethylene (20) sorbitan monooleates, in combination with bicarbonate sodium (NaHCO3); (iv) a dosage form comprising an insulin peptide, a caprylocaproyl polyoxyl-8 glyceride, glycerol and sodium bicarbonate, optionally in combination with water; (v) a dosage form comprising an insulin peptide, a caprylocaproyl polyoxyl-8 glyceride, glycerol, sodium bicarbonate and magnesium hydroxide, optionally in combination with water; (vi) a dosage form comprising an insulin peptide, a caprylocaproyl-polyoxyl-8 glyceride, sodium bicarbonate and an adsorbent, optionally in combination with water; and (vii) a dosage form comprising a first part comprising an insulin peptide, sodium bicarbonate, mannitol and povidone K-30, and a second part comprising a caprylocaproyl polyoxyl-8 glyceride, glycerol and water.