CN115887419A - Drug-loaded microneedle patch and application thereof - Google Patents

Abstract

The invention provides a drug-carrying microneedle patch and application thereof, wherein the drug-carrying microneedle patch consists of a plurality of needle bodies and a back lining, the needle bodies are arranged in the back lining in an array manner, the needle bodies are prepared from a matrix solution through a film forming process, and the matrix solution contains drugs. The invention is based on local administration of the microneedle technology, can greatly reduce the administration amount and reduce the cost; local administration also reduces systemic exposure of the drug, greatly reducing immune-related adverse reactions. Compared with the traditional process, the preparation method of the soluble microneedle patch based on the freeze drying technology is quicker in preparation and has lower time cost; the product has low water content, and is very helpful for preserving the activity of the medicine; and the microneedle based on the freeze-drying technology has a faster dissolved drug release speed in the skin. The freeze drying degree of automation is higher, can carry out aseptic technique, is suitable for being used for industrial production.

Description

Drug-loaded microneedle patch and application thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and relates to a drug-loaded microneedle patch and application thereof.

Background

Psoriasis is commonly called as psoriasis, is a chronic inflammatory skin disease, has long course of disease and easy recurrence tendency, and some cases are not cured almost for the whole life. The disease is mainly developed in young and old years, and has great influence on the physical health and mental conditions of patients. The clinical manifestations mainly include erythema and scales, the disease can occur in the whole body, the symptoms are common on the scalp and the four limbs, and the symptoms aggravate in winter.

Atopic Dermatitis (AD), also known as atopic dermatitis and atopic dermatitis, is a chronic, recurrent, inflammatory skin disease characterized clinically by dry skin, severe itching and eczematoid skin rash, which often begins to develop from infancy. The etiology is not clear at present. The pruritus is often recurrent and severe at night, which can affect sleep, and serious people affect daily life, work and study.

Currently, the specific drugs with the best clinical effect on psoriasis and atopic dermatitis are monoclonal antibodies and tyrosine kinase inhibitors aiming at targets such as TNF-alpha, IL-17, IL-4, IL-6, IL-13, IL-12/23, IL-31, IFN-gamma, JAK and the like. However, in the clinical application process, these specific drugs have problems of high cost and unit price, high cancer and infection risk caused by systemic immunosuppression, and the like.

The pathological effects of psoriasis and atopic dermatitis mainly occur in local skin, and only a very small proportion of the medicine circulates to the focus part through a systemic administration mode (intravenous injection, subcutaneous injection, intramuscular injection, oral administration and the like), so that a large amount of medicine is wasted, and the high concentration of the medicine at other parts in the body is easy to generate adverse reactions, such as extremely common adverse reaction respiratory tract infection of adalimumab and common adverse reaction systemic infection; and adalimumab often causes some skin cancers and benign tumors, occasional lymphomas and solid tumors (breast, lung, thyroid); wu Sinu monoclonal antibody can cause dizziness, headache, oropharyngeal pain, diarrhea, nausea, pruritus, muscle pain, hypersensitivity, pain and pruritus at injection position and the like besides causing infection; systemic administration of securituximab causes common problems of diarrhea, watery nasal discharge, upper respiratory tract infection and the like. Thus, a high systemic clinical exposure of immunosuppressive drugs can lead to a risk of systemic adverse events.

CN115089862A discloses a hydrogel microneedle patch based on a three-dimensional skeleton structure, a preparation method and an application thereof, wherein the microneedle patch comprises microneedles; the raw materials of the microneedle comprise polyvinyl alcohol and an acrylic resin aqueous dispersion; and uniformly blending the acrylic resin aqueous dispersion with polyvinyl alcohol, and forming to obtain the microneedle. The hydrogel microneedle patch has good strength, and has excellent swelling performance and puncture performance.

CN110917176A discloses an implantable sustained release microneedle patch and a preparation method thereof. The invention firstly discloses an implantable slow-release micro-needle, which comprises a needle point, a needle body and a substrate; the needle tip comprises a needle tip central layer and a needle tip outer layer; the needle tip central layer is formed by a biodegradable water-insoluble high polymer material matrix; the needle tip outer layer, the needle body and the base are formed by a matrix containing a water-soluble high polymer material. The microneedle or microneedle patch is characterized in that a microneedle central layer is made of a high polymer material, a substrate, a needle body and a microneedle outer layer are made of a water-soluble high polymer material to form the microneedle or microneedle patch, wherein the microneedle or microneedle patch is insoluble in water in the microneedle central layer, and after the microneedle or microneedle patch acts on skin, the water of the skin is absorbed, so that the substrate, the needle body and the microneedle are quickly separated within 0.5-2h, the microneedle can be remained in the skin after the substrate is removed, and a user can ensure that a medicament is released in vivo for a long time without applying for a long time.

