CN1744881A - Pharmaceutical compositions having reduced bitter taste - Google Patents
Pharmaceutical compositions having reduced bitter taste Download PDFInfo
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- CN1744881A CN1744881A CNA038260204A CN03826020A CN1744881A CN 1744881 A CN1744881 A CN 1744881A CN A038260204 A CNA038260204 A CN A038260204A CN 03826020 A CN03826020 A CN 03826020A CN 1744881 A CN1744881 A CN 1744881A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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Abstract
Masking the taste of bitter pharmaceuticals in dispersible compositions is difficult. A novel formulation for dispersible compositions has been found where the bitterness of active ingredients is reduced and the amount of lipid in the formulation is minimised thereby reducing the retardation affect lipids have on release of the active ingredient from the composition. The invention is particularly relevant to basic bitter tasting pharmaceuticals such as macrolide antibiotics, especially erythromycin, roxithromycin, azithromycin, and clarithromycin.
Description
Invention field
The taste that the present invention relates to bitter pharmaceutical agents is had is covered.Specifically, the present invention relates to but the taste that dispersive composition had that contains bitterness alkalescence active component is covered, described bitterness alkalescence active component is macrolide antibiotic, for example erythromycin, Roxithromycin, azithromycin, clarithromycin etc. especially.
Background technology
The bitterness that overcomes the some drugs active component brings lasting challenge for the medicament scholar.With the formulation example of other type such as capsule with can not compare by dispersive tablet, the challenge that dispersible pharmaceutical composition brought is bigger.The advantage of dispersible pharmaceutical composition is than capsule or tablet is easier swallows.This advantage has advantage especially for department of pediatrics of more being ready to select easily to swallow preparation and gerontal patient.
The present known bitterness that exists several different methods to be used for covering oral drugs powder agent, granule and dispersible tablets active component.These methods comprise with powder agent or granule coating, with active principle microcapsulesization and make active component form complex.Yet these methods may be subjected to the restriction of following factor: the quantity of required excipient, required various components contents, the complexity of preparation method and the use of volatile organic solvent.In addition, these complex technologys also involve the problem of batch process.
French Patent (FRP) FR 2793690 (Dominique) has described at the sweeting agent rather than the sugar that can disperse to use in the macrolide compositions high concentration (up to 20%).Yet for example the sweeting agent of aspartame (aspartame), glucide and ammonium glycerrhizinate has unusual and undesirable taste after trial test.When using with high concentration, they also have other side effect separately.In any case these traditional sweeting agents also can't be covered the active constituents of medicine taste of azithromycin for example with strong bitterness effectively.
U.S. Patent number 5,609,909 (Meyer) disclose utilize water-fast oil or wax as plasticizer with prolamin part coating on medicine nuclear.This method has limited the macrolide suspensoid and has disengaged immediately.This method also requires organic coating material and installs for example Glatt-Wurster fluidized bed coater.
U.S. Patent number 6,153,220 (Cumming) disclose active medicine with the cation copolymer spray drying with taste masking, and this cation copolymer is by dimethylaminoethyl methacrylate and methyl acrylic ester is synthetic obtains.Used organic solvent in the method.In addition, this method is restricted to spendable drug dose, and for example the ratio of medicine and polymer is at most 1: 6.
For taste masking, pH dependent form polymer is used to enteric coatings or is used for time-delay disengage preparation usually.U.S. Patent number 5,409,711 (Mapelli) disclose and have used the taste that is used to cover granule at the polymeric membrane that is higher than solubility under the pH5.In order to prevent film stripping in mouth, acidic materials in compositions, have been added.But the dispersible granule of Huo Deing only disengages being higher than under the pH5 by this method.
Its important inferior position of preparation by encapsulation and spray drying process preparation is, in order to dissolve coating materials, needs various volatile organic solvents for example dichloromethane, chloroform, cyclohexane extraction, carbon tetrachloride, butanone, acetone, ethanol, methanol or isopropyl alcohol.It is disadvantageous that this kind solvent is considered on environmentology, therefore they need be removed from product so that its content is reduced to acceptable level.
In medicinal mixture, estimate using alkaline matter from the encapsulation microcapsule, to disengage with the minimizing medicine.U.S. Patent number 4,656,027 (Sjoovist) thus the taste of alkaline matter being covered bitter substance with medicine and hydrophobic polymer encapsulation is disclosed.Based on the environmentology reason, it also is unfavorable with an organic solvent carrying out encapsulation equally.In addition, this filling to medicine also is construed as limiting, thereby brings difficulty to batch process.
U.S. Patent number 5,633,006 (Catania) use alkaline earth oxide, alkaline earth metal hydroxide and alkali metal hydroxide to cover the taste of the amara compositions that contains the macrolide antibiotic azithromycin.Azithromycin is absorbed by alkaline earth oxide easily, thereby makes the bitterness of compositions reduce.Yet in some cases, this absorption has changed the kinetics of disengaging of medicine.The dosage form of advising at this method only only limits to chewable tablet and oral suspensions.
