KR20200000923A - Composition improving pharmacokinetics performance of pharmaceutical material included in microneedle - Google Patents

Abstract

The present invention relates to a composition of a soluble or coating-type microneedle comprising a medicine, which contains an additive which increases bioavailability or a maximum blood concentration, which are pharmacokinetic factors of the medicine or increase both bioavailability and the maximum blood concentration. According to the present invention, a microneedle comprising the composition can be provided and a method for manufacturing the microneedle comprising a step of having the composition can be provided.

Description

COMPOSITION IMPROVING PHARMACOKINETICS PERFORMANCE OF PHARMACEUTICAL MATERIAL INCLUDED IN MICRONEEDLE}

The present invention relates to a composition for improving the pharmacokinetic performance of drugs contained in microneedles.

Numerous drugs and bioactive substances have been developed for the treatment of diseases, but in the delivery of drugs and bioactive substances into the body, problems with the passage of biological barriers (e.g. skin, oral mucosa and brain-vascular barrier), and The problem of efficiency of drug delivery remains to be improved.

Drugs and bioactive substances are generally administered orally in tablet or capsule form, but cannot be effectively delivered by such a method of administration alone due to the large number of drugs being digested or absorbed in the gastrointestinal tract or lost by the mechanism of the liver. In addition, some drugs cannot effectively pass through the intestinal mucosa. Patient compliance is also a problem (for example, in critically ill patients who need to take medication at certain intervals or cannot take medication).

Another common technique for the delivery of drugs and bioactive substances is the use of conventional needles. While this method is effective compared to oral administration, there are problems such as accompanying pain at the injection site and local damage of the skin, bleeding and disease infection at the injection site.

In order to solve the problems of the oral administration and subcutaneous injection, the method of transdermal administration through a patch is used. Transdermal administration using patches has fewer side effects, higher patient compliance, and easier maintenance of drug blood levels.

In order to solve the above problems, various microstructures including microneedles have been developed. Microneedles developed to date have been used mainly for drug delivery, body blood, and detection of analytes in vivo.

의 각질층 (stratum corneum)을 관통하여야 하므로, 충분한 물리적 경도를 가질 것이 요구된다. 또한, 모세혈관까지 도달함으로써 약물 전달의 효율성을 높이기 위한 적정 길이도 고려되어야 한다.Unlike conventional needles, microneedles are characterized by painless skin penetration and trauma, and painless skin penetration is important for top diameter for minimal aggression. Microneedle also has 10-20, the most powerful obstacle in the skin.

Since it must penetrate the stratum corneum, it is required to have sufficient physical hardness. In addition, the proper length for increasing the efficiency of drug delivery by reaching capillaries should also be considered.

직경, 500

의 길이로 솔리드 실리콘 마이크로니들을 제작하지만, 무통증 피부 관통을 실현하는 것이 불가능하였으며, 목적 부위로 약물 및 미용성분을 전달하는데 어려움이 있었다.After the conventional in-plane type microneedle ("Silicon-processed Microneedles", Journal of microelectrochemical system 8, 1999) has been proposed, various types of microneedles have been developed. The method of manufacturing an out-of-plane solid microneedle (US Patent Application Publication No. 2002138049 "Microneedle devices and methods of manufacture and use thereof") using an etching method is 50-100.

Diameter, 500

Although the solid silicone microneedle was manufactured to a length of, it was impossible to realize painless skin penetration, and it was difficult to deliver drugs and cosmetic ingredients to the target site.

Meanwhile, Prausnitz of the University of Georgia has proposed a method of fabricating biodegradable polymer microneedle by etching a glass or making a mold by photolithography. This method has the advantage that the drug can be manufactured in capsule form freely, but as the drug loading increases, the hardness of the microneedles is weakened. Since then, various methods for preparing biodegradable polymer microneedle have been proposed.

As one of the methods of manufacturing microneedles including biodegradable polymer microneedles, the present inventors have proposed a new method of manufacturing microneedles called droplet air-born blowing. The method for manufacturing various microneedle of blow blowing tensile method proposed by the present invention is Korean Patent Application Nos. 10-2009-94018, 10-2010-30127, 10-2010-130169, 10-2012-117936, 10-2015-174066, 10-2016-61903, and the like. This new manufacturing method overcomes the disadvantages of the conventional molding method, such as denaturation of the drug, insufficient hardness, and drug loss due to complex and long production time by using the manufacturing method through molding technology. However, R & D continues today.