Therefore, how to develop a microneedle preparation for treating psoriasis and atopic dermatitis based on the existing method has important value for practical application.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a drug-loaded microneedle patch and application thereof, which solve the problems of high cost and unit price of the existing preparation for treating psoriasis and atopic dermatitis and high cancer and infection risk caused by systemic immunosuppression.

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect, the invention provides a drug-loaded microneedle patch, which comprises a plurality of needle bodies and a backing, wherein the needle bodies are arranged in an array, the needle bodies are fixed on the backing, the needle bodies are prepared from a matrix solution through a film forming process, and the matrix solution contains drugs.

The drugs contained in the matrix solution of the present invention include, but are not limited to, the following drugs: adalimumab, etanercept, infliximab, alfacalcizumab, golimumab, certolizumab, stekuchi You Shankang, wu Sinu mab, guceqi You Shankang, eculizumab, tosubuzumab, ezoft 4232 mab, recombinant human II type tumor necrosis factor receptor-antibody fusion protein for injection (sanshengke), anti-IL-17A humanized monoclonal antibody (sanshengke), SSGJ-608 (sanshengke), recombinant human IL-17A/F humanized monoclonal antibody injection (lizumab), LZM012 (lizumab), bai Dalu mab/broglie You Shankang (Brodalumab), telbizumab (tildaruzumab); tiltrazuimab) Rissalizumab (Risankizumab), tibilizumab (Tibulizumab), doripuzumab, interferon gamma-1 b (activine), suplatast (Sulatast Tosylate), pimecrolimus (Pimecrolimus), CM310 (Kang Nuoya), AZD-1402 (Asricon), PRS-060 (Asricon), CBP-201 (Kang Naide), AK120 (Zhongshan 79 zxft 3579), 611 item (Sanshengkin), MG-K10 (Maijie), QX-005N (Jiangsuxing), SHR-1819 (Henry medicine), LQ036 (Luoqiong organism), ASP-004 (Medtion), MDNA413 (Thernnapedituzumab), MDNA132 (Thernperamican), 3525 (Thermozumab), and Medflex group (Medflex) Ela Sha Jishan anti (ebolasakimab), nei Mo Lizhu mab (Nemolizumab), ALX-0761 (Ablynx corporation/Merchano), GR-1501 (Chongqingzhixiang), JNJ-63823539 (Johnson/Yansen), RO-7040547 (Genta/Roche), vedodememus (Vidofludumus, 4SC AG company), AK101 (Zhongshan Kang Fang), AK111 (Zhongshan Kang Fang), JS005 (Junzhen organism), COVA-322 (Covagen company), UCB-0159 (Youta), fu Naji Betulab (Vunakizumab), SHR-1314 (Jiangsu Henrei), ABY-035 (Aflubody company), SCH-900117 (Moshadong), CJM-002 (Nowa), QX-004N (Jiangsuquanjin), QX-N (Jiangsuquanjin), IBI-112 (Nedanbio), HOT-3010 (Huaao/Huahai pharmaceutical industry) HB0017 (Huaotai/Huahai pharmacy), HB0034 (Huaotai/Huahai pharmacy), tofacitinib (Tofacitinib), phenanthrene Zhuo Tini (fedratinib), non-gonitinib (filgonitinib), abuxitinib (abrocitinib), piricitinib (Pefiticitinib), digatinib (Delgotinib), ricotinib (Ruxolitinib), wu Pati (Uptacetinib), baricitinib (baritinib), pacritinib (pacitinib), jactinib, roflumilast (roflumilast), krilvasil, kriginburtinib (roflumilast), apremilast, ori Mi Site (orismilast), geo Mi Site (Difamilast) or HPP737 (Hexagon), and any one or more of the quasi-drugs and biological analogs of these drugs.

The drug of the present invention may be the above-mentioned drug, or a product such as a pharmaceutical imitation, a biological analogue or the like of the above-mentioned drug, and is not limited to the above-mentioned specific drug.