In order to obtain the concealed product of taste, the medicament scholar of research macrolide antibiotic once used various functional polymers and basic anhydride.U.S. Patent number 5,707,646 (Yajima) disclose unites that to use functional polymer and low melting point be that a kind of basic anhydride and sugar alcohol are with taste masking.Yet this method needs drying process with atomizing and the medicine loadings is low, also need high-load fatty acid ester simultaneously, makes this method be restricted.
U.S. Patent number 5,792,373 (Yajima) use the monoglyceride of the polymer dissolve in the gastric juice and beta-crystal to cover the taste of combination of oral medication.Yet for active component, a high proportion of monoglyceride has postponed disengaging of medicine.The limiting factor of this method comprises has used at high temperature unsettled functional polymer, low medicine loadings and spray drying process.
U.S. Patent number 4,808 has been described a kind of taste masked particle agent that contains the complex of clarithromycin and carbomer among 411 (Lu).The aqueous particulate agent of this clarithromycin and carbomer complex is described in U.S. Patent number 5,919, among 489 (Gerhardt).Yet owing to need carry out the rapid medicine processing of multistep, for example compound, granulation and dry makes this method also not ideal.
Various taste masking preparations are characterised in that and have merged for example fatty acid ester of lipid.Yet the lipid ratio is quite high in known taste masking preparation, usually the high 20 weight % of specific activity composition.
For example, U.S. Patent number 5,635,200 (Douglas) have described a kind of taste masking compositions of ranitidine medicine, wherein with ranitidine nuclear lipid coating.The amount of used lipid is greater than 20 weight %.Well-known is to disperse required lipid consumption to be higher than simply with the medicine nuclear required lipid consumption of lipid coating far away by lipid medicine.Therefore, if desired ranitidine is disperseed by lipid, just may be in the compositions far above the lipid of 20 weight %.
U.S. Patent number 5,380,535 (Geyer) have described a kind of chewable tablet, and wherein the medicine with taste bad will is dispersed or dissolved in the lipid.The amount of used lipid is the 5-50 weight % of compositions.Yet the above-mentioned weight ratio of compositions is equivalent to be higher than the weight ratio of active component far away.For chewable tablet, the dispersible formulation agent requires higher lipid consumption usually.
Be restricted activity composition disengaging or stripping in mouth (for chewable tablet) in the main purpose of using lipid in the taste masking preparation, and restriction is when to adding entry in the active component or the disengaging or the stripping behavior of active component when it is arranged in mouthful (but for the dispersive composition) that can be discerned taste.Therefore, the lipid that accounts for compositions 20% that needs floor level usually.Yet, contain the result that the high concentration lipid brought and postponed medicine from compositions, to disengage, cause the absorption of active component in blood flow to be delayed.Therefore, but need a kind of like this dispersive composition, when when being used by the patient, it can not cause that when covering some active component bitterness the active component in the compositions disengages the problem of delay.
The applicant find now a kind of be used for dispersible pharmaceutical composition not only simply but also reproducible novel drugs delivery system, it has reduced the bitterness of bitterness alkalescent medicine, contains beat all low content lipid simultaneously.
The present invention relates to the purposes that for example lipid, alkaline matter and the surfactant of fatty acid ester are used to form the particle matrix that reduces the active component bitterness.But dispersive composition contains the granule of active component and the granule of quick disintegrate diluent.
The object of the invention is to provide a kind of dispersible pharmaceutical composition that contains the low content lipid, and it has covered the taste of bitterness active component at least to a certain extent, and useful selection perhaps is provided at least.
Summary of the invention
First aspect present invention provides a kind of dispersible pharmaceutical composition, and it comprises:
(i) bitterness active component;
(ii) content is the lipid granulating agent of the 1-16 weight % of active component; With
(iii) content is the alkaline agent of the 1-20 weight % of active component;
Wherein the bitterness of active component is partially or completely covered.
Preferred described bitterness active component is a macrolide antibiotic, and more preferably this macrolide antibiotic is selected from erythromycin, clarithromycin, Roxithromycin and azithromycin, comprises its solvate or hydrate arbitrarily.Used azithromycin is preferably the Isostructural pseudopolymorphs that is disclosed among the Croatia number of patent application P20020231 A, has outstanding dissolution characteristic.
The content of described lipid granulating agent is preferably the 2-8 weight % of active component.
Described lipid granulating agent can be any one fatty acid ester, oil, fat or wax.Certainly; described lipid granulating agent be preferably selected from the glycerol list-, two-and three-stearate; the glycerol list-, two-and three-palmitostearate; the glycerol list-, two-and 3-behenic acid esters, the glycerol list-, two-and three-oleate, castor oil hydrogenated, cetomacrogol emulsifying wax, Brazil wax (carnubawax), cetyl alcohol and cetyl ester.
The content of preferred described alkaline agent is the 2-12 weight % of active component.Various alkaline agents all can use, but preferred described alkaline agent is selected from sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide and potassium hydroxide.
Preferred said composition also further contains the surfactant that content is no more than 2 weight % of active component.Described surfactant is preferably selected from sodium lauryl sulphate, docusate sodium, polysorbate and sorbitan fatty acid esters.