Meanwhile, microneedles for delivering drugs into the human body may be classified into soluble microneedles or coated microneedles according to the method of mounting the drug. Soluble microneedles are manufactured in a state in which a drug is dissolved together with a biodegradable substance that is a constituent of the microneedles, and is produced by dissolving together with the components of the needles when the microneedles penetrate and dissolve into the skin. Coated microneedles are manufactured in such a way that the drug is coated on the outer wall of the microneedles with the microneedles made in advance.

In both of these soluble microneedles or coated microneedles, the drug is in the solid state in the microneedles, and it is essential for the drug in the solid state to be converted into the liquid state through a dissolution process. On the other hand, when peptide and protein drugs are delivered in the body in the form of microneedle, the site where the drugs are first delivered is the skin layer. More specifically, the microneedles are initially located in the epidermal and dermal layers below the stratum corneum, where various proteolytic enzymes, immunological defense mechanisms and metabolism are present, and the peptide and protein are intact. structure) becomes difficult to maintain. The longer these peptide and protein drugs stay in the dermal layer, the higher the likelihood of drug modification or degradation, which can lead to the reduction of intact drugs that can be absorbed into the body. This is why drugs need to be absorbed into the body quickly.

In addition, rapid absorption of drugs can lead to an increase in peak concentration in plasma (Cmax) and bioavailability, one of the pharmacokinetics performance factors. Pharmacokinetics is the study of the absorption, distribution, metabolism and excretion of drugs by changing the concentration of drugs in the body over time. Bioavailability refers to the extent to which the active ingredient is absorbed into the systemic circulation, and AUC (Area Under the plasma Concentration-time curve) is widely used as a factor for bioavailability. AUC is a parameter that indicates the amount of drug exposure to the human body during a specific time period, and corresponds to the area under the curve of the graph physically on the x-axis and time on the y-axis. One of the major researchers in this field, Prausnitz, of the University of Georgia, USA, mentioned earlier in the previous study of soluble microneedles of human growth hormone, a protein drug, through the rapid absorption of drugs, In addition, a research report was published in 2011 that showed an increase in AUC.

As mentioned above, in the development of soluble or coated microneedle formulations, particularly in the development of peptide and protein drugs, the development of rapid dissolution composition techniques that affect the pharmacokinetic properties of the drug is important.

Forteo (trade name), a recombinant human parathyroid hormone (a hormone that regulates blood calcium levels, hereinafter referred to as PTH (1-34)), is currently the only anabolic therapeutic agent approved for the treatment of osteoporosis. This peptide hormone uniquely has a bone producing effect, the ability to improve bone strength, and long-term fracture risk reduction compared to bisphosphonates (anti-absorbers). Despite these clinical benefits, the use of PTH (1-34) therapy is limited by practical factors and one of the most important factors is the method of administration. Because PTH (1-34) is a peptide hormone, it cannot be administered orally and is currently only administered by daily subcutaneous injection. Many patients who benefit from this treatment do not opt for this medication because of the need for daily injections. Because of the need to develop a more user-friendly alternative delivery method, a transdermal microneedle array patch delivery system for PTH (1-34) was developed.

The effect of PTH (1-34) varies greatly depending on the method of administration. Twice daily, short exposure to PTH (1-34) using subcutaneous injection increases bone formation resulting in an increase in the total weight of bone. On the other hand, prolonged exposure to PTH (1-34) increases the rate of calcium release from bone compared to bone formation. This has been shown to cause an increase in serum calcium levels and a decrease in the total weight of bone in both humans and rats.

Due to the aforementioned properties of PTH (1-34), rapid absorption in the body is important in the development of microneedle patches containing PTH (1-34) as a drug, and rapid dissolution for rapid absorption is important. Nevertheless, reports on fast dissolving microneedles, including peptide and protein drugs, are very limited. However, in relation to the rapidly dissolving composition, it is reported and known in the academic field before the present application as follows.

First, according to a 2011 report from the Georgia Institute of Technology concerning fast dissolving compositions (2011, small), trehalal was used to prepare soluble microneedles using carboxy methyl cellulose (CMC) as a matrix. The microneedle was dissolved at a faster rate by adding trehalose up to a 1: 1 level as an additive. According to the report, Cmax and AUC increased by 4 times compared to before adding trehalose as an additive.