The invention uses the micro-needle to load specific drugs to locally treat psoriasis and atopic dermatitis so as to achieve the effects of reducing the systemic exposure of the drugs and reducing the side effects related to immunosuppression. The micro-needle is an array with a plurality of needle points with the length of 50-1500 mu m, is a novel transdermal drug delivery mode, and has the advantages of painless minimally invasive, self-drug delivery, high patient compliance and no generation of sharp wastes. Can reduce the cost of psoriasis and atopic dermatitis treatment, and reduce the systemic exposure of specific drugs in the psoriasis and atopic dermatitis treatment to reduce the side effects related to immunosuppression.

Preferably, the height of the needle body is 50 to 1500 μm, for example, 50 μm, 100 μm, 200 μm, 400 μm, 700 μm, 1000 μm, 1200 μm, 1500 μm, or the like. More preferably 200 to 1400 μm.

Preferably, the needle body has a tip pitch of 50 to 1500 μm, for example, 50 μm, 100 μm, 200 μm, 400 μm, 700 μm, 1000 μm, 1200 μm, 1500 μm, or the like. More preferably 400 to 1000. Mu.m.

Preferably, the needle body has a shape of a quadrangular pyramid, a cone, a tower, or an irregular shape.

Preferably, the matrix solution contains a needle-preparing material, which includes any one of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hyaluronic Acid (HA), sodium hyaluronate, sucrose, carbomer, polyvinyl acid, polyethylene oxide, polyacrylic acid, polyacrylamide, poly (methyl vinyl ether/maleic acid) half-ester copolymer, polyethylene glycol, pullulan, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, or carboxymethyl cellulose, or a combination of at least two thereof.

Preferably, the mass percentage of the raw material in the matrix solution is 5% to 60%, and may be, for example, 5%, 10%, 20%, 30%, 40%, 50%, 60%, or the like.

Preferably, the matrix solution further comprises a drug protecting agent, wherein the drug protecting agent comprises any one or a combination of at least two of glucose, sucrose, lactose, trehalose, alpha-mannopyranose, cellobiose, mannose, maltose, inositol, raffinose, inulin, dextrose, maltodextrin, maltopolysaccharide, sucrose octasulfate, dextran, heparin, 2-hydroxypropyl-propylcyclodextrin, albumin, collagen, proline, tryptophan, glutamic acid, sodium glutamate, alanine, glycine, lysine hydrochloride, sarcosine, L-tyrosine, phenylalanine, arginine, polyvinylpyrrolidone, mannitol, gelatin, tween 80, pluronic, brij, sodium dodecylsulfonate, ascorbic acid, ethylene glycol, phosphate, acetate, citrate, 2-hydroxypropyl-propylcyclodextrin, collagen, polyethylene glycol, gelatin and polyethyleneimine.

Preferably, the drug protector comprises: 2-hydroxypropyl-propylene cyclodextrin, collagen, polyethylene glycol (PEG), gelatin, polyethyleneimine, and other protective agents.

In the present invention, the drug protecting agent has a function of enhancing the mechanical strength of the microneedle. The drug protecting agent in the above preferable range has a better effect of enhancing the mechanical strength of the microneedle.

Preferably, the mass percentage of the protective agent in the matrix solution is 0.1% to 30%, and may be, for example, 1%, 5%, 10%, 15%, 20%, 30%, or the like.

Preferably, the film forming process is: and injecting the matrix solution into a microneedle mould, and drying to obtain the needle body.

Preferably, the drying is natural drying or freeze drying.

In the present invention, the natural drying is generally performed by injecting the matrix solution into a microneedle mold and then drying the microneedle mold in a ventilated place for about 6 hours. The freeze-drying is generally to inject the matrix solution into a microneedle mould and then freeze the microneedle mould at-196 ℃ to 0 ℃.

Preferably, the backing is prepared by film forming from a solution of a backing material.

Preferably, the backing material comprises any one of or a combination of at least two of polyvinylpyrrolidone, polyvinyl alcohol, hyaluronic acid, sucrose, carbomer, polyvinyl acid, polyethylene oxide, polyacrylic acid, polyacrylamide, poly (methyl vinyl ether/maleic acid) half ester copolymer, polyethylene glycol, pullulan, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, or carboxymethyl cellulose.