Also preferred in addition said composition further contains the diluent that content is the 5-60 weight % of whole compositionss.Described diluent is preferably selected from cellulose, microcrystalline Cellulose, lactose, mannitol, Sorbitol, starch, calcium carbonate, calcium hydrogen phosphate, silicon dioxide and starch,pregelatinized.
Be that 1: 3 to 3: 1 the microcrystalline Cellulose and the combination and the water-insoluble preparation of cellulose of starch become particle form with containing proportional preferably with described diluent.Described water-insoluble cellulose is preferably the ethyl cellulose of the 2-10 weight % that accounts for particle weight.The ratio of microcrystalline Cellulose and starch is preferably 1.25: 1 to 2: 1.
Further preferred said composition contains the disintegrating agent that content is the 1-12 weight % of whole compositionss.Described disintegrating agent is preferably selected from carmethose, cross-linked carboxymethyl cellulose sodium, primojel, crospovidone, amino alkyl acrylates copolymer E and Polacrillin potassium.
In the preferred embodiment of the invention, described disintegrating agent is cationic polymer aminoalkyl methacrylate copolymer E.
Also preferred in addition said composition further contains the sweeting agent that content is the 1-10 weight % of whole compositionss.Described sweeting agent is preferably selected from aspartame, coating aspartame, ammoniumglycerrhizinate, saccharin sodium, acesulfame-K (acesulfam potassium) and saccharide.
Preferred said composition further also contains the flavoring agent that one or more content are the 1-6 weight % of whole compositionss.Described one or more flavoring agents be preferably selected from have Rhizoma et radix valerianae, Fructus Musae, Fructus Pruni pseudocerasi, Fructus Ananadis comosi, chocolate, caramel or mint flavored flavoring agent.
Preferred said composition also contains the lubricating system of being made up of lubricant, fluidizer and flowable.Described lubricant is preferably selected from magnesium stearate, calcium stearate, stearic acid and Myrj 45.Preferred fluidizer is a Talcum, and preferred flowable is selected from silicon dioxide (siliconedioxide), fatty acid ester and sodium lauryl sulphate.
Second aspect present invention provides the method for compositions of a kind of preparation according to claim 1, and it comprises the steps:
(i) the bitterness active component is mixed with lipid granulating agent and alkaline agent obtain particulate substrates;
(ii) further randomly this particulate substrates is mixed with in disintegrating agent, sweeting agent, flavoring agent and the flowable one or more.
Preferred this particulate substrates is by the preparation of hot melt spiral shotting.Hot melt spiral shotting can be carried out under the temperature of any suitable, preferably carries out being lower than under 80 ℃ the temperature.
In an embodiment of described method, said composition is suppressed the tablet that obtains to be scattered in the water.In alternate embodiment, not repressed granule or the powder agent that obtains being scattered in the water of said composition.
Detailed Description Of The Invention
But the present invention relates to contain separately or with the dispersive composition of other active compound combined bitterness alkalescent medicine that comprises macrolide antibiotic and the method for preparing this based composition.
Term as used herein " but dispersive composition " is meant any solid dosage forms, comprises tablet, granule, pill and powder agent, and they are scattered in and (comprise cold water) in the water and form the suspensoid Gong drink.
The present invention is suitable for the combination of any bitterness alkalescent medicine or bitterness medicine.Certainly, The present invention be more particularly directed to macrolide antibiotic, particularly erythromycin, Roxithromycin, azithromycin and clarithromycin.Medicine is generally stable hydrate, solvate or salt form, also can be crystallization arbitrarily or amorphous form.Used azithromycin is preferably the Isostructural pseudopolymorphs that is disclosed among the Croatia number of patent application P20020231 A, has outstanding dissolution characteristic.
But the present composition comprises dispersive composition arbitrarily, particularly granule, powder agent and tablet.Although tablet and capsule are taken simple and convenient, child and gerontal patient are not easy to swallow.For the medicine of high dose, size also is a restriction.Therefore, dispersible pharmaceutical composition seems convenient and is easy to take.If needs of patients, dispersible pharmaceutical composition can also be used for titration.
When but the dispersive composition of bitterness medicine was scattered in the water, the bitterness of formed oral suspensions was difficult to be covered.Dispersible pharmaceutical composition prepared in accordance with the present invention has alleviated bitterness, and can not hinder the dissolution characteristic (or even by tabletting after) of medicine.Described compositions satisfies the requirement of British Pharmacopoeia for the dispersible pharmaceutical composition that comprises dispersible tablets.
The particulate substrates of dispersible pharmaceutical composition can be by a lot of method preparations.A kind of method for optimizing is a hot melt spiral shotting.The traditional fluidized bed dryer of known use can form granule and alleviate bitterness simultaneously.Other device, the reinforcement blender and the mixing arrangement that for example have the hot-air supply also can be used for realizing above-mentioned purpose.When using fatty acid ester for example when dibehenolin or glycerol distearate, the baking temperature of powder bed can remain between 65 ℃ to 70 ℃.
Hot melt spiral shotting has advantage than the spray drying that requires special device, microcapsule and granule coating or encapsulation techniques.This technology environmental sound and renewable and amplification.
