Patent Description:
Transdermal drug delivery preparations are a dosage form by which drugs are administered through skin, which can avoid the interference of the gastrointestinal environment with the drug effect and the "first pass effect" of the liver, maintain a constant optimal plasma-drug concentration or physiological effect, prolong the effective acting time, and reduce the dosage frequency. The drugs can be administrated by patients on their own, and the patient compliance is good. However, the stratum corneum in the outer layer of the skin will hinder the absorption of drugs, and the drugs are not easy to penetrate into the body, resulting in very limited choices of drugs. In recent years, microneedle technology has received widespread attention. It is one of physical penetration enhancement methods using transdermal drug delivery, which can achieve painless and precise drug delivery.

Traditional microneedles made of metal, glass, and silicon materials will inevitably be broken and left in the skin during use due to the properties of their materials, causing damage to the human body. In recent years, the emerging polymer microneedles use materials including water-soluble polymer that can be absorbed by the skin, biocompatible polymer, and biodegradable polymer materials, greatly reducing the risk of use; furthermore, polymer microneedles are advantageous in low production cost, simple manufacturing process, mass production, and environmental friendliness, and microneedle manufacturing can achieve controlled release of drugs by selecting water-soluble polymer materials or biodegradable polymer materials having different physical and chemical properties. In recent years, many scientific researchers have devoted themselves to using polylactic acid-based degradable polymer materials to make polymer microneedles that are biocompatible, naturally degradable, and easy to prepare.

Chinese patent (<CIT>) discloses a polymer solid microneedle and a batched preparation method therefor. The material described in this invention is a biodegradable water-insoluble polymer material. The preparation method used is to place polymer material particles on a microneedle mold, heat the particles in a closed heating device until the particles melt, and use the preparation device to implement press molding of the melt while the melt is hot. However, the microneedle prepared in this patent cannot load drugs, and the microneedle only plays a role in pretreating the skin and destroying the skin stratum corneum barrier during use.

International patent (<CIT>) discloses a solid drug solution perforator containing drug particles and/or drug-adsorbed or loaded particles with an associated drug reservoir (SSPP system). In order to deliver drugs, the SSPP system comprises an active drug ingredient in a particulate form or a drug adsorbed on a particle surface in a matrix material that dissolves upon contact with a patient's body. The inert particles are poly(lactic-co-glycolic acid) (PLGA) or aluminum hydroxide and aluminum phosphate. The microneedle made by this method can be loaded with protein and vaccine drugs. However, in this method, the drug barely has a sustained-release effect since it is adsorbed on the PLGA inert particles.

Literature <NUM> (<NPL>. ) proposes a method for preparing a microneedle by using poly(lactic-co-glycolic acid) (PLGA) as a material of a microneedle support. The method achieves controlled release of drugs by loading into the microneedle the drugs or microspheres of polylactic acid or sodium carboxymethyl cellulose loaded with the drugs. However, in this method, since the matrix material of the body of the microneedle is PLGA, the user needs to apply it for a long time until the material PLGA of the support is completely degraded.

Literature <NUM> (<NPL>) proposes a method for preparing a porous multi-layered biodegradable microneedle by using PLA, PGA or PLGA microspheres. The method is to prepare a porous or multi-layered microneedle by injecting microspheres made of a biodegradable polymer material into a mold, and using extrusion and ultrasonic welding or thermal welding technology. In the microneedle manufacturing, the microspheres need to be prepared by spray drying technology or by emulsification at first, and thus the process is complicated. Compared with a single microneedle, the porous multi-layered microneedle is weaker and easier to break, and is difficult to be effectively demolded from the mold. <CIT> discloses an implantable sustained-release microneedle, comprising a needle tip, a needle body, and a base; the needle tip comprising a needle tip center layer and a needle tip outer layer; the needle tip center layer being formed of a matrix comprising a biodegradable water-insoluble polymer material; and the needle tip outer layer in form of an adhesive, the needle body and the base being formed of a matrix comprising a water-soluble polymer material. <CIT> discloses the use of water-soluble polymer material in such microneedle (example <NUM> chondroitin sulfate C).

In summary, from the current point of view, taking polylactic acid microneedles as an example, the manufacturing of microneedles can be divided into two categories: one is to first make polylactic acid-based biodegradable polymer materials and drugs into microspheres, then add them into a microneedle mold, and then heat, melt, and cool them to form a microneedle with a certain mechanical strength, such microneedle can be loaded with drugs, but it needs to make microspheres at first to form the microneedle, the operation is cumbersome and the cost is high; the other is to directly add polylactic acid powder into a microneedle mold, and then heat, melt (above <NUM>) and then cool them to form a microneedle, but this manufacturing method is difficult to load drugs.

Therefore, there is a need to provide a polylactic acid-based implantable sustained-release microneedle which is simple in process and high in safety, and does not need long-term application.

A first objective of the present invention is to provide an implantable sustained-release microneedle, which has sufficient mechanical strength and can implant a polylactic acid-based needle tip into the skin, realizing purposes of convenience, safety, biodegradability, and efficient administration.

The second objective of the present invention is to provide a preparation method for the above-mentioned implantable sustained-release microneedle, which has simple process and low cost.

The third objective of the present invention is to provide a microneedle patch comprising the above-mentioned implantable sustained-release microneedle.

To achieve the above objectives, the present invention adopts the following technical solutions:
The present invention provides an implantable sustained-release microneedle, comprising a needle tip, a needle body, and a base; the needle tip comprises a needle tip center layer and a needle tip outer layer; the needle tip center layer is formed of a matrix comprising a biodegradable water-insoluble polymer material; and the needle tip outer layer, the needle body, and the base are formed of a matrix comprising a water-soluble polymer material.

Further, the biodegradable water-insoluble polymer material includes, but is not limited to, one or more of polylactic acid, poly-L-lactide, poly-DL-lactide, poly(lactic-co-glycolic acid), polyglycolic acid, and polycaprolactone.

In the present invention, the water-soluble polymer material of the needle tip outer layer of the microneedle is connected with the water-soluble polymer material of the needle body of the microneedle, which can enhance the mechanical strength of the microneedle and improve the success rate of the microneedle puncturing the skin. Without the wrapping by the outer layer of the microneedle, since the biodegradable material of the center layer of the microneedle has weak hydrophilicity, and the strength of connection with the water-soluble polymer matrix material of the needle body is low, the microneedle will easily break at the time of puncturing, the success rate of the needle tip entering the skin is relatively low, and the quality of the microneedle puncturing the skin is uncontrollable.

Further, the needle tip center layer comprises at least one active ingredient; preferably, a mass ratio of the biodegradable water-insoluble polymer material to the active ingredient is <NUM>:<NUM>-<NUM>:<NUM>, so as to ensure the mechanical strength and skin penetration of the microneedle.

In a preferred embodiment of the present invention, the needle tip center layer further comprises a pore-forming agent. The pore-forming agent helps intradermal water molecules enter the interior of the matrix of the needle tip center layer, so as to regulate the drug release rate. The pore-forming agent includes, but is not limited to, one or more of sodium chloride, sodium carbonate, sodium bicarbonate, ammonium bicarbonate, trehalose, maltose, polyethyleneglycol, cyclodextrin and its derivatives, polyvinylpyrrolidone (PVP), a low-molecular weight hyaluronic acid and its sodium salt (with a molecular weight of <NUM>-<NUM> kDa), and low-molecular weight cellulose derivatives (with a molecular weight of <NUM>-<NUM> kDa).

Preferably, the pore-forming agent accounts for <NUM>%-<NUM>% of the total mass of the needle tip center layer.

In a preferred embodiment of the present invention, the needle tip center layer further comprises a protective agent. The protective agent includes, but is not limited to, one or more of polyhydroxy compounds (mannitol, sorbitol, xylitol, polyethyleneglycol, etc.), carbohydrate compounds (trehalose, dextrin, lactose, sucrose, maltose, etc.), serum albumin, polyvinylpyrrolidone, chondroitin sulfate, amino acids (proline, tryptophan, glutamic acid, glycine, etc.).

Preferably, the protective agent accounts for <NUM>%-<NUM>% of the total mass of the needle tip center layer.

Further, the water-soluble polymer material includes, but is not limited to, one or more of carboxymethyl cellulose, hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose, polyvinyl alcohol and its derivatives, polyvinylpyrrolidone (PVP) and its derivatives, sodium hyaluronate and its derivatives, chondroitin sulfate, chitosan derivatives, polyacrylamide derivatives, polyglutamic acid, polydopamine, pullulan, gelatin, collagen, plant protein, and silk protein.

Preferably, the molecular weight of the water-soluble polymer material is <NUM>-<NUM> kDa.

Preferably, the needle tip outer layer, the needle body, and the base further comprise low-molecular weight carbohydrates and polyol compounds (specifically, one or more of trehalose, sucrose, maltose, sorbitol, mannitol, xylitol, and glycerol, etc.), so as to accelerate a dissolution rate of the water-soluble polymer material.

Preferably, the needle tip outer layer, the needle body, and the base are the same type of water-soluble polymer material.

Further, the needle tip has a conical shape or a polygonal conical shape, preferably, the needle tip has a conical shape; the density of the needle tip of the microneedle is: <NUM>-<NUM> needle bodies and needle tips per square centimeter of the base; the height of the needle tip and the needle body is <NUM>-<NUM>; the angle of the needle tip is <NUM>-<NUM>°; and the thickness of the base is <NUM>-<NUM>. The height of the needle tip center layer is not greater than two-thirds of the height of the needle tip and the needle body.

The present invention further provides a preparation method for the above-mentioned implantable sustained-release microneedle, comprising the following steps:.

Further, the organic solvent includes, but is not limited to, acetone, ethylacetate, chloroform, dichloro or N-methylpyrrolidone; preferably, the organic solvent is N-methylpyrrolidone.

Further, the mass concentration of the biodegradable water-insoluble polymer material in the needle tip center layer injection molding liquid is <NUM>-<NUM>%; the mass concentration of the water-soluble polymer material in the needle tip outer layer injection molding liquid is <NUM>-<NUM>%; the mass concentration of the water-soluble polymer material in the needle body and base injection molding liquid is <NUM>-<NUM>%; and the mass ratio of the biodegradable water-insoluble polymer material to the active ingredient is <NUM>:<NUM>-<NUM>:<NUM>.

Further, in said step <NUM>), the needle tip center layer injection molding liquid, the needle tip outer layer injection molding liquid, or the needle body and base injection molding liquid are added to the microneedle mold by means of a pressurization method or a vacuum method, so as to avoid the formation of air bubbles in the needle during manufacturing. If the pressurization method is adopted, then the applied pressure is <NUM>-<NUM> MPa, and the pressurization time is <NUM>-<NUM>. If the vacuum method is adopted, then the vacuum degree is <NUM>-<NUM> MPa, and the vacuuming time is <NUM>-<NUM>.

Preferably, the drying time after the needle tip outer layer injection molding liquid is injected into the microneedle mold is <NUM>-<NUM>.

Preferably, the heating temperature after the needle tip center layer injection molding liquid is injected into the microneedle mold is <NUM>-<NUM>, and the heating time is <NUM>-<NUM>, so as to volatilize the organic solvent and ensure that the microneedle has sufficient mechanical strength and skin puncturing ability after cooling.

Preferably, the drying condition after the needle body and base injection molding liquid is injected into the microneedle mold is drying for <NUM>-<NUM> hours under <NUM>-<NUM> and <NUM>-<NUM>% humidity.

The present invention further provides an implantable sustained-release microneedle patch comprising the above-mentioned implantable sustained-release microneedle and a backing; preferably, the backing is a pressure-sensitive adhesive backing or a silicone backing or a hydrocolloid backing.

The preparation method for the above-mentioned implantable sustained-release microneedle patch is to, based on preparing the implantable sustained-release microneedle, further paste the backing on the backside of the dried base and then demould to obtain the implantable sustained-release microneedle patch.

The implantable sustained-release microneedle patch described in the present invention can be applied in fields of disease treatment and prevention, health care, and cosmetology.

The term "active ingredient" refers to a substance used for diagnosis, treatment, prevention, cosmetic or health care purposes that is delivered through the microneedle or the microneedle patch of the present invention in a transdermal manner and has the efficacy of acting on animals or humans. According to the present invention, the active ingredient includes, but is not limited to, pharmaceutical active ingredients, vaccine active ingredients, cosmetic active ingredients, health care product active ingredients, etc., which are specifically selected according to actual needs.

In the microneedle or the microneedle patch of the present invention, a biodegradable water-insoluble polymer material is used to make the needle tip center layer of the microneedle, and a water-soluble polymer material is used to make the needle body, the base, and the needle tip outer layer, so as to form a microneedle having a needle tip center layer insoluble in water. After acting on the skin, the water-soluble material of the needle tip outer layer and the needle body absorbs the moisture within the skin, so that the needle body and the base are quickly separated from the needle tip within <NUM>-<NUM>; and after the base of the patch is removed, the needle tip of the microneedle will be completely left in skin, and thus weeks of long-term in vivo release of a drug can be ensured without a user sticking the microneedle patch for a long time. Such microneedle patches are not limited by the manufacturing area, and the drug load can be greatly increased by extending the area, which is suitable for long-term intradermal release of various drugs. In addition, the preparation process for the microneedle or the microneedle patch of the present invention avoids the cumbersome process such as encapsulating the drug in the microsphere liposome, but uses a low-toxic organic solvent such as N-methylpyrrolidone to dissolve biodegradable polylactic acid-based polymer materials, the process cost is reduced, and the process is similar to conventional manufacturing methods for a dissolvable microneedle or a microneedle patch, the operation is simple and fast, high temperature melting is not required, and the applicable drug range is wide.

The specific embodiments of the present invention will be described in further details below with reference to the accompanying drawings.

In order to explain the present invention more clearly, the present invention will be further described below in conjunction with preferred examples and accompanying drawings. Similar components in the accompanying drawings are denoted by the same reference numerals. Those skilled in the art should understand that the content described in detail below is illustrative rather than restrictive, and should not limit the protection scope of the present invention.

In this example, etonogestrel can be replaced by other active ingredients of small molecular compounds having thermal stability at <NUM>, which include, but are not limited to ethinyl estradiol, levonorgestrel, norgestrel, gestodene, desogonolone, desogestrel, artemisinin derivatives, paclitaxel derivatives and other active ingredients, and the obtained microneedle patch has a similar sustained-release effect.

The polyvinyl alcohol in the needle tip outer layer injection molding liquid and the needle body and base injection molding liquid of the this example can be replaced by carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol derivatives, polyvinylpyrrolidone and its derivatives, sodium hyaluronate and its derivatives, chondroitin sulfate, chitosan derivatives, polyacrylamide derivatives, polyglutamic acid, polydopamine, pullulan, gelatin, collagen, and silk protein, and the obtained microneedle patch has a similar sustained-release effect.

In the needle tip center layer injection molding liquid of this example, a pore-forming agent such as <NUM>-<NUM>% sodium chloride, <NUM>-<NUM>% sodium carbonate, <NUM>-<NUM>% sodium bicarbonate, <NUM>-<NUM>% ammonium bicarbonate, <NUM>-<NUM>% trehalose, <NUM>-<NUM>% maltose, <NUM>-<NUM>% cyclodextrin and its derivatives, <NUM>-<NUM>% polyvinylpyrrolidone, <NUM>-<NUM>% sodium hyaluronate, and <NUM>-<NUM>% carboxymethyl cellulose can be further added, and the obtained microneedle patch can be sustained-released for <NUM>-<NUM> days.

The prepared microneedle patch is as shown in <FIG>. Photographs taken by a stereo microscope are as shown in <FIG>. There are <NUM> needles in per square centimeter of the microneedle patch, and the height of the needle tip and the needle body is <NUM>.

If the microneedle is applied to pigskin and peeled off from the base within <NUM> minutes, it can be sustained-released for one month.

In this example, the red fluorescent dye can be replaced by other active ingredients of small molecular compounds with a heat resistance of <NUM>, and the obtained microneedle patch has a similar sustained-release effect.

The prepared microneedle patch is as shown in <FIG>. There are <NUM> needles in per square centimeter of the microneedle patch, and the height of the needle tip and the needle body is <NUM>.

If the microneedle patch is applied to pigskin, the base can be completely peeled off within <NUM> hour, and the microneedle patch can be sustained-released for <NUM> weeks according to in vitro transdermal results.

In this example, the interferon a-2b can be replaced by other types of interferons, and can also be replaced by other proteins and polypeptides or hydrophilic small molecules, such as insulin, growth hormones, cytokines, nerve growth factors, amino acids, etc. The obtained needle patch has a similar sustained-release effect.

The carboxymethyl cellulose in the needle tip outer layer injection molding liquid and the polyvinyl alcohol in the needle body and base injection molding liquid of the this example can be replaced by carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol derivatives, polyvinylpyrrolidone and its derivatives, sodium hyaluronate and its derivatives, chondroitin sulfate, chitosan derivatives, polyacrylamide derivatives, polyglutamic acid, polydopamine, pullulan, gelatin, collagen, and silk protein, and the obtained microneedle patch has a similar sustained-release effect.

In the needle tip center layer injection molding liquid of this example, a pore-forming agent such as <NUM>-<NUM>% sodium chloride, <NUM>-<NUM>% sodium carbonate, <NUM>-<NUM>% sodium bicarbonate, <NUM>-<NUM>% ammonium bicarbonate, <NUM>-<NUM>% trehalose, <NUM>-<NUM>% maltose, <NUM>-<NUM>% cyclodextrin and its derivatives, <NUM>-<NUM>% polyvinylpyrrolidone, <NUM>-<NUM>% sodium hyaluronate, and <NUM>-<NUM>% carboxymethyl cellulose can be added, and the sustained-release time of the obtained microneedle patch ranges between <NUM>-<NUM> days.

A protective agent can be added to the needle tip center layer injection molding liquid of this example, such as one or more of <NUM>-<NUM>% polyhydroxy compounds (such as <NUM>% glycerin, <NUM>% butylene glycol, <NUM>-<NUM>% xylitol, <NUM>-<NUM>% mannitol), <NUM>-<NUM>% carbohydrate compounds (<NUM>-<NUM>% trehalose, <NUM>-<NUM>% sucrose), <NUM>-<NUM>% serum albumin, <NUM>-<NUM>% polyvinylpyrrolidone, and <NUM>-<NUM>% amino acids, and the sustained-release time of the obtained microneedle patch ranges between <NUM>-<NUM> days.

In the carboxymethyl cellulose in the needle tip outer layer injection molding liquid and the needle body and base injection molding liquid of this example, low-molecular weight carbohydrates and polyol compounds, specifically <NUM>-<NUM>% trehalose , <NUM>-<NUM>% sucrose, <NUM>-<NUM>% sorbitol, <NUM>-<NUM>% mannitol, <NUM>-<NUM>% xylitol, <NUM>-<NUM>% glycerol or the like can further be added to accelerate a dissolution rate of the water-soluble polymer materials, and the sustained-release effect of the obtained microneedle patch is similar to this example.

If the microneedle patch is applied to pigskin, it can be separated from the needle tip after <NUM> minutes, and the sustained-release time of the drug is respectively <NUM> days, <NUM> days, and <NUM> days, according to in vitro transdermal results. As the content of PLGA increases, the sustained-release time extends.

In this example, granisetron hydrochloride can also be replaced by leuprolide acetate, octreotide acetate, amlodipine besylate/ketoprofen, cyclosporine, diclofenac sodium controlled release, everolimus, methylphenidate, clarithromycin, mycophenolic acid, griseofulvin, mabilone, tacrolimus and other drugs, and the obtained microneedle patch has a similar sustained-release effect.

If the microneedle patch is applied to pigskin, the base can be completely peeled off within <NUM> minutes, and the microneedle patch can be sustained-released for <NUM> weeks.

Polylactic acid-based sustained-release microneedle patches comprising a pore-forming agent were prepared respectively according to the preparation method of Example <NUM>. The specific formulations are shown in Table <NUM>.

The preparation methods of Examples <NUM>-<NUM> are as shown in Example <NUM>, and the specific parameters of each component in Examples <NUM>-<NUM> are shown in Table <NUM>.

Examples <NUM>-<NUM> are also applicable to the preparation of other microneedle patches for macromolecular drugs or vaccines.

If the microneedle patch is applied to pigskin, the base can be completely peeled off within <NUM> minutes, and the microneedle patch can be sustained-released for <NUM> days.

The preparation methods of Examples <NUM>-<NUM> are as shown in Example <NUM>, and the specific parameters of each component are shown in Table <NUM>.

The microneedle patch prepared in Examples <NUM>-<NUM> (except Example <NUM>) was applied to fresh pigskin, pressed with fingers for <NUM>, and dyed with <NUM>% concentration of trypan blue for <NUM>, the excess trypan blue was wiped off with a cotton swab, and then whether there were pinholes on the skin was observed. As shown in <FIG> (taking Example <NUM> as an example), a photograph of trypan blue-dyed pigskin is shown. Microneedle pinholes can be clearly seen. The effects of other examples are the same as those in Example <NUM>.

The microneedle patch prepared in Examples <NUM>-<NUM> (except Example <NUM>) was applied to fresh pigskin, pressed with fingers for <NUM>, and the microneedle patch was kept on the skin for <NUM> hour, then an intradermal implantation situation of the needle tip was observed under a fluorescence microscope. <FIG> (taking Example <NUM> as an example) shows a photograph of the needle tip of the microneedle implanted in the skin under a fluorescence microscope. Array implantation of the fluorescent dye can be clearly seen. The effects of the microneedle patch in other examples are the same as those in Example <NUM>.

Claim 1:
An implantable sustained-release microneedle, comprising a needle tip, a needle body, and a base; the needle tip comprising a needle tip center layer and a needle tip outer layer; the needle tip center layer being formed of a matrix comprising a biodegradable water-insoluble polymer material; and the needle tip outer layer, the needle body, and the base being formed of a matrix comprising a water-soluble polymer material, wherein the water-soluble polymer material of the needle tip outer layer is connected with the water-soluble polymer material of the needle body.