In a study related to the use of sugar as an additive in the Georgia Institute of Technology above, Zosano Pharma Ltd. has developed a PTH (1-34) transdermal patch with a microneedle in the form of a coating and is currently undergoing clinical trials. There is. The research firm Pharma has published three papers. First, in 2009 he published a paper on deterioration mechanisms and improvements on safety (Pharm Research, 2009). Next, in 2010, he published a paper on a method for effectively performing a coating on a solid type microneedle (Pharm Research, 2010). Next, in 2011, a paper reporting the results of clinical pharmacokinetics and pharmacokinetics (clinical PK and PD) was published (Pharm Research, 2011). Although sucrose is included in the composition introduced in the 2009 paper, and sucrose is a disaccharide such as trehalose used in the aforementioned Georgia Tech report, sucrose is apparently PTH in the research paper. It has only been used as an additive to reduce the aggregation of (1-34), and no association is shown with the rapid dissolution of PTH (1-34). Incidentally, it is common knowledge in the art that the purpose of the use of sugars contained in the composition of peptides and protein drugs known before the present application date is only a stabilizer, and the purpose of reducing coagulation in the 2009 literature of the above investigational Pharma There is no description regarding the rapid dissolution of the microneedle or the rapid absorption of the drug.

As such, in the case of microneedles containing PTH (1-34) as a drug, the above-mentioned essential characteristics of PTH (1-34), that is, rapid absorption, are not achieved beyond the intake of intact drugs, and the human body does not have PTH (1). Although long-term exposure to PTH (1-34) is a very important and intrinsic issue, in view of its effect of increasing the rate of calcium release from bone compared to bone formation and reducing the total weight of bone, The results of previous studies that consider the rapid absorption of N are not known at all.

PVP, commonly called polyvidone or povidone, is a water-soluble polymer synthesized through the polymerization of N-vinylpyrrolidone and is widely used in biomedical applications due to its biocompatible properties. It has been used and has been widely used as a binder, especially in many pharmaceutical tablets. In addition, PVP has been used for various purposes in the medical field. For example, PVP has been widely used in the field of contact lenses, eye drops, personal care products such as shampoos and toothpastes, hair sprays and hair gels.

In the field of microneedles, PVP has been widely studied as a material for soluble microneedles. However, PVP alone has a disadvantage in that the mechanical properties are not excellent, and when the microneedle is manufactured by itself, there is a limit that does not have sufficient strength to penetrate the skin, and studies for overcoming this have been continued.

On the other hand, PVP has been recognized in the microneedle industry as a matrix of microneedles. Attempts to use PVP as an additive are not confirmed. In addition, as described above, although PVP is a widely used substance, the most common use is for combining substances used in the composition during the tableting process of oral preparation. It is important to note that bonding is a concept that is completely different from dissolution, but rather a concept at the opposite point.

Combining the above, no attempt was made to use PVP as an additive in the manufacture of microneedles, nor to attempt to use it as an additive for the purpose of rapid dissolution until the present application.

The present invention provides compositions of microneedles, in particular soluble or coated microneedles, which improve the pharmacokinetic properties of the drug, more specifically the maximum blood concentration (Cmax) and bioavailability (AUC) of the drug. It aims to do it.

In addition, the present invention is a composition of a soluble or coated microneedle containing PTH (1-34) as a drug, the pharmacokinetic properties of the drug, more specifically the maximum concentration (Cmax) and bioavailability (AUC) in the blood It is an object to provide a composition which improves).

The composition of a soluble or coated microneedles comprising a drug according to an embodiment of the present invention includes an additive which increases both bioavailability or maximum blood concentration or bioavailability and maximum blood concentration, which are pharmacokinetic factors of the drug. Here, the additive is a disintegrant. Furthermore, the disintegrant is selected as PVP.

On the other hand, the drug is a peptide and protein drug, preferably the peptide and protein drug is PTH (1-34).

In addition, the soluble or coated microneedles comprising a drug according to an embodiment of the present invention comprises a pharmacokinetic factor bioavailability or maximum blood concentration or an additive that increases both the bioavailability and the maximum blood concentration as a composition. do.

In addition, the method for producing a soluble or coated microneedle comprising a drug according to an embodiment of the present invention is an additive that increases both bioavailability or maximum blood concentration or bioavailability and maximum blood concentration, which is a pharmacokinetic factor of the drug. Incorporating into the composition.