Forming the used granulating agent of particulate substrates by the hot melt granulation is lipid.Described lipid can be wax, oil, fatty acid, aliphatic alcohol, monoglyceride, diglyceride or triglyceride.Carbon chain lengths is generally C12-C30, and they can be saturated or undersaturated.Example comprises glyceryl monostearate, glycerol distearate, Gan You behenic acid ester, dibehenolin and glycerol palmityl behenic acid ester.Described lipid can also be castor oil hydrogenated, cetomacrogol emulsifying wax, Brazil wax, cetyl alcohol or cetyl ester.Expection also can be used the suitable mixture of both or multiple lipid.
Preferred lipid usually at room temperature (18-22 ℃) is a solid, but just is easy to fusing (being about 55-95 ℃) after applying proper temperature.But the fusing point that also comprises contained each independent component wherein is at the mixture of its average fusing point within above-mentioned scope outside the said temperature scope.
The applicant is surprised to find that preferred lipid content can be low to moderate the 1-16% of active pharmaceutical ingredient weight, preferred 2-8%.Keep the alap main advantage of lipid content to be to alleviate influence, also reduced the bitterness of medicine simultaneously medicine stripping/disengage.
Preferably integrate with for example sodium lauryl sulphate (for the granule that has alleviated bitterness, being no more than 2%) of humidizer.Other humidizer comprises docusate sodium, polysorbate and sorbitan fatty acid esters.Humidizer is a dispersing aid.When a small amount of use, humidizer helps the dispersion and the stripping of tablet usually.
For the pH of stable composition, adding content is the 1-20% of active pharmaceutical ingredient weight, the alkaline matter of preferred 2-14%, for example sodium carbonate or tertiary sodium phosphate.Assessment is found, but add the bitterness that alkaline matter has all alleviated dispersive composition in granule He outside the granule.When but dispersive composition was injected towards in the water, rapid dissolved alkaline matter helped to form uniform dispersion.Common alkaline agent comprises sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide and potassium hydroxide.
But, can add separately or other excipient of cooperative programs in order to improve the flow behavior of dispersive composition.These diluent comprise cellulose, microcrystalline Cellulose, mannitol, sorbitol, starch, starch,pregelatinized, gelling starches, the microcrystalline Cellulose that can directly suppress, lactose, calcium carbonate, silicon dioxide and calcium hydrogen phosphate.
Preferred composition of the present invention has used the dilution granule, and it is by 1:3 to 3: the microcrystalline Cellulose of 1 different proportion and corn starch mixture are formed, and the preferred proportion scope is 1.25: 1.0 to 1.75: 1.0.For the dilution granule, granulating agent can use ethyl cellulose (2-10%) and plasticizer (Surelease for example
TM) the aqueous dispersion form.When particulate substrates that bitterness has alleviated mixes, the excipient combination estimated for the compressibility of formation mixture.If use these dilution granules, can improve the disintegrate and the flow behavior of dispersible pharmaceutical composition of the present invention.
Can use dilution granule and other diluent materials that the particulate substrates of this bitterness active component further is processed into and to disperse dosage form.The granule of diluent has good flowability, compressibility and disintegration properties.Unexpectedly, discover cation amino alkylmethacrylate copolymer E (Eudragit
TME is that this can disperse disintegrating agent suitable in the dosage form composition EPO).Aminoalkyl methacrylate copolymer E is poly-(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate 1: 2: 1).Other disintegrating agent comprises carmethose, cross-linked carboxymethyl cellulose sodium, primojel, crospovidone and Polacrillin potassium.
Preferably with sweeting agent aspartame, ammonium glycerrhizinate (magnasweet for example for example
TM), saccharin sodium and other saccharide, acesulfame-K or mannitol sneaks into as second sweeting agent.It is unfavorable using the sweeting agent of high dose, because this can bring offending pleasant impression and also be avoided increasing unnecessary additive amount to the patient usually.In the present invention, in order to obtain sweet taste, preferably add the sweeting agent of (2-5%) of low content.But preferred aspartame is as the dispersive composition sweeting agent in the tablet for example.
Select the flavoring agent of suitable alkaline bitterness medicine relatively more difficult.Mandarin orange fragrance is owing to discharge bitterness thereby inapplicable, yet for example Herba Menthae and Rhizoma et radix valerianae can be worked in coordination with the bitterness that alleviates preparation in other seasoning.The flavoring agent of being estimated has Rhizoma et radix valerianae, Fructus Musae, Fructus Pruni pseudocerasi, Fructus Ananadis comosi, caramel, chocolate, Herba Menthae and relevant flavor compounds.
If use gentle spice or do not add the preparation that flavoring agent also can obtain having acceptable taste.
Preferably integrate with lubricant, for example magnesium stearate or calcium stearate or relevant pharmaceutically acceptable lubricant compound.Because magnesium stearate the most normal use in pharmaceutical composition, thereby be preferred lubricant.But also preferably in dispersive composition of the present invention, use for example silicon dioxide, antitack agent (fluidizer) purification Talcum for example of flowable.
But the present invention may be better understood with reference to following dispersive composition example.Yet this is that embodiment only is an illustrative purposes presented for purpose of illustration, should be appreciated that the present invention is not subjected to the restriction of these embodiment.