Preferably, the mass percentage of the backing material in the solution of the backing material is 5% to 60%, for example, 5%, 10%, 20%, 30%, 40%, 50%, 60%, etc.

Preferably, the film forming process is: and injecting the solution of the backing material into a backing mould, and drying to obtain the backing.

Preferably, the drying of the solution of backing material in the backing mould is natural drying or freeze drying.

In the present invention, the solution drying process of the backing material corresponds to the needle drying process. If the matrix solution of the needle body is naturally dried, the solution drying process of the backing material is generally naturally dried; if the matrix solution of the needle body is freeze-dried, the solution drying process of the backing material is generally freeze-dried.

Preferably, the backing has a thickness of 0.5 to 5mm, and may be, for example, 0.5mm, 1mm, 2mm, 3mm, 4mm, or 5mm, etc.

Preferably, the method of injecting the matrix solution into the microneedle mold is any one of a vacuum method, a centrifugal method, or a spray method.

Preferably, the method for injecting the solution of the backing material into the backing mold is any one of a vacuum method, a centrifugal method or a spraying method.

The drug-loaded microneedle patch has the specific administration mode that a drug-loaded microneedle is placed at an affected part, the back lining is pressed to enable the needle point to penetrate into the skin, and the back lining is taken down after the back lining is maintained for a period of time, so that the administration process is completed.

In a second aspect, the invention provides the use of a drug-loaded microneedle patch in the manufacture of a pharmaceutical formulation for the treatment of psoriasis and atopic dermatitis.

Compared with the prior art, the invention has the beneficial effects that:

the invention is based on local administration of the microneedle technology, can greatly reduce the administration amount and reduce the cost; local administration also reduces systemic exposure of the drug, greatly reducing immune-related adverse reactions. Compared with the traditional process, the preparation method of the soluble microneedle patch based on the freeze drying technology is quicker in preparation and has lower time cost; the protective agent is added, so that the structure of the protein polypeptide can be maintained, and the activity of the medicament can be greatly preserved; the cross-linking or compounding effect of the drug protective agent and the needle body raw material enables the mechanical strength of the microneedle to be remarkably improved and the skin penetrating performance to be more excellent; the product has low water content, and is helpful for maintaining the stability of the medicine; and the microneedle based on the freeze-drying technology has a faster dissolution and release speed in the skin. The freeze drying has high automation degree, can perform aseptic operation, and is suitable for industrial production.

Drawings

Fig. 1 is a schematic view of a drug-loaded microneedle patch provided in example 1 of the present invention.

Fig. 2 is a schematic illustration of skin penetration of a drug-loaded microneedle patch provided in example 1 of the present invention.

Fig. 3 is a drug-loaded microneedle patch film and a drug delivery plan provided in example 1 of the present invention.

Figure 4 is a mouse PASI score following administration of a drug-loaded microneedle patch as provided in example 1 of the present invention.

Figure 5 is a graph of psoriasis in mice.

Fig. 6 shows the results of the skin penetration rate and the drug content of the microneedles according to example 2 of the present invention.

Detailed Description

In order to better illustrate the present invention and facilitate the understanding of the technical solutions, the present invention is further described in detail below.

Example 1

Scukiteuzumab microneedle therapy for psoriasis

Firstly, two microneedles loaded with securititumumab are prepared, and the preparation method comprises the following two steps:

1. preparation of microneedle body containing securititumumab

Freeze-drying the microneedles: 25% HA as matrix, 1% gelatin as protective agent, 10mg/ml of Securiuzumab was loaded, and mixed well using ultrasound or vortexer. Injecting the drug-containing matrix into a microneedle mould, filling by a vacuum method, and then recovering the redundant matrix solution; the mold with the drug-loaded matrix was frozen at-20 ℃ for 15 minutes. The height of the needle bodies is 550 mu m, and the space between the needle points of the needle bodies is 800 mu m.

Drying the microneedle at normal temperature: 25% HA as matrix, 1% gelatin as protective agent, 10mg/ml of Securiuzumab was loaded, and mixed well using ultrasound or vortexer. Injecting the drug-containing matrix into a microneedle mould, filling by a vacuum method, and then recovering the redundant matrix solution; the mold with the drug matrix was left to dry naturally for 6 hours in the open air. The height of the needle bodies is 600 mu m, and the space between the needle points of the needle bodies is 800 mu m.