In addition to the additional configuration may be further included in the present invention.

According to the invention, a composition of microneedles, in particular soluble or coated microneedles, which improves the pharmacokinetic properties of the drug, more specifically the maximum concentration (Cmax) and bioavailability (AUC) of the drug in the blood This may be provided.

In addition, according to the present invention, a soluble or coated microneedle composition comprising PTH (1-34) as a drug, the pharmacokinetic properties of the drug, more specifically the maximum concentration (Cmax) and bioavailability (blood) , AUC) may be provided.

Meanwhile, according to the present invention, a microneedle including the above-described composition may be provided, and a microneedle manufacturing method including the step of having the above-described composition may be provided.

1 is a graph showing the results of measuring blood concentrations of PTH (1-34) as an active ingredient of a drug when the compositions A, B, and C were applied to the skin of rats, respectively.

DETAILED DESCRIPTION The following detailed description of the invention refers to the accompanying drawings that show, by way of illustration, specific embodiments in which the invention may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention. It should be understood that the various embodiments of the present invention are different but need not be mutually exclusive. For example, certain shapes, structures, and characteristics described herein may be implemented with changes from one embodiment to another without departing from the spirit and scope of the invention. In addition, it is to be understood that the location or arrangement of individual components within each embodiment may be changed without departing from the spirit and scope of the invention. Accordingly, the following detailed description is not to be taken in a limiting sense, and the scope of the present invention should be taken as encompassing the scope of the claims of the claims and all equivalents thereto. Like reference numerals in the drawings indicate the same or similar elements throughout the several aspects.

Hereinafter, various preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art can easily implement the present invention.

 Additives of drugs may be classified into excipients, stabilizers, dispersants, binders, disintegrants, sustained-release agents and the like depending on the purpose of the formulation. As for the additives, the substances used themselves may be classified and used differently depending on the purpose of the formulation even if they are the same, which is obvious to those skilled in the art (KFDA guideline, 2015/12).

The inventors have identified each compounding purpose for fast dissolving compositions to find suitable additive candidates. As a result, attention has been paid to disintegrants, which are components needed to expand in the digestive tract before they are absorbed. Thus, when a disintegrant is added to the microneedle in a solid state, it is expected to be a composition in which rapid solubility is enhanced by the action of the disintegrant, and planned and performed the following experiment.

The inventors made up a total of three compositions. These are as follows.

Composition A: A formulation using hyaluronic acid as a matrix of microneedles and containing no additives.

Composition B: A formulation comprising trehalose as an additive in composition A.

Composition C: A formulation comprising a disintegrant as an additive in composition A.

The KFDA Additive Guidelines describe the following types of substances as disintegrants:

Hydroxypropyl Methyl Cellulose, Corn Starch, Agar Powder, Methyl Cellulose, Bentonite, Hydroxypropyl Starch, Sodium Carboxy Methyl Cellulose, Sodium Alginate, Carboxy Methyl Cellulose, Calcium Phosphate, Sodium Lauryl Sulfate, Silic Anhydride, I-Hydrate Roxypropyl cellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde treated casein and gelatin alginic acid, amylose, guar gum, thickener, polyvinylpyrrolidone, calcium phosphate, gelled starch, gum arabic, Amylopectin, pectin, sodium polyphosphate, ethyl cellulose, white sugar, magnesium aluminum silicate, di-sorbitol liquid, hard silicic anhydride

Among these, the inventors carried out the test by selecting polyvinylpyrrolidone. In addition, PTH (1-34) was used as an active ingredient of the drug. More accurate components of the three compositions are listed in the table below.

Composition Microneedle Matrix Component wt% Additive wt% PTH (1-34) wt% A Hyaluronic Acid 96.5% - 3.5% B Hyaluronic Acid 70.0% Trehalose 26.5% 3.5% C Hyaluronic Acid 70.0% PVP 26.5% 3.5%

The present inventors prepared the microneedle with the above three compositions including hyaluronic acid as a matrix component, PTH (1-34) as an active ingredient of a drug, and different components of additives. In addition, a test was conducted to evaluate the in vivo pharmacokinetic performance of these three types of microneedles, namely drug delivery efficiency. The inventors applied microneedles of the above three different compositions to the dorsal skin of rats to evaluate drug delivery efficiency according to different compositions of microneedles. Thereafter, rat blood samples were taken at various time points to measure blood levels of PTH (1-34). the results are as follow.

First, the microneedle composed of Composition A was measured with a bioavailability (AUC) value of 490 ± 210 (h pg / ml). Maximum blood concentration (Cmax) values were determined to be 1043 ± 523 (pg / ml).

Next, the microneedle composed of Composition B was measured with a bioavailability (AUC) value of 910 ± 770 (h pg / ml). Maximum blood concentration (Cmax) values were measured at 2920 ± 140 (pg / ml). The microneedle containing trehalose as an additive was measured to have a bioavailability (AUC) value of about 1.9 times and a maximum blood concentration (Cmax) of about 2.8 times compared to the control group consisting of Composition A without using the additive.

Next, the microneedle composed of Composition C was measured with a bioavailability (AUC) value of 6,005 ± 2720 (h pg / ml). Maximum blood concentration (Cmax) values were measured at 10,012 ± 4270 (pg / ml) (pg / ml). The microneedles, including polyvinylpyrrolidone (PVP) as an additive, had a bioavailability (AUC) value of about 12.3 times and a maximum blood concentration (Cmax) of about 9.6 compared to the control group consisting of composition A without the additive. Measured by fold.

The graph shown in FIG. 1 shows the results of measuring blood concentrations of PTH (1-34) as an active ingredient of the drug when the compositions A, B, and C were applied to the skin of rats, respectively. Here, the x-axis is time (one scale on the x-axis is one hour, i.e. 60 minutes), and the y-axis is the measured blood concentration of PTH (1-34) contained in the microneedle as an active ingredient of the drug. The area under the plasma concentration-time curve (AUC) used as an indicator of bioavailability, as defined by the term itself, means the area under the curve in the graph of FIG. 1 and can be calculated as an integral of blood concentration over time. The maximum blood concentration (Cmax) can be directly obtained as a measurement graph as the peak value of each graph.

The superior pharmacokinetic properties of microneedles in the presence of trehalose or PVP when compared to additive-free microneedles may be due to the rapid dissolution of microneedles. In addition, the antifouling properties of PVP may facilitate facilitating rapid peptide drug diffusion in systemic circulation. The drug reached its maximum concentration in the blood at 5 to 15 minutes and was quickly removed within 2 hours.

In summary, we compared the peptide drug delivery efficiency of fully soluble hyaluronic acid microneedles in the absence and presence of additives such as trehalose and PVP. The measured pharmacokinetic profile suggests that PVP is the most suitable additive for delivering macromolecular peptide drugs. Compared with no additive or trehalose-added hyaluronic acid microneedle, the addition of PVP to the hyaluronic acid microneedle promotes rapid and efficient diffusion of the peptide drug into the systemic circulation. This excellent property is understood to be due to the antifouling effect of PVP, which is understood to prevent peptide aggregation and enzymatic degradation.

Although the present invention has been described in detail by specific matters such as components and the like, and limited embodiments and drawings, the present invention is provided only to help a more general understanding of the present invention, and the present invention is not limited to the above embodiments. Those skilled in the art may make various modifications and variations from this description.

Therefore, the spirit of the present invention should not be limited to the above-described embodiments, and all the scopes equivalent to or equivalent to the scope of the claims as well as the claims to be described later belong to the spirit category of the present invention. will be.

Claims (7)

A composition of soluble or coated microneedles comprising a drug,
A composition comprising a bioavailability or maximum blood concentration or an additive which increases both the bioavailability and the maximum blood concentration which are pharmacokinetic factors of the drug.
The method of claim 1,
Wherein said additive is a disintegrant.
The method of claim 2,
Wherein said disintegrant is PVP.
The method of claim 1,
The drug is a peptide and protein drug.
The method of claim 4, wherein
Wherein said peptide and protein drug is PTH (1-34).
Soluble or coated microneedles containing drugs,
A microneedle comprising as a composition a bioavailability or maximum blood concentration, which is a pharmacokinetic factor of a drug, or an additive which increases both the bioavailability and the maximum blood concentration.
Method for producing a soluble or coated microneedle containing a drug,
A method of making a microneedle comprising the step of including in the composition a bioavailability or maximum blood concentration or an additive that increases both the bioavailability and the maximum blood concentration, which are pharmacokinetic factors of the drug.

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