Embodiment
Embodiment 1: the particulate substrates that bitterness has alleviated
| Composition | Quality (mg) | Form (%w/w) |
| Azithromycin (Isostructural pseudopolymorphs) 500mg azithromycin | 528.26 | ?89.63 |
| Sodium lauryl sulphate | 3.00 | ?0.51 |
| Tertiary sodium phosphate (anhydrous) | 36.98 | ?6.27 |
| Dibehenolin | 21.13 | ?3.59 |
| Gross weight | 589.37 | ?100.00 |
Use azithromycin, dibehenolin and sodium lauryl sulphate to prepare particulate substrates.Tertiary sodium phosphate can the granule interior (intra-granularly) in particulate substrates add, but also can outside adding in dispersive composition.Particulate substrates uses scanning electron microscope (SEM) to detect.
Each component is mixed, and the bed process that is used for spiral shotting adnexa is then granulated.But these granules are used for the preparation dispersive composition subsequently.
Embodiment 2: the particulate substrates that bitterness has alleviated
| Composition | Quality (mg) | Form (%w/w) |
| Azithromycin (Isostructural pseudopolymorphs) 500mg azithromycin | 528.26 | ?86.53 |
| Sodium lauryl sulphate | 3.00 | ?0.49 |
| Tertiary sodium phosphate, anhydrous | 36.98 | ?6.06 |
| Dibehenolin | 42.22 | ?6.92 |
| Gross weight | 610.46 | ?100.00 |
Particulate substrates obtains containing the substrate of 8 weight % dibehenolins by add the dibehenolin preparation in granule interior.These granules with high level fatty acid ester demonstrate good taste masking characteristic.But the not repressed dispersive composition that is directly used in of this granule.
Embodiment 3: the particulate substrates that bitterness has alleviated
| Composition | Quality (mg) | Form (%w/w) |
| Azithromycin (Isostructural pseudopolymorphs) 500mg azithromycin | 528.26 | ?89.63 |
| Sodium lauryl sulphate | 3.00 | ?0.51 |
| Tertiary sodium phosphate (anhydrous) | 36.98 | ?6.27 |
| Glycerol distearate | 21.13 | ?3.59 |
| Gross weight | 589.37 | ?100.00 |
Above-mentioned granule is by preparing at the outside or inner use tertiary sodium phosphate of granule.Use glycerol distearate as granulating agent.But these granules can be used for forming various dispersive compositions.
Embodiment 4: the dilution granule
| Composition | Quality (g) | Form (%w/w) |
| Microcrystalline Cellulose (Avicel PH 101) | 240.00 | ?57.69 |
| Starch (corn starch) | 160.00 | ?38.46 |
| Ethyl cellulose (Surelease) | 16.00 | ?3.85 |
| Gross weight | 416.00 | ?100.00 |
The dilution granule uses microcrystalline Cellulose (Avicel
TMPH 101) and the corn starch preparation.Used granulating agent is ethyl cellulose (Surelease
TM) aqueous dispersion.Granule is dry down at 60 ℃.Obtain quick disintegrate and mobile granule behind the dried particles sizing (Sized).
Embodiment 5:Eudragit
TMEPO is as the disintegrating agent/dispersant in the dispersible tablets
Particulate substrates among the embodiment 2 is mixed with dilution granule among the embodiment 4.Granule sieves, and (40#) is back to be mixed with other excipient: aspartame, disintegrating agent/dispersant, tertiary sodium phosphate, colloidal silica anhydrous and Talcum.Mixture is lubricated with magnesium stearate then.Use following disintegrate/dispersant: aminoalkyl methacrylate copolymer E (Eudragit
TMEPO), carmethose, primojel and polacrillin potassium.
But the granule of dispersive composition is pressed into tablet, and tablet is estimated dispersive easy degree by being dropped in 25 ℃ the 60ml water in the 150ml glass beaker.
The result who utilizes carmellose, primojel and polacrillin potassium to obtain is unsatisfactory.In beaker, observed some accumulative tablet agglomerates in the end 3 minutes.
If every piece of tablet uses the Eudragit of 100mg
TMEPO observes and has good tablet dispersibility (seeing the following form).These tablets meet the disintegration of tablet test at dispersible tablets and dispersing uniformity.
To Eudragit
TMEPO is as the evaluation of disintegrate/dispersant
| Eudragit TMThe content (mg) of EPO in embodiment 6 preparations | Observed result |
| 0 | Tablet disperses not exclusively in 3 minutes |
| 50 | The tablet dispersibility makes moderate progress, but incomplete in 3 minutes |
| 100 | Tablet disperses fully in 1-3 minute |
| 150 | Tablet disperses fully in 1-3 minute |
Embodiment 6: dispersible pharmaceutical composition is tablet for example
| Composition | Quality/tablet (mg) | Form (%w/w) |
| The particulate substrates (for the 500mg azithromycin) that bitterness has alleviated | 552.41 | ?43.33 |
| The dilution granule | 523.59 | ?41.07 |
| Aspartame | 30.00 | ?2.35 |
| Aminoalkyl methacrylate copolymer E (Eudragit TM?E，EPO) | 100.00 | ?7.84 |
| Tertiary sodium phosphate (anhydrous) | 40.00 | ?3.14 |
| Colloidal silica anhydrous | 5.00 | ?0.39 |
| Talcum | 12.00 | ?0.94 |
| Magnesium stearate | 12.00 | ?0.94 |
| Tablet weight | 1275.00 | ?100.00 |
Particulate substrates among the embodiment 1 is mixed with dilution granule among the embodiment 4.Granule sieves, and (40#) is back to be mixed with other excipient: aspartame, aminoalkyl methacrylate copolymer E (Eudragit
TMEPO), tertiary sodium phosphate, colloidal silica anhydrous and Talcum.Mixture is lubricated with magnesium stearate then.