2. Backing for making microneedles

Freeze-drying the microneedles: 20% of PVA as a matrix, which was poured into a needlepoint-containing mold at an ambient temperature of less than 0 ℃ and filled by vacuum method. Moving the matrix carrying mold to-80 ℃ for freezing for 30 minutes; subsequently, the mixture was transferred to a lyophilizer and freeze-dried for 3 hours. The pressure in the freeze dryer was 0.05mbar and the cold trap temperature was-85 ℃. The thickness of the backing was 3mm.

Drying the microneedle at normal temperature: using PVA as a matrix in an amount of 20% by volume, filling the mixture into a mold, discharging air bubbles, and allowing the mixture to stand in a ventilated place for 8 hours to complete natural drying. The thickness of the backing was 2mm. The schematic diagram of the drug-loaded microneedle patch manufactured as described above is shown in fig. 1, and the schematic diagram of the drug-loaded microneedle patch penetrating into the skin is shown in fig. 2.

Modeling a psoriasis mouse by taking Imiquimod (IMQ) as a modeling medicament; the progression of psoriasis in mice was assessed using the PASI score (table 1), with higher scores indicating more severe. Shaving the back hair of the mice, preparing skin using depilatory cream, and then administering IMQ to the back of the mice daily from day 0 onward for psoriasis modelling; different groups were set up, normal (no intervention), control (no therapy), subcutaneous injection (SC), normothermic (MNP), lyophilized (FD-MNP), and the specific dosing schedule is shown in fig. 3; wherein the dosage of the microneedle is 40 mug per tablet, and the dosage of subcutaneous injection is 800 mug; from day 0 onwards, mice were scored daily for psoriasis status.

TABLE 1

Scoring	Erythema	Scale and chip	Infiltration of
				0	No erythema	Is invisible	The skin lesion is flush with the normal skin
1	Is light red	Fine scale	The skin lesion is slightly higher than the normal skin
				2	Red colour	The scale is in the form of flake	With moderate relief, rounded or bevelled edges
3	Deep red color	Thicker layers, almost all covering	The skin damage is thick and the uplift is obvious
				4	Extremely deep red color	Covering	100% with thick scale	The skin damage is highly thickened and the uplift is very obvious

After 8 days, the experimental results are comprehensively evaluated, the psoriasis score of the mice is shown in figure 4, and the psoriasis condition of the subcutaneous injection group is improved and shows a benign trend on the next day after the administration; the psoriasis condition was improved and also developed benignly one day after the administration of the lyophilized microneedle group, and the condition of the two groups of mice was similar to that of the control group at day 8, with a significant difference.

Psoriasis in mice is shown in FIG. 5 (a, b, c, d, e are normal, control, SC, MNP, FD-MNP, day 8, post-treatment mice, respectively).

The microneedle loaded with the securititumumab prepared by the preparation process provided by the invention has the advantages that the freeze-drying technology is more favorable for preserving the activity of the medicament, and the treatment effect of the freeze-dried microneedle group is better than that of a normal-temperature microneedle group; meanwhile, local administration can achieve the same effect as systemic treatment, greatly reduces the exposure of the whole body and can reduce the adverse reactions related to immunity.

Example 2

Adalimumab microneedle preparation

1. Preparation of microneedle body containing adalimumab

Freeze-drying the microneedles: 30% HA as matrix, loaded with 10mg/ml adalimumab, and 2% collagen as protective agent, mixed well using ultrasound or vortexer. Injecting the drug-containing matrix into a microneedle mould, filling by a vacuum method, and then recovering the redundant matrix solution; the mold with the drug-loaded matrix was frozen at-20 ℃ for 15 minutes. The height of the needle bodies is 700 mu m, and the space between the needle points of the needle bodies is 600 mu m.

Lyophilized microneedles without protective agent: 30% HA as matrix, loaded with 10mg/ml adalimumab and mixed well using an ultrasonic or vortexer. Injecting the drug-containing matrix into a microneedle mould, filling by a vacuum method, and then recovering the redundant matrix solution; the mould carrying the drug matrix was frozen at-20 ℃ for 15 minutes. The height of the needle bodies is 700 mu m, and the space between the needle points of the needle bodies is 600 mu m.

