KR20230010586A - Composition for microneedle, microneedle array, and transdermal patch comprising the same - Google Patents

Abstract

According to the present invention, disclosed are: a composition for a microneedle, in which a drug is stably delivered into the skin, pain can be minimized, bioavailability of the drug can be increased, side effects such as gastrointestinal disorders can be avoided, and a non-steroidal analgesic is contained; a microneedle array; and a transdermal patch comprising the same.

Description

Composition for microneedle, microneedle array, and transdermal patch comprising the same

The present invention relates to a microneedle composition, a microneedle array, and a transdermal patch including the same.

The microneedle is a transdermal drug delivery system that delivers drugs to the epidermal and dermal layers using microneedles with a length of 100 to 1,000 μm to deliver drugs intradermally through the stratum corneum of the skin.

The microneedle was first conceptualized by Martin S. Gerstel and Virgil A. Place in the 1970s, and then published as a thesis for the first time in 1998 by Professor Mark Prausnitz's team at Georgia Institute of Technology's Drug Delivery Laboratory (Henry et al. 1998). The microneedle is drawing attention as a next-generation drug delivery system that eliminates rosacea by combining the efficacy of an existing syringe with the convenience of a patch, and many studies are being conducted worldwide, and as such, various patents for related technologies are being filed.

Microneedles are classified into solid microneedles, coated microneedles, soluble microneedles, and hollow microneedles according to the drug delivery method.

A dissolving microneedle is a microstructure in which a drug loaded into a needle and all components constituting the needle are made of a biodegradable material harmless to the human body, completely dissolved into the application site and delivered to the dermal layer of the skin.

The biodegradable material of the soluble microneedle uses a biodegradable polymer based on biocompatibility. The biodegradable polymer may be hyaluronic acid or a pharmaceutically acceptable salt thereof, carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polylactic glycolic acid, gelatin, collagen, chitosan, or mixtures thereof, Among them, hyaluronic acid is mainly used.

Dissolvable microneedles must have skin insertion ability to penetrate the skin, and materials such as hyaluronic acid are difficult to satisfy the mechanical strength required for skin penetration.

Patent Document 1 discloses that a hyaluronic acid hydrogel crosslinked using a crosslinking agent is used, and skin insertion ability can be improved according to the degree of crosslinking. However, due to crosslinking, the skin solubility of the microneedle is lowered, and it is not easy to control the crosslinking in the manufacturing process, so it is not suitable for mass production. In addition, in the case of a hydrogel-type microneedle, since it swells when penetrating into the skin, pressure may be applied to the skin to cause irritation, and pain may occur during the removal process.

On the other hand, non-steroidal analgesics (NSAIDs) are the most prescribed drugs worldwide for the treatment of osteoarthritis and musculoskeletal disorders.

Among non-steroidal analgesics, ketoprofen is a potent non-steroidal anti-inflammatory drug that is widely used for rheumatoid arthritis and related diseases. Oral administration of this drug causes systemic side effects and gastrointestinal disturbances.

Therefore, in order to reduce the above-mentioned side effects or concentrate many drugs locally, formulations such as injections, external gels, and patches are commercially available. However, even in the case of existing commercial formulations, disadvantages exist. For example, in the case of injections, an expert's help is required because they must be injected intramuscularly, and the pain is great. Since it is on the low side, it has the disadvantage of having to carry a high capacity.

KR 10-2018-0023934A (published on 2018.03.07)

In order to improve the disadvantages of existing ketoprofen formulations such as external gels, patches and injections, a drug absorption method through a new formulation is required.

The microneedle is a transdermal drug delivery system that delivers drugs to the epidermal and dermal layers using microneedles within a few hundred micrometers in length to deliver active ingredients into the transdermis through the stratum corneum of the skin. When non-steroidal analgesics, in particular, ketoprofen, are delivered into the body using the microneedle, pain can be minimized, bioavailability of the drug can be increased, and side effects such as gastrointestinal disorders can be avoided.

In the present invention, in order to manufacture non-hydrogel soluble microneedles, polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA) are selected from various biodegradable polymers and their contents are controlled to obtain non-steroidal analgesics. A microneedle was designed, and it was confirmed that the microneedle had appropriate breaking strength and yield strength, and excellent skin insertion ability and skin solubility after manufacturing a transdermal patch.

An object of the present invention is to provide a composition for microneedle, a soluble microneedle array, and a transdermal patch including the same.

Another object of the present invention is to provide a microneedle composition containing a nonsteroidal analgesic, a soluble microneedle array, and a transdermal patch containing the same.

The present invention is a drug for microneedle; and a composition for microneedles comprising a biodegradable polymer.

In this case, the biodegradable polymer includes polyvinylpyrrolidone and polyvinyl alcohol in a weight ratio of 1:0.1 to 1:10.

The polyvinylpyrrolidone has an average molecular weight of 20 to 50 kDa, and the polyvinyl alcohol has an average molecular weight of 10 to 90 kDa.

The drug for the microneedle: the biodegradable polymer is included in a weight ratio of 1:2.3 to 1:9.

The drug for the microneedle is an anti-inflammatory analgesic, an anti-arthritis agent, an antispasmodic, an antidepressant, an antipsychotic, a tranquilizer, an anti-anxiety, a narcotic antagonist, an anti-Parkinson's disease drug, a cholinergic agonist, an anticancer agent, an anti-angiogenesis inhibitor, an immunosuppressive agent, Antiviral, antibiotic, appetite suppressant, analgesic, anticholinergic, antihistamine, antimigraine, hormone, coronary, cerebrovascular, peripheral vasodilator, contraceptive, antithrombotic, diuretic, antihypertensive, cardiovascular disease treatment, anti-wrinkle , At least one of a skin aging inhibitor and a skin whitening agent.

The anti-inflammatory drug is a non-steroidal antiinflammatory drug (NSAID).

The nonsteroidal analgesics include ketoprofen, flubiprofen, acetylsalicylic acid, indomethacin, diclofenac, piroxicam, tenoxicam, ibuprofen, naproxen, nabumetone, ketorolac, azapropazone, mefenamic acid, Tolfenamic acid, sulindac, diflunisal, thiaprofenic acid, acemetacin, aceclofenac, droxicam, oxaprozin, floctafenin, phenylbutazone, proglumethacin, tolmetin, fenbufen, their pharmacology It is at least one selected from the group consisting of generally acceptable salts, precursors thereof, and mixtures thereof.

The microneedles are soluble microneedles.

In addition, the present invention and the substrate in close contact with the skin; It provides a soluble microneedle array comprising a plurality of microneedles formed by forming sharp peaks at an end thereof and arranged vertically and horizontally at regular intervals on one surface of the substrate.

At this time, the substrate and the plurality of microneedles are prepared by mixing a drug for the microneedle and a biodegradable polymer, polyvinylpyrrolidone and polyvinyl alcohol, in a weight ratio of 1:0.1 to 1:10.

The microneedle array has a breaking strength of 50 N or more and a yield strength of 3 to 5 N/needle.

In addition, the present invention is the soluble microneedle array; and an adhesive sheet to which at least one soluble microneedle array is attached.

At this time, the transdermal patch has an insertion ability per unit area in the skin of 90% or more.

The transdermal patch has a drug content of 3.0 to 15.0 mg/patch for microneedles.

The transdermal patch has a drug content uniformity for microneedles of less than 15%.

The soluble microneedle array containing a non-steroidal analgesic according to the present invention can stably deliver into the skin, thereby minimizing pain, increasing the bioavailability of the drug, and avoiding side effects such as gastrointestinal disorders.

In addition, the microneedle array has appropriate breaking strength and yield strength, and has excellent skin insertion ability and skin solubility after manufacturing a transdermal patch, enabling stable drug delivery into the skin.

In addition, since the manufacturing process is simple, microneedles can be produced at a lower cost, making it suitable for mass production.

1 is a schematic diagram showing a manufacturing method of a soluble microneedle array of the present invention.
2 is a photograph showing microneedles attached to pig skin.
Figure 3 is (a) front, (b) cross-sectional images of the microneedle array measured by an optical microscope.
Figure 4 is (a) front, (b) cross-sectional images of the microneedle array measured by an electron microscope.
5 is a schematic diagram showing a Franz-diffusion cell.
6 is a photograph showing pig skin to which microneedles are attached to be applied to the Franz diffusion test apparatus.
7 is a dissolution image of a microneedle over time.
8 is a graph comparing the dissolution rate of ketoprofen according to the microneedle time.
9 is a graph comparing the cumulative permeability of ketoprofen according to the time of the microneedle.

In order to achieve the object of the present invention, the present invention provides a microneedle composition, a soluble microneedle array, and a microneedle transdermal patch.

In the present invention, the term “microneedle” refers to a needle-like structure having a length in micrometers (μm). The microneedle is formed with a pointed tip formed at the end, and delivers the drug through the hole formed by forming a hole in the stratum corneum, which is the outermost layer of the skin. In addition, since the length of the microneedle is very short and has an appropriate length that does not affect nerve cells, little pain occurs.

Microneedles are soluble microneedles unless otherwise indicated in the present specification. The dissolving microneedle is a micro structure that is completely dissolved into the application site of the skin and delivers the drug.

Composition for microneedle

The microneedle composition according to the present invention includes a microneedle drug; and biodegradable polymers.

Drugs for microneedles are not limited in the present invention, and drugs, protein drugs, peptide drugs, nucleic acid molecules for gene therapy, nanoparticles, functional cosmetics drugs, and cosmetic ingredients may be used.

Preferably, the drugs that can be used in the present invention are, for example, anti-inflammatory drugs, anti-arthritic drugs, antispasmodics, anti-depressants, anti-psychotic drugs, tranquilizers, anti-anxiety drugs, narcotic antagonists, anti-Parkinson's disease drugs, cholinergic agonists , anticancer drugs, anti-angiogenesis inhibitors, immunosuppressants, antiviral drugs, antibiotics, appetite suppressants, analgesics, anticholinergics, antihistamines, antimigraine drugs, hormones, coronary, cerebrovascular, peripheral vasodilators, contraceptives, antithrombotics, It is any one or more of diuretics, antihypertensive agents, cardiovascular disease treatment agents, anti-wrinkle agents, skin aging inhibitors, and skin whitening agents, but is not limited thereto.

According to one embodiment, the drug for the microneedle is an anti-inflammatory analgesic.

Anti-inflammatory drugs are non-steroidal antiinflammatory drugs (NSAIDs).

The non-steroidal analgesics include ketoprofen, flubiprofen, acetylsalicylic acid, indomethacin, diclofenac, piroxicam, tenoxicam, ibuprofen, naproxen, nabumetone, ketorolac, azapropazone, mefenamic acid, Tolfenamic acid, sulindac, diflunisal, thiaprofenic acid, acemetacin, aceclofenac, droxicam, oxaprozin, floctafenin, phenylbutazone, proglumethacin, tolmetin, fenbufen, their pharmacology It may be one or more selected from the group consisting of generally acceptable salts, precursors thereof, and mixtures thereof. Preferably, the non-steroidal analgesic is ketoprofen represented by Formula 1 below.

[Formula 1]

Non-steroidal analgesics, represented by ketoprofen of Formula 1, are anti-inflammatory drugs, and exhibit strong anti-inflammatory effects when administered orally, but have side effects such as gastrointestinal irritation and other systemic side effects when administered orally. In addition, for transdermal administration such as the skin, it should be loaded in a high dose due to low bioabsorption. However, when formulated in the form of a microneedle as in the present invention, it is possible to minimize pain, increase the bioavailability of the drug, and avoid side effects such as gastrointestinal disorders as it is stably delivered into the skin. This can be achieved due to a new formulation that can improve the disadvantages of existing ketoprofen formulations such as external gels, patches, and injections, that is, a drug absorption method using a microneedle.

A biodegradable polymer is used together with the non-steroidal analgesic to manufacture the microneedle. The biodegradable polymer is a polymer having hydrophilicity, and ketoprofen is chemically structurally highly polar and has a hydrophilic property, so that the compatibility between the two is very good.

A microneedle prepared using a composition containing a biodegradable polymer together with a non-steroidal analgesic must have a certain level of strength in order to be inserted into the surface layer of the skin and/or the stratum corneum of the skin. In addition, elasticity and flexibility must be secured so that the microneedle does not cause pain or bleeding when applied to a local area. In addition, when the nonsteroidal analgesic is attached to the skin in the form of a patch, the content of the nonsteroidal analgesic contained in each microneedle is more than a certain level to have a sufficient pharmacological effect, and the nonsteroidal analgesic contained in each microneedle The content of the analgesic should be similar to exert a uniform pharmacological effect.

Specifically, in the microneedle composition of the present invention, the content ratio of the microneedle drug and the biodegradable polymer is 1:2.3 or more, 1:2.5 or more, 1:3.0 or more, 1:3.5 or more, 1:4.0 or more, 1: 4.5 or more, 1:5.0 or more, 1:5.5 or more, 1:6.0 or more, 1:6.5 or more, 1:7.0 or more, 1:7.5 or more, 1:8.0 or more, 1:8.5 or more, 1:9.0 or less, 1:8.5 or less, 1:8.0 or less, 1:7.5 or less, 1:7.0 or less, 1:6.5 or less, 1:6.0 or less, 1:5.5 or less, 1:5.0 or less, 1:4.5 or less, 1:4.0 or less, It has a range of 1:3.5 or less and 1:2.5 or less. Preferably, it has a weight ratio of 1:2.3 to 1:9, or 1:3 to 1:9. If the content of the microneedle drug is less than the above range, it is difficult to secure a sufficient pharmacological effect due to content variation between patches. A decrease in elasticity and flexibility occurs.

Although various biodegradable polymers have been proposed for the manufacture of soluble microneedles, in the present invention, biodegradable polymers of specific components were selected to secure excellent mechanical strength, elasticity and flexibility while maintaining the property of rapidly dissolving upon skin invasion. In addition, these polymers do not cause pain and bleeding due to swelling of the hydrogel polymer as they do not form a hydrogel unlike conventional hydrogel polymers.

Polyvinyl pyrrolidone (hereinafter referred to as 'PVP') and polyvinyl alcohol (hereinafter referred to as 'PVA') are biodegradable polymers having hydrophilic properties.

PVP is not toxic or irritating enough to be used as a binder for pharmaceutical tablets, and has very high stability. Since the drug administration route using the microneedle is based on the principle that the drug is released after being attached to the skin, the PVP has the advantage of not causing irritation even when it is in contact with the skin for a long time enough to be used as an irritation reliever for transdermal preparations. However, when the PVP is applied alone to the microneedle, the mechanical strength is low, that is, the strength that can withstand being inserted into the skin surface layer and/or the stratum corneum layer cannot be secured.

On the other hand, PVA is a long-chain polymer with a structure in which vinyl alcohol is repeated. It has a hydroxyl group (-OH) in the structure, so it does not tear easily and is elastic even when a considerable level of shear stress or tensile stress is applied from the outside. It has the advantage of excellent resilience.

PVP and PVA having these characteristics have a faster dissolution rate compared to other biodegradable polymers, including hyaluronic acid widely used in microneedles, so that rapid dissolution properties can be secured when invasive to the skin. In addition, when these two are used in a specific mixing ratio, strength, elasticity and flexibility required for skin invasion can also be secured. In particular, PVP and PVA are soluble in purified water, so they can be easily applied to the microneedle manufacturing process without using a separate organic solvent or homogenizer, and can be manufactured through simple mixing, so the production process is also It can be very simplified.

In particular, in the present invention, PVP and PVA are mixed and used as biodegradable polymers in a specific composition ratio.

According to one embodiment, the content ratio of PVP:PVA is 1:0.1 or more, 1:0.2 or more, 1:0.3 or more, 1:0.4 or more, 1:0.5 or more, 1:0.6 or more, 1:0.7 or more, 1: 0.8 or more, 1:0.9 or more, 1:1 or more, 1:10 or less, 1:9 or less, 1:8 or less, 1:7 or less, 1:6 or less, 1:5 or less, 1:4 or less have a range Preferably, they are mixed and used in a weight ratio of 1:0.1 to 1:10, more preferably in a weight ratio of 1:1 to 1:4. As already mentioned, the use of PVP and PVA alone has problems with low mechanical strength and solubility for use as microneedles.

The present invention not only solves the above problem by using the two biodegradable polymers in a specific content ratio, but also secures the advantages of each polymer. That is, the low mechanical strength of PVP can be compensated for by the use of PVA, and the solubility problem can be compensated for by the use of PVP.

In the manufacture of the microneedle by the mixed use of PVP and PVA, a solution is prepared by dissolving each biodegradable polymer in a solvent. When manufacturing a microneedle array, which will be described later, a composition for microneedle, that is, a casting solution, is prepared and then constantly dropped on an intaglio mold. At this time, the loss of the casting solution and the mass deviation between each patch are caused by the molecular weight and content of PVP and PVA. not only occurs, but also affects physical properties. In addition, in the process of separating the microneedle array from the cathode mold after manufacturing, if the strength is low, the microneedle array is damaged.

Accordingly, the molecular weight of each biodegradable polymer is limited.

Specifically, PVP is used with an average molecular weight of 20 to 50 kDa, more preferably 20 to 35 kDa is 40 to 60% by weight, greater than 35 kDa and 45 kDa is 10 to 30% by weight. PVA having an average molecular weight of 10 to 90 kDa is used, more preferably 10 to 30 kDa (10 to 30% by weight), and 75 to 90 kDa is used in a mixture of 1 to 5% by weight. If the molecular weight is too small, it is difficult to secure physical properties and the viscosity is low, resulting in loss of casting solution and mass deviation between patches.

In the composition for microneedle of the present invention, PVP and PVA having a limited average molecular weight are dissolved in a hydrophilic solvent at a specific content ratio together with a drug for microneedle.

The viscosity of the composition for microneedle of the present invention is 300 to 1000 cps, and the final concentration is 10 to 30% by weight, preferably 10 to 25% by weight, using a hydrophilic solvent. If the viscosity is less than or exceeds the above range, loss of the casting solution and mass deviation between patches occur, so it is appropriately used within the above range.

The hydrophilic solvent may include, for example, water, ionized water, physiological saline, distilled water, purified water, sterilized purified water, etc., but is not limited thereto, and is preferably purified water.

If necessary, the composition may further include a solubilizing agent, a plasticizer, a surfactant, a preservative, an anti-inflammatory agent, and the like according to the purpose of use.

Using the composition for microneedle as described above, it is possible to manufacture a soluble microneedle array having mechanical strength, elasticity, and flexibility suitable for insertion into the skin, as well as solubility and biodegradability, and a transdermal patch including the same.

Soluble Microneedle Array

A soluble microneedle array according to the present invention includes a substrate in close contact with the skin; A plurality of microneedles formed by forming sharp peaks at an end thereof and arranged vertically and horizontally at regular intervals on one surface of the substrate;

At this time, the substrate and the plurality of microneedles are made of the above-described composition for microneedles.

The substrate has a thickness of 0.3 mm to 10 mm, and has a certain degree of elasticity and flexibility so that the microneedle array adheres to the skin. In addition, when having the above thickness, mechanical strength is secured and deformation due to change over time is small.

The plurality of microneedles may have a conical shape, a truncated cone shape, a quadrangular pyramid shape, a triangular pyramid shape, a cone shape, and the like, but a conical shape, a truncated cone shape, and a conide shape are most suitable considering insertion resistance into the skin.

The shape of the microneedle may not form an intermediate stage, or may form one, two or three stages in the intermediate stage. In addition, the microneedle may be filled, porous, or may include a hollow part.

The length of the microneedle measured from the top of the substrate may be 10 to 1000 μm, preferably 400 to 1000 μm. In addition, the diameter of the microneedle in contact with the substrate may be 100 to 900 μm, preferably 300 to 700 μm, and the diameter of the peak may be 1 to 50 μm, preferably 5 to 30 μm. there is. However, the length and diameter of the microneedle can be changed and used by a person skilled in the art in consideration of the purpose of use of the microneedle, the depth of the target skin layer, the type of drug, etc., and is limited to the length and diameter. it is not going to be

At this time, the number of microneedles formed per array varies depending on the area to be applied and the size of the patch, and it is possible to form tens to tens of thousands without limitation.

The soluble microneedle array of the present invention is manufactured by controlling the contents of PVP and PVA in the base material and a plurality of microneedles, so that it has appropriate strength, elasticity and flexibility, adheres well to the skin, and penetrates into the skin easily and is applied to the skin. Since it disappears afterward, there is little irritation to the skin and there is no need for removal. This has the advantage that there is no stimulation or pressure on the skin and no pain in the removal process because it does not swell when penetrating into the skin compared to the case of conventional hydrogel types such as hyaluronic acid.

In addition, the soluble microneedle array of the present invention has an advantage in that the manufacturing process can be simplified by manufacturing the substrate and the plurality of microneedles from the same material.

Hereinafter, a method for manufacturing a soluble microneedle array will be described with reference to the drawings.

1 is a schematic diagram showing a manufacturing method of a soluble microneedle array of the present invention.

Specifically, the soluble microneedle array,

(S1) dropping a composition for microneedle into an intaglio mold having a needle-shaped groove;

(S2) defoaming and drying the injected composition in a vacuum atmosphere; and

(S3) recovering the microneedle array from the intaglio mold;

Each step is described below.

First, the microneedle composition 20 is dripped into the intaglio mold 10 having the needle-shaped groove P (FIG. 1A).

In step (S1), the intaglio mold 10 having the needle-shaped groove P is at least one selected from the group consisting of silicon-based polymers, fluorine-based polymers, UV-curable polymers, thermosetting polymers, thermoplastic polymers, ceramic oxides, and metallic inorganic materials. It may be made of a material, but is not limited thereto.

For example, the intaglio mold 10 may be manufactured so that needles having an embossed pyramidal shape are arranged at regular intervals using micromachinery technology. The intaglio mold 10 uses a mold made of PDMS.

The droplet of the composition 20 for microneedle may use a method commonly used in this field.

Among them, in the present invention, the composition 20 is dropped into the intaglio mold 10 to perform decompression under vacuum, or after the drop is inserted into a centrifugal separator, and then the composition 20 is added to the intaglio mold by using centrifugal force ( 10) to be injected into the Loss of the drug and the composition 20 can be maximally prevented by dripping the composition 20 .

If necessary, in order to improve release or wetting of the composition 20 filled in the intaglio mold 10, plasma treatment, SAM (self-assembly monolayer) treatment, and surface deposition in the groove P It may be treated with one or more surface treatment processes selected from the group consisting of Specifically, the intaglio mold 10 having the needle-shaped groove P may be subjected to hydrophilic surface treatment by plasma treatment, hydrophobic release treatment by SAM treatment, and the like.

Next, it is degassed and dried in a vacuum atmosphere (Fig. 1b).

The solvent in the composition is removed through defoaming and drying to form the microneedle array 21 . At this time, when the hydrophilic solvent is water, it is dried under reduced pressure at 35 to 50 ° C.

Next, the microneedle array 21 is separated and recovered from the intaglio mold 10 (FIG. 1c).

The soluble microneedle array of the present invention prepared as above has breaking strength and yield strength within a specific range.

The breaking strength (or breaking strength) is a parameter related to the elasticity of the microneedle array. When the microneedle array is separated from the intaglio mold, a certain level of tensile force is applied to the microneedle array. At this time, when the elasticity is low, the microneedle array separated from the intaglio mold is damaged.

When a certain level of force is applied to the microneedle array, at the beginning of the deformation, when the stress disappears, it returns to its original state by elastic force. destruction occurs in When the microneedle array of the present invention has a breaking strength of 50 N or more when applied at a tensile speed of 10 mm/min similar to the level that occurs during the manufacturing process, the microneedle array separated from the intaglio mold does not break. Therefore, as a result of adjusting the contents of PVP and PVA through the experimental example of the present invention, it was confirmed that it had a breaking strength of 50N or more.

Yield strength is the limiting stress at which elastic deformation occurs, and is a parameter related to the insertion ability of the microneedle into the skin. That is, if the microneedle has low strength, it cannot penetrate the skin, making drug delivery difficult. For drug delivery, the skin insertion ability of the microneedle must be 90% or more, and when the yield strength of 3 to 5 N/needle is obtained under the conditions of compression displacement: about 1 mm and compression speed: 0.5 mm/sec, the above 90% The above skin insertion ability can be achieved.

In addition, the manufacturing process of the microneedle array of the present invention can be further simplified by manufacturing the substrate and the plurality of microneedles with the same composition. In addition, when the conventional microneedle and substrate are designed with different compositions or two or more stages of substrate or microneedle are formed, damage or separation occurs during the separation process of the microneedle array from the intaglio mold. However, this problem can be fundamentally avoided when manufactured with the same composition as described above.

transdermal patch

In the present invention, the term "patch" refers to a dosage form that is attached to the skin to deliver a drug into the body, and a transdermal patch refers to a patch capable of transdermal drug delivery.

The microneedle transdermal patch of the present invention includes a soluble microneedle array; and an adhesive sheet to which at least one soluble microneedle array is attached.

The adhesive sheet may include, for example, silicone, polyurethane, polyethylene, polyester, polypropylene, polyvinyl chloride, hydrocolloid, or a mixture thereof.

The microneedle transdermal patch includes a microneedle array on one surface, and a plurality of microneedles can be inserted into the skin by pressing. As the microneedle penetrating the skin dissolves in the skin, the drug is rapidly injected into the skin.

For drug injection, the ability of the microneedle to be inserted into the skin per unit area in the skin is 90% or more, preferably 95% or more, and more preferably 99% or more.

The microneedle transdermal patch of the present invention contains 1.0 to 6.0 mg/patch of a non-steroidal analgesic, that is, ketoprofen, per patch, effectively permeates after being absorbed into the skin, compared to those applied in liquid form. It can be seen that it exhibits high permeability and excellent bioavailability.

In addition, the microneedle transdermal patch of the present invention has a non-steroidal analgesic, that is, ketoprofen content uniformity of less than 15%, preferably 9 to 10%, and the content deviation of the drug loaded per microneedle is very small. . As a result, it is possible to reduce the fluctuation of drug concentration in the local area, and a continuous anti-inflammatory analgesic effect can be expected.

The microneedle transdermal patch according to the present invention can minimize pain, increase the bioavailability of drugs, and avoid side effects such as gastrointestinal disorders by stably delivering the patch into the skin.

In addition, the microneedle array has appropriate breaking strength and yield strength, and has excellent skin insertion ability and skin solubility after manufacturing a transdermal patch, enabling stable drug delivery into the skin.

In addition, since the manufacturing process is simple, microneedles can be produced at a lower cost, making it suitable for mass production.

[Example]

Hereinafter, the present invention will be described in detail through examples and experimental examples. However, these Examples and Experimental Examples are only examples of the present invention, and the scope of the present invention is not limited only to these.

[Evaluation of physical properties]

(1) yield strength

Of the mechanical strength of the microneedle array, the yield strength was measured using a texture analyzer.

The resistance to compression of the microneedle array was repeatedly measured for three samples prepared in the same Example, and an average strength value was calculated.

<Strength measurement conditions>

Compression displacement: about 1 mm

Compression speed: 0.5 mm/sec

(2) breaking strength

After connecting to both ends of the base of the microneedle array, when tensile force was applied, the breaking strength of the central portion was measured according to the evaluation conditions specified below. Each result is an average value for three specimens prepared in each example.

<Breaking strength measurement conditions>

Measuring area: 3 cm x 5 cm

Tensile speed: 10 mm/min

(3) Skin insertion ability

The microneedle patch prepared in Example was attached to pig skin (0.8 to 1.2 mm) that had not been exfoliated. Remove the microneedle patch after 5 minutes. 0.4% Trypan blue reagent was applied to the pig skin surface for about 10 minutes. After 10 minutes, the remaining reagent was removed, and the number of stained pores on the skin surface was observed as shown in FIG. 2 .

(4) drug content

In order to analyze the content of ketoprofen in the microneedle patch, it was derivatized using a 9-fluorenylmethylchloromate reagent, and then measured using an HPLC device under the following analysis conditions.

<Analysis conditions - LC>

Column: 150 Х 4.6 mm, 3 μm particle size, L1 packing or equivalent column

Analysis Wavelength: 233nm

Flow Rate: 1.0ml/min

Mobile phase: 0.02M potassium dihydrogen phosphate solution (pH 3.5): acetonitrile = 57 : 43 (v/v)

(5) Content uniformity

It was performed according to the formulation uniformity test method in the 10th edition of the Korean Pharmacopoeia. At this time, if it exceeds 15%, it means that the content uniformity is low.

Test Example 1: Microneedle manufacturing and evaluation

(1) Manufacture of PDMS intaglio mold

The PDMS solution was mixed well to completely remove air bubbles, and then injected into a master mold made of Resin. After curing by drying at 80 ° C. for about 8 hours, it was taken out of the master mold and used.

(2) Preparation and casting of composition for microneedle

After adding the biodegradable polymer to water in the amount shown in Table 1 below, the drug is Ketoprofen, a non-steroidal analgesic (NSAID) After adding 30% by weight, a composition for microneedle with a concentration of 20% by weight was prepared (drug:biodegradable polymer = 1:2.33 weight ratio).

PVP: 24 kDa (50%), 40 kDa (20%)

PVA: 24 kDa (20%), 83 kDa (2%)

PVA-1: 83 kDa

PVP-1: 24 kDa

Hyaluronic acid: 340 kDa

Cellulose Gum (CMC): 90 kDa

About 350 ul of the prepared casting solution was precisely taken and dropped onto the microneedle structure mold. After inserting the mold in which the solution was dripped into a centrifuge, the pressure was reduced for about 3 hours or centrifugal force was applied for 15 minutes at a speed of 3500 rpm using a centrifuge so that the solution was injected into the intaglio pattern of the mold. The structure of the mold used at this time has 7x7 (49) needles in a unit area (1cm x 1cm), and was manufactured to have a square pyramid shape with a height of 1000μm and a base of 500μm.

(3) Microneedle array manufacturing

The mold into which the casting solution was injected was dried for about 12 hours at 40°C and ≤20% RH under temperature and humidity conditions, and then separated from the mold to fabricate a microneedle array.

(4) Manufacture of transdermal patches

A transdermal patch was prepared by attaching the prepared microneedle array to a polyurethane adhesive sheet.

weight% PVP PVA hyaluronic acid cellulose gum Example 1 63 7 - - Example 2 56 14 - - Example 3 49 21 - - Example 4 42 28 - - Example 5 35 35 - - Example 6 28 42 - - Example 7 21 49 - - Example 8 14 56 - - Example 9 7 63 - - Example 10 35 (PVP-1) 35 - - Example 11 35 35 (PVP-1) - - Example 12 35 (PVP-1) 35 (PVA-1) - - Comparative Example 1 70 - - - Comparative Example 2 - 70 - - Comparative Example 3 - - 70 - Comparative Example 4 - - - 70 Comparative Example 5 35 - 35 - Comparative Example 6 - 35 35 -

Test Example 2: Shape analysis

For shape analysis, the surface shape and microstructure of the microneedle array prepared in Example 5 were observed with an optical microscope (Olympus, SZX7) and an electron microscope (Hitachi. TM2000).

FIG. 3 is an optical microscope image of the microneedle array prepared in Example 5, showing (a) front and (b) cross-sectional images of the microneedle array. Referring to FIG. 3 , it can be seen that a substrate and a plurality of microneedles are formed.

4 is an electron microscope image of the microneedle array prepared in Example 5, showing (a) front and (b) cross-sectional images of the microneedle array. Referring to FIG. 4 , it can be seen that a substrate and a plurality of microneedles are formed.

Test Example 3: Measurement of microneedle array properties

After measuring the physical properties of the prepared microneedle array as follows, the results are shown in the table below.

Biodegradable polymer (PVP:PVA) Breaking strength (N) yield strength
(N/needle) skin insertion dissolution rate Example 1 1:0.1 8.9 4.5 90% 7 minutes Example 2 1:0.3 14.4 4.8 87% 8 minutes 20 seconds Example 3 1:0.4 32.1 4.6 90% 8 minutes 30 seconds Example 4 1:0.7 47.2 4.7 91% 9 minutes 10 seconds Example 5 1:1 62.1 4.3 95% 9 minutes 30 seconds Example 6 1:1.5 85.3 4.1 96% 13 minutes Example 7 1:2.3 94.1 4.4 97% 13 minutes 30 seconds Example 8 1:4 115.8 4.2 96% 14 minutes 30 seconds Example 9 1:9 120.7 3.6 93% 18 minutes 20 seconds Example 10 1:1 (PVP24kDa) 44.1 2.8 78% 9 minutes 10 seconds Example 11 1:1 (PVA83kDa) 90.1 3.1 85% 17 minutes Example 12 1:1 (PVP24kDa) (PVA83kDa) 49.2 2.5 82% 15 minutes Comparative Example 1 PVP 3.2 4.9 93% 5 minutes Comparative Example 2 PVA 130.1 3.1 90% 23 minutes Comparative Example 3 hyaluronic acid 70.2 8.2 92% 53 minutes Comparative Example 4 CMC 70.2 0.8 24% 11 minutes Comparative Example 5 1:1 (PVP: hyaluronic acid) 15.2 3.1 90% 32 minutes Comparative Example 6 1:1 (PVA: hyaluronic acid) 80.6 4.0 91% 40 minutes

Looking at the microneedle arrays of Examples 1 to 9 in the table above, when PVP:PVA was mixed at a ratio of 1:1 or more, the breaking strength was 50 N or more. When PVA and CMC of Comparative Examples 2 and 4 were used alone, high breaking strength was exhibited. However, when looking at their yield strengths, they showed low values of 3.1 and 0.8, respectively. In the case of hyaluronic acid of Comparative Example 3, the breaking strength was excellent, but it had a problem of dissolution rate described below.

In addition, it can be seen that 90% or more of the transdermal patches of Examples 1 to 9 of the present invention were inserted, and among them, 95% or more of the transdermal patches of Examples 5 to 8 were inserted. In addition, when looking at the dissolution rate, the transdermal patches of Examples 5 to 8 showed a dissolution rate of 9 to 15 minutes.

As in Comparative Examples 2 and 3, if the transdermal patch needs to be attached for more than 20 minutes, it may cause skin trouble.

Test Example 4: Microneedle manufacturing and evaluation

In order to compare the physical properties according to the content ratio of the drug for microneedle and the biodegradable polymer, it was performed as follows. At this time, the biodegradable polymer was a mixture of polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) presented in Example 5 in a ratio of 1: 1 and a final concentration of 20% by weight in a hydrophilic solvent was used.

In order to prepare a low absolute amount of drug for permeability evaluation, about 200 ul of the casting solution was precisely taken and prepared by dropping it on a microneedle structure mold. At this time, a 40mg patch having a solute concentration of 20% in 200ul was prepared and evaluated.

ingredient Comparative Example 7 Comparative Example 8 Example 13 Example 14 Example 15 Comparative Example 9 Comparative Example 10 Ketoprofen (mg) 0.0 2.0 4.0 10.0 12.0 16.0 20.0 Biodegradable Polymer (mg) 40.0 38.0 36.0 30.0 28.0 24.0 20.0 Drug: high molecular ratio - 1:19 1:9 1:3 1:2.3 1:1.5 1:1 Yield strength (N/needle) 4.3 4.0 3.8 3.7 3.6 1.1 0.8 skin insertion 95% 93% 95% 93% 91% 62% 24% Content (mg/patch) (n=3) - 2.1 (105%) 3.93 (98%) 10.1 (101%) 11.9 (99%) 15.7 (98%) 20.2 (101%) Content uniformity (pancheongchi) (n=10) - 18.3% 7.2% 6.8% 7.0% 8.1% 7.4%

Referring to the above table, in the case of the microneedle in which the drug was not loaded in Comparative Example 7, the yield strength was 4.3 N/needle. However, as in Comparative Example 9, when the ratio of the drug to the polymer is less than 1:2.3, the yield strength is reduced to 1.1 N/needle or less, and the skin insertion rate is less than 90% when evaluating the skin insertion ability. The performance results were confirmed.

In addition, as in Comparative Example 8, when the ratio of the biodegradable polymer to the drug is 1:9 or more, the drug is not evenly dispersed when preparing the casting solution, so that the content uniformity is 18.3%, which exceeds the general acceptance standard of 15% or less. It was confirmed that the ketoprofen content variation of the microneedle patch was large.

Through these results, it was confirmed that when the ratio of drug and biodegradable polymer is appropriate, it is possible to manufacture a microneedle patch with good skin insertion ability and small variation in the content of the loaded drug.

Test Example 2: Evaluation of transmittance (Franz diffusion test)

The skin permeability of the microneedle patch containing ketoprofen was evaluated using a Franz diffusion test apparatus, which is a permeability evaluation apparatus for percutaneously absorbable preparations.

Using the device shown in FIG. 5, a ketoprofen-containing microneedle is applied to the pig skin in a vertical direction with a force of about 20 N for 1 minute, and attached to the pig skin as shown in FIG. 6, and the microneedle penetrates into the pig skin After melting, the microneedle was removed. The pig skin in which ketoprofen was absorbed by the microneedle was put into a Franz diffusion cell, and the behavior of ketoprofen being released from the pig skin into the receptor solution over time was confirmed (n = 3).

At this time, 9 mL was sampled at a predetermined time in the receptor device containing about 10 mL of pH 7.4 PBS buffer, and 9 mL of receptor medium was supplemented again. The temperature of the receptor medium was maintained at 37°C using a water jacket. The sampled sample solution was subjected to pre-treatment for derivatization, and skin permeability per hour was evaluated using the same analysis equipment and conditions.

As Comparative Example 11, it was used as a formulation prepared in a solution state. At this time, as the biodegradable polymer, PVP and PVA were mixed at a weight ratio of 1:1 (see Example 5).

ingredient Comparative Example 11 Example 14 Ketoprofen (mg) 10.0 10.0 Biodegradable Polymer (mg) 30.0 30.0 Drug: high molecular ratio 1:3 1:3 formulation solution microneedle

7 is a dissolution image of the microneedle of Example 14 over time. As shown in FIG. 7, the shape of the microneedle was no longer observed 10 minutes after the microneedle patch was attached. 8 shows the dissolution rate of ketoprofen over time from the microneedle, and FIG. 9 is a graph comparing the cumulative ketoprofen permeation rate over time from the microneedle.

8 and 9, in the case of Comparative Example 11 of the liquid formulation, a low skin permeability of 2.1 ± 0.2% was shown after 24 hours. When comparing the cumulative permeability, it was confirmed that the skin permeability of ketoprofen increased about 20 times when prepared as a microneedle patch. That is, it can be seen that the microneedle of the present invention exhibits biodegradability and effectively permeates ketoprofen after being absorbed into the skin.

10: intaglio mold
20: composition for microneedle
21: microneedle array
P: home

Claims (16)

Including drugs and biodegradable polymers for microneedles,
Wherein the biodegradable polymer comprises polyvinylpyrrolidone: polyvinyl alcohol in a weight ratio of 1:0.1 to 1:10, microneedle composition. According to claim 1,
Wherein the polyvinylpyrrolidone and polyvinyl alcohol are mixed in a weight ratio of 1:1 to 1:4, microneedle composition. According to claim 1,
The polyvinylpyrrolidone has an average molecular weight of 20 to 50 kDa, the microneedle composition. According to claim 1,
The polyvinyl alcohol has an average molecular weight of 10 to 90 kDa, a composition for a microneedle. According to claim 1,
The microneedle drug: biodegradable polymer is included in a weight ratio of 1:2.3 to 1:9, a composition for a microneedle. According to claim 1,
The drug for the microneedle is an anti-inflammatory analgesic, an anti-arthritis agent, an antispasmodic, an antidepressant, an antipsychotic, a tranquilizer, an anti-anxiety, a narcotic antagonist, an anti-Parkinson's disease drug, a cholinergic agonist, an anticancer agent, an anti-angiogenesis inhibitor, an immunosuppressive agent, Antiviral, antibiotic, appetite suppressant, analgesic, anticholinergic, antihistamine, antimigraine, hormone, coronary, cerebrovascular, peripheral vasodilator, contraceptive, antithrombotic, diuretic, antihypertensive, cardiovascular disease treatment, anti-wrinkle , At least one of a skin aging inhibitor and a skin whitening agent, a composition for a microneedle. According to claim 6,
The anti-inflammatory analgesic is a non-steroidal antiinflammatory drug (NSAID), a composition for a microneedle. According to claim 7,
The nonsteroidal analgesics include ketoprofen, flubiprofen, acetylsalicylic acid, indomethacin, diclofenac, piroxicam, tenoxicam, ibuprofen, naproxen, nabumetone, ketorolac, azapropazone, mefenamic acid, Tolfenamic acid, sulindac, diflunisal, thiaprofenic acid, acemetacin, aceclofenac, droxicam, oxaprozin, floctafenin, phenylbutazone, proglumethacin, tolmetin, fenbufen, their pharmacology A composition for a microneedle, which is at least one member selected from the group consisting of generally acceptable salts, precursors thereof, and mixtures thereof. According to claim 1,
The microneedle composition is for preparing a soluble microneedle, a composition for a microneedle. a substrate in close contact with the skin;
In the soluble microneedle array comprising; a plurality of microneedles formed by forming a sharp peak at an end and arranged at regular intervals vertically and horizontally on one surface of the substrate,
A soluble microneedle array wherein the substrate and the plurality of microneedles are made of the composition for microneedles according to any one of claims 1 to 9. According to claim 10,
The microneedle array has a breaking strength of 50 N or more, a soluble microneedle array. According to claim 10,
The microneedle array has a yield strength of 3 to 5 N / needle, a soluble microneedle array. The soluble microneedle array according to claim 10; and an adhesive sheet to which at least one soluble microneedle array is attached. According to claim 13,
The transdermal patch has an insertion capacity per unit area in the skin of 90% or more, a microneedle transdermal patch. According to claim 13,
The transdermal patch has a microneedle drug content of 3.0 to 15.0 mg / patch, microneedle transdermal patch. According to claim 13,
The transdermal patch has a microneedle drug content uniformity of less than 15%, microneedle transdermal patch.

Images