But the granule of dispersive composition is pressed into tablet, then its taste, dispersing uniformity and the test of other pharmacopeia is estimated.Find that this reorganization (reconstitution) tablet is being acceptable aspect taste and for example stripping of other tablet properties, chemical examination, hardness, brittleness and the easy degree of recombinating.
Embodiment 7: to covering the confirmation of bitterness
The compositions that is used to estimate taste comprises and contains azithromycin 500mg, dilution granule (granule of starch and microcrystalline Cellulose), aminoalkyl methacrylate copolymer E (Eudragit
TMEPO), the granule of Talcum, silica sol and magnesium stearate.The content of fatty acid ester in the granule that bitterness has alleviated have nothing in common with each other (as shown in the table).The content of tertiary sodium phosphate and aspartame (as shown in the table) also inequality.In 5 volunteers, compositions is estimated.
| Composition | Be used to test the compositions test of taste | |||||||
| I | ?II | ?III | ?IV | ?V | ?VI | ?VII | ?VIII | |
| Dibehenolin | 4％ | 4％ | ?4％ | 4％ | ?4％ | |||
| Trisodium Phosphate Anhydrous | 7％ | 7％ | 7％ | 7％ | ?7％ | |||
| Aspartame (mg) | 30 | 100 | 30 | ?100 | 30 | ?100 | ||
| The preference ranking evaluation that taste is estimated | F | F | F | E | F | ?E | B | ?C |
Percentage ratio refers to for azithromycin (dehydrated form) weight.
Above-mentioned composition is dispensed into respectively in the 60ml water, estimates its taste after the dispersion immediately.
Taste is estimated:
A: good to eat and acceptable preparation
B: good to eat and acceptable preparation has extremely shallow bitterness and extremely low pleasant impression
C: good to eat and acceptable preparation has light bitterness and low pleasant impression
D: good to eat and acceptable preparation has light bitterness and unacceptable pleasant impression
E: non-good to eat preparation, because pleasant impression hardship and taste are also bitter
F: non-good to eat preparation, because taste is extremely bitter
The compositions VII and the VIII that contain fatty acid ester dibehenolin, alkaline buffer salt sodium phosphate and sweeting agent aspartame significantly are better than I-VI.Compositions VIII is too sweet, and feels that bitter pleasant impression is arranged.
Embodiment 8: to covering the evidence of bitterness
The compositions that is used to estimate taste comprises and contains azithromycin 500mg, dilution granule (granule of starch and microcrystalline Cellulose), aminoalkyl methacrylate copolymer E (Eudragit
TMEPO), the granule of Talcum, silica sol and magnesium stearate.Content and the content of aspartame immobilize (as shown in the table) of fatty acid ester in the granule that bitterness has alleviated.The content of tertiary sodium phosphate immobilizes, except in XI be granule is outside use, all the other all are to use in granule interior.In 5 volunteers, compositions is estimated.
| Component | Be used to test the compositions test of taste | |||
| VII | IX | X | XI | |
| Dibehenolin | 4％ | 4％ | 4％ | 4％ |
| Trisodium Phosphate Anhydrous | 7％ | 7％ | 7％ | 7% (in the granule) |
| Aspartame (mg) | 30 | 30 | 30 | 30 |
| Rhizoma et radix valerianae (mg) | - | 25 | - | - |
| Fructus Musae (mg) | - | - | 25 | - |
| Preferred ranking | B | C | C | B |
Percentage ratio refers to for azithromycin (dehydrated form) weight.
In following table, compositions XII is equal to the VII that does not have azithromycin.Taste and the compositions VII contrast that does not have the medicine azithromycin with described dispersant.Said composition is labeled as XII.
The preferred ranking that compositions VII, IX, X and XI obtain through 20 volunteers.
| Volunteer's numbering | Be used to test the compositions of taste | ||||
| ?VII | ?IX | ?X | ?XI | ?XII | |
| ?1 | ?B | ?C | ?D | ?B | ?A |
| ?2 | ?B | ?C | ?C | ?B | ?A |
| ?3 | ?B | ?C | ?D | ?A | ?A |
| ?4 | ?B | ?D | ?C | ?B | ?A |
| ?5 | ?C | ?D | ?D | ?B | ?A |
| ?6 | ?B | ?C | ?C | ?B | ?A |
| ?7 | ?B | ?D | ?D | ?B | ?A |
| ?8 | ?B | ?C | ?C | ?B | ?A |
| ?9 | ?B | ?D | ?D | ?B | ?B |
| ?10 | ?B | ?C | ?C | ?A | ?A |
| ?11 | ?B | ?C | ?C | ?B | ?A |
| ?12 | ?B | ?D | ?D | ?B | ?A |
| ?13 | ?B | ?C | ?C | ?B | ?A |
| ?14 | ?B | ?D | ?D | ?B | ?A |
| ?15 | ?A | ?C | ?D | ?B | ?A |
| ?16 | ?B | ?C | ?C | ?B | ?A |
| ?17 | ?B | ?C | ?C | ?B | ?A |
| ?18 | ?B | ?C | ?C | ?B | ?A |
| ?19 | ?B | ?C | ?C | ?A | ?A |
| ?20 | ?B | ?D | ?D | ?B | ?A |
| Preferred ranking | ?B | ?C | ?C | ?B | ?A |
Taste is estimated:
A: good to eat and acceptable preparation
B: good to eat and acceptable preparation has extremely shallow bitterness and extremely low pleasant impression
C: good to eat and acceptable preparation has light bitterness and low pleasant impression
D: good to eat and acceptable preparation has light bitterness and unacceptable pleasant impression
E: non-good to eat preparation, because pleasant impression hardship and taste are also bitter
F: non-good to eat preparation, because taste is extremely bitter
Observed result:
Volunteer's evaluation table reveals the acceptable level to above-mentioned azithromycin preparation.Do not have the acceptable degree of the compositions of flavoring ingredient to be higher than to have for example compositions of Rhizoma et radix valerianae and Fructus Musae of flavoring ingredient, this shows that flavoring agent is not necessary for this class preparation.When trisodium Phosphate Anhydrous and fatty acid ester are used for granule interior, demonstrate better acceptable degree slightly.
Although the present invention is illustrated by way of example, should be appreciated that, only otherwise depart from the scope of claims, can carry out various modification and modification to it.In addition, under the situation of existence for the known equivalents of concrete feature, these equivalents are introduced into, and are quoted the same in this manual like it.
Claims (31)
1. dispersible pharmaceutical composition, it comprises:
(i) bitterness active component;
(ii) content is the lipid granulating agent of the 1-16 weight % of active component; With
(iii) content is the alkaline agent of the 1-20 weight % of active component; Wherein the bitterness of active component is partially or completely covered.
2. according to the compositions of claim 1, wherein said bitterness active component is a macrolide antibiotic.
3. according to the compositions of claim 2, wherein said macrolide antibiotic is selected from erythromycin, clarithromycin, Roxithromycin and azithromycin, comprises and preferably be the azithromycin (as disclosed azithromycin among the Croatia number of patent application P20020231 A) of the isomorphism pseudopolymorphic forms with fabulous dissolution characteristic.
4. according to compositions any among the claim 1-3, the content of wherein said lipid granulating agent is the 2-8 weight % of active component.
5. according to compositions any among the claim 1-4, the list that wherein said lipid granulating agent is wax, fatty acid, aliphatic alcohol or one or more fatty acids-, two-or Three-glycerol ester.
6. according to the compositions of claim 5, wherein said lipid granulating agent be selected from the glycerol list-, two-and three-stearate, glycerol list-, two-and three-palmitostearate, glycerol list-, two-and three-behenic acid ester, glycerol list-, two-and three-oleate, castor oil hydrogenated, cetomacrogol emulsifying wax, Brazil wax, cetyl alcohol and cetyl ester.
7. according to compositions any among the claim 1-6, the content of wherein said alkaline agent is the 2-12 weight % of active component.
8. according to compositions any among the claim 1-7, wherein said alkaline agent is selected from sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide and potassium hydroxide.
9. according to compositions any among the claim 1-8, further contain the surfactant that content is no more than active component 2 weight %.
10. according to the compositions of claim 9, wherein said surfactant is selected from sodium lauryl sulphate, docusate sodium, polysorbate and sorbitan fatty acid esters.
11. according to compositions any among the claim 1-10, further containing content is the diluent of the 5-60 weight % of whole compositionss.
12. according to the compositions of claim 11, wherein said diluent is selected from cellulose, microcrystalline Cellulose, lactose, mannitol, sorbitol, starch, calcium carbonate, calcium hydrogen phosphate, silicon dioxide and starch,pregelatinized.
13. according to the compositions of claim 11, wherein to be to use ratio be that 1: 3 to 3: 1 the microcrystalline Cellulose and the combination and the water-soluble cellulose of starch prepare to the granule of diluent.
14. according to the compositions of claim 13, wherein said water-soluble cellulose is an ethyl cellulose, its content is particulate 2-10 weight %.
15. according to the compositions of claim 13, wherein the ratio of microcrystalline Cellulose and starch is 1.25: 1 to 2: 1.
16. according to compositions any among the claim 1-15, further containing content is the disintegrating agent of the 1-12 weight % of whole compositionss.
17. according to the compositions of claim 16, wherein said disintegrating agent is selected from carmethose, cross-linked carboxymethyl cellulose sodium, primojel, crospovidone, aminoalkyl methacrylate copolymer E and Polacrillin potassium.
18. according to the compositions of claim 17, wherein said disintegrating agent is cationic polymer aminoalkyl methacrylate copolymer E.
19. according to compositions any among the claim 1-18, further containing content is the sweeting agent of the 1-10 weight % of whole compositionss.
20. according to the compositions of claim 19, wherein said sweeting agent is selected from aspartame, coating aspartame, ammonium glycerrhizinate, saccharin sodium, acesulfame-K and saccharide.
21. according to compositions any among the claim 1-20, further containing one or more content is the flavoring agent of the 1-6 weight % of whole compositionss.
22. according to the compositions of claim 21, wherein said one or more flavoring agents be selected from have Rhizoma et radix valerianae, Fructus Musae, Fructus Pruni pseudocerasi, Fructus Ananadis comosi, chocolate, caramel or mint flavored flavoring agent.
23., further contain the lubricating system of forming by lubricant, fluidizer and flowable according to compositions any among the claim 1-22.
24. according to the compositions of claim 23, wherein said lubricant is selected from magnesium stearate, calcium stearate, stearic acid and Myrj 45.
25. according to the compositions of claim 23, wherein said fluidizer is a Pulvis Talci.
26. according to the compositions of claim 23, wherein said flowable is selected from silicon dioxide, fatty acid ester and sodium lauryl sulphate.
27. a method for compositions for preparing according to claim 1, it comprises the steps:
(i) the bitterness active component is mixed with lipid granulating agent and alkaline agent obtain particulate substrates; With
(ii) optionally sneak into humidizer and further described particulate substrates is mixed with in disintegrating agent, sweeting agent, flavoring agent and the flowable one or more.
28. according to the method for claim 27, wherein said particulate substrates is by the preparation of hot melt spiral shotting.
29. according to the method for claim 28, hot melt spiral shotting is wherein carried out being lower than under 80 ℃ the temperature.
30., wherein described compositions compacting is obtained being scattered in the tablet in the water according to method any among the claim 27-29.
31. according to method any among the claim 27-29, not repressed granule or the powder agent that obtains being scattered in the water of wherein said compositions.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/HR2003/000013 WO2004087096A1 (en) | 2003-04-02 | 2003-04-02 | Pharmaceutical compositions having reduced bitter taste |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1744881A true CN1744881A (en) | 2006-03-08 |
Family
ID=33104888
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA038260204A Pending CN1744881A (en) | 2003-04-02 | 2003-04-02 | Pharmaceutical compositions having reduced bitter taste |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1608333A1 (en) |
| JP (1) | JP2006514968A (en) |
| CN (1) | CN1744881A (en) |
| AU (1) | AU2003214486A1 (en) |
| CA (1) | CA2521253A1 (en) |
| EA (1) | EA200501552A1 (en) |
| HR (1) | HRP20050867A2 (en) |
| WO (1) | WO2004087096A1 (en) |
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| WO2022227116A1 (en) * | 2021-04-25 | 2022-11-03 | 海南通用三洋药业有限公司 | Method for preparing roxithromycin capsule |
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| JP6315741B2 (en) * | 2015-08-18 | 2018-04-25 | 合同会社Ｐｈａｒｍａ Ｓｅｅｄｓ Ｃｒｅａｔｅ | Composition for oral cavity containing NSAIDs or heparins |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5380535A (en) * | 1991-05-28 | 1995-01-10 | Geyer; Robert P. | Chewable drug-delivery compositions and methods for preparing the same |
| TW271400B (en) * | 1992-07-30 | 1996-03-01 | Pfizer | |
| JP2001526212A (en) * | 1997-12-19 | 2001-12-18 | スミスクライン・ビーチャム・コーポレイション | Manufacturing method of chewable dispersible tablets |
| WO2000054811A1 (en) * | 1999-03-17 | 2000-09-21 | Daiichi Pharmaceutical Co., Ltd. | Medicinal compositions |
-
2003
- 2003-04-02 EP EP03710062A patent/EP1608333A1/en not_active Withdrawn
- 2003-04-02 JP JP2004570049A patent/JP2006514968A/en active Pending
- 2003-04-02 CA CA002521253A patent/CA2521253A1/en not_active Abandoned
- 2003-04-02 EA EA200501552A patent/EA200501552A1/en unknown
- 2003-04-02 AU AU2003214486A patent/AU2003214486A1/en not_active Abandoned
- 2003-04-02 CN CNA038260204A patent/CN1744881A/en active Pending
- 2003-04-02 WO PCT/HR2003/000013 patent/WO2004087096A1/en not_active Application Discontinuation
-
2005
- 2005-09-30 HR HR20050867A patent/HRP20050867A2/en not_active Application Discontinuation
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2004087096A1 (en) | 2004-10-14 |
| EP1608333A1 (en) | 2005-12-28 |
| JP2006514968A (en) | 2006-05-18 |
| CA2521253A1 (en) | 2004-10-14 |
| AU2003214486A1 (en) | 2004-10-25 |
| HRP20050867A2 (en) | 2005-12-31 |
| EA200501552A1 (en) | 2006-04-28 |
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