Drying the microneedles at normal temperature: 30% HA as matrix, loaded with 10mg/ml adalimumab, and 2% collagen as protective agent, mixed well using ultrasound or vortexer. Injecting the drug-containing matrix into a microneedle mould, filling by a vacuum method, and then recovering the redundant matrix solution; the mould with the drug-loaded matrix is placed in a ventilated place for 6 hours to be naturally dried. The height of the needle bodies is 800 mu m, and the space between the needle points of the needle bodies is 600 mu m.

Normal temperature microneedle without protective agent: 30% HA as matrix, loaded with 10mg/ml adalimumab and mixed well using an ultrasonic or vortexer. Injecting the drug-containing matrix into a microneedle mould, filling by a vacuum method, and then recovering the redundant matrix solution; the mould with the drug-loaded matrix is placed in a ventilated place for 6 hours to be naturally dried. The height of the needle bodies is 800 mu m, and the space between the needle points of the needle bodies is 600 mu m.

2. Backing for making microneedles

Freeze-drying the microneedles: 20% by weight of PVP as a base, which was poured into a pinpoint-containing mold at an ambient temperature of less than 0 ℃ and vacuum-filled. Moving the matrix carrying mold to-80 ℃ for freezing for 30 minutes; subsequently, the mixture was transferred to a lyophilizer and freeze-dried for 3 hours. The pressure in the freeze dryer was 0.05mbar and the cold trap temperature was-85 ℃. The thickness of the backing was 5mm.

Lyophilized microneedles without protective agent: 20% by weight of PVP as a base, which was poured into a pinpoint-containing mold at an ambient temperature of less than 0 ℃ and vacuum-filled. Transferring the matrix carrying mold to-80 ℃ for freezing for 30 minutes; subsequently, the mixture was transferred to a lyophilizer and freeze-dried for 3 hours. The pressure in the freeze dryer was 0.05mbar and the cold trap temperature was-85 ℃. The thickness of the backing was 5mm.

Drying the microneedles at normal temperature: PVP (20% by weight) was poured into the mold and filled, and the mold was vented and left to stand for 8 hours to complete natural drying. The thickness of the backing was 0.5mm.

Normal temperature microneedle without protective agent: PVP (20% by weight) was poured into the mold and filled, and the mold was vented and left to stand for 8 hours to complete natural drying. The thickness of the backing was 0.5mm.

The property of the microneedle penetrating into the skin of the psoriasis is inspected, and the result shows that the skin penetration rate of the freeze-dried microneedle is higher than 90% and the skin penetration rate of the normal-temperature microneedle is higher than 95% after the protective agent is loaded; and the protective agent is not loaded, the skin penetration rate of the freeze-dried microneedle is lower than 50%, and the penetration rate of the normal-temperature microneedle is lower than 60%.

Detecting the content of the drug carried in the microneedle to investigate the influence of the preparation process on the stability of the drug, and finding out that the content of the drug in the microneedle is 16% of the initial amount by normal temperature drying and 71% of the initial amount by freeze-drying when the protective agent is not loaded; after loading the protective agent, the drug content of the normal temperature dried microneedle is 50% of the initial amount, and the drug content of the freeze-dried microneedle is 97%.

The results of skin penetration rate and drug content are shown in fig. 6.

According to the prescription process provided by the invention, the mechanical strength and the skin penetration performance of the micro-needle can be improved through the cross-linking or compounding effect of the protective agent and the needle body raw material. The protective agent can better preserve the activity of the medicines in the microneedle, improve the stability of the microneedle and achieve better treatment effect.

Example 3

Preparation of Cetuzumab microneedles

1. Manufacture of microneedle bodies containing trastuzumab

Freeze-drying the microneedles: taking 20% carbomer as matrix, loading 10mg/ml certolizumab, taking 2% 2-hydroxypropyl-propyl cyclodextrin as protective agent, and mixing uniformly by using ultrasonic or vortex apparatus. Injecting the drug-containing matrix into a microneedle mould, filling by a vacuum method, and then recovering the redundant matrix solution; the mold with the drug-loaded matrix was frozen at-20 ℃ for 15 minutes. The height of the needle bodies is 900 mu m, and the space between the needle points of the needle bodies is 800 mu m.

Lyophilized microneedles without protective agent: taking 20% carbomer as a matrix, loading 10mg/ml certolizumab and uniformly mixing by using an ultrasonic or vortex instrument. Injecting the drug-containing matrix into a microneedle mould, filling by a vacuum method, and then recovering the redundant matrix solution; the mold with the drug-loaded matrix was frozen at-20 ℃ for 15 minutes. The height of the needle bodies is 900 mu m, and the space between the needle points of the needle bodies is 800 mu m.

Drying the microneedle at normal temperature: taking 20% carbomer as matrix, loading 10mg/ml certolizumab, taking 2% 2-hydroxypropyl-propyl cyclodextrin as protective agent, and mixing uniformly by using ultrasonic or vortex apparatus. Injecting the drug-containing matrix into a microneedle mould, filling by a vacuum method, and then recovering the redundant matrix solution; the mould with the drug-loaded matrix is placed in a ventilated place for 6 hours to be naturally dried. The height of the needle bodies is 100 mu m, and the space between the needle points of the needle bodies is 800 mu m.

Normal temperature microneedle without protective agent: taking 20% carbomer as a matrix, loading 10mg/ml certolizumab and uniformly mixing by using an ultrasonic or vortex instrument. Injecting the drug-containing matrix into a microneedle mould, filling by a vacuum method, and then recovering the redundant matrix solution; the mold with the drug matrix was left to dry naturally for 6 hours in the open air. The height of the needle bodies is 1000 mu m, and the space between the needle points of the needle bodies is 800 mu m.

2. Backing for making microneedles

Freeze-drying the microneedles: 40% polyethylene acid is used as a substrate, and the substrate is injected into a mold containing a needle point at the ambient temperature of less than 0 ℃ and filled by a vacuum method. Moving the matrix carrying mold to-80 ℃ for freezing for 30 minutes; subsequently, the mixture was transferred to a lyophilizer and freeze-dried for 3 hours. The pressure in the freeze dryer was 0.05mbar and the cold trap temperature was-85 ℃. The thickness of the backing was 4mm.

Lyophilized microneedles without protective agent: using 40% polyethylene acid as matrix, injecting into a mold containing a needle point at the temperature of less than 0 ℃, and filling by a vacuum method. Transferring the matrix carrying mold to-80 ℃ for freezing for 30 minutes; subsequently, the mixture was transferred to a lyophilizer and freeze-dried for 3 hours. The pressure in the freeze dryer was 0.05mbar and the cold trap temperature was-85 ℃. The thickness of the backing was 4mm.

Drying the microneedles at normal temperature: and (3) taking 40% polyethylene acid as a matrix, injecting the matrix into a mold, filling, discharging bubbles, and placing in a ventilated place for 8 hours to finish natural drying. The thickness of the backing was 1mm.

Protective agent-free normal-temperature microneedle: and (3) taking 40% polyethylene acid as a matrix, injecting the matrix into a mold, filling, discharging bubbles, and placing in a ventilated place for 8 hours to finish natural drying. The thickness of the backing was 1mm.

The content of the drug loaded in the microneedle is detected to investigate the influence of the preparation process on the stability of the drug, and the result shows that when the protective agent is not loaded: the drug content in the normal temperature dried microneedle is 21% of the initial amount, and the drug content in the freeze-dried microneedle is 73% of the initial amount; after loading the protective agent, the drug content in the normal temperature dried microneedle was 65% of the initial amount, while the drug content in the freeze-dried microneedle was 94%.

Example 4

Eiqizhuzumab microneedle preparation

1. Manufacture of microneedle bodies containing Eiqizhuzumab

Drying microneedles at normal temperature at a distance of 400 μm: load 10mg/ml eculizumab and 1% hydroxypropyl- β cyclodextrin using 50% pvp as a matrix, mix well using an ultrasonic or vortexer. Injecting the drug-containing matrix into a microneedle mould, filling by a vacuum method, and then recovering the redundant matrix solution; the mold with the drug-loaded matrix was frozen at-20 ℃ for 15 minutes. The height of the needle bodies is 1200 mu m, and the space between the needle points of the needle bodies is 400 mu m.

Normal temperature drying microneedle 200 μm pitch: load 10mg/ml eculizumab and 1% hydroxypropyl- β cyclodextrin using 50% pvp as a matrix, mix well using an ultrasonic or vortexer. Injecting the drug-containing matrix into a microneedle mould, filling by a vacuum method, and then recovering the redundant matrix solution; the mold with the drug matrix was left to dry naturally for 6 hours in the open air. The height of the needle bodies is 1500 mu m, and the space between the needle points of the needle bodies is 200 mu m.

2. Backing for making microneedles

Both microneedle backings were prepared by filling a matrix of 40% pvp into a mold, and then air-drying the mold in a ventilated place for 8 hours. The thickness of the backing was 1mm.

When the properties of microneedles penetrating into psoriatic skin were examined, it was found that the rate of penetration into psoriatic skin was 95% or more for microneedles having a pitch of 400 μm, and less than 65% for microneedles having a pitch of 200 μm, so that the pitch of the tips of the microneedles was preferably 400 μm or more.

The present invention is illustrated by the above-mentioned examples, but the present invention is not limited to the above-mentioned detailed process equipment and process flow, i.e. it is not meant to imply that the present invention must rely on the above-mentioned detailed process equipment and process flow to be practiced. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.

Claims (10)

1. The utility model provides a medicine-carrying microneedle paster which characterized in that, medicine-carrying microneedle paster comprises the needle body and the backing of a plurality of component arrays, the needle body is fixed in the backing, the needle body is obtained through the preparation of film forming process by matrix solution, contain the medicine in the matrix solution.

2. The drug-loaded microneedle patch according to claim 1, wherein the height of the needle body is 50-1500 μm; more preferably 200 to 1400 μm;

preferably, the space between the needle points of the needle body is 50-1500 μm; more preferably 400 to 1000 μm;

preferably, the needle body has a shape of a quadrangular pyramid, a cone, a tower, or an irregular shape.

3. The drug-loaded microneedle patch according to claim 1 or 2, the medicine comprises adalimumab, etanercept, infliximab, alfacast, golimumab, certuzumab, steuzumab, stekucke You Shankang, wu Sinu monoclonal antibody, guceqi You Shankang, eqilizumab, toslizumab, E Ma Liyou monoclonal antibody, recombinant human II-type tumor necrosis factor receptor-antibody fusion protein for injection, anti-IL-17A humanized monoclonal antibody, SSGJ-608, recombinant anti-human IL-17A/F humanized monoclonal antibody injection, LZM012, bai Dalu monoclonal antibody/brogliomab, tiragluzumab, riseduzumab, tipuzumab, domperitumomab, interferon gamma-1 b, mesolast, pimecrolimus, CM310, AZD-1402, 060-PRS, CBP-201, MG-120, project, MG-K10, QX-3535 zz35, ASQ 359-03611-004, ASQ-3 MDNA413, MDNA132, qu Luolu monoclonal antibody, lerey monoclonal antibody, irela Sha Ji monoclonal antibody, nei Mo Lizhu monoclonal antibody, ALX-076, GR-1501, JNJ-63823539, RO-7040547, fodias, AK101, AK111, JS005, COVA-322, UCB-0159, fu Naji bead monoclonal antibody, SHR-1314, ABY-035, SCH-900117, CJM-112, QX-004-N, QX-002N, IBI-112, HOT-3010, HB0017, HB0034, tofacitinib, phenanthrene Zhuo Tini, non-gatitinib, abxitinib, pircetib, gatinib, gastritib, lucitinib, RCOCTIB 6898, RCTITITICOTIB 3476, geTIMIG, ORTIMIG-3476, or HPPT-W-3476.

4. The drug-loaded microneedle patch according to any one of claims 1 to 3, wherein the matrix solution contains a raw material for preparing needle bodies, the raw material comprising any one or a combination of at least two of polyvinylpyrrolidone, polyvinyl alcohol, hyaluronic acid, sodium hyaluronate, sucrose, carbomer, polyvinyl acid, polyethylene oxide, polyacrylic acid, polyacrylamide, poly (methyl vinyl ether/maleic acid) half ester copolymer, polyethylene glycol, pullulan, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, or carboxymethyl cellulose;

preferably, the mass percentage of the raw material in the matrix solution is 5-60%;

preferably, the matrix solution further comprises a drug protecting agent, wherein the drug protecting agent comprises any one or a combination of at least two of glucose, sucrose, lactose, trehalose, alpha-mannopyranose, cellobiose, mannose, maltose, inositol, raffinose, inulin, dextrose, maltodextrin, maltopolysaccharide, sucrose octasulfate, dextran, heparin, 2-hydroxypropyl-propylcyclodextrin, albumin, collagen, proline, tryptophan, glutamic acid, sodium glutamate, alanine, glycine, lysine hydrochloride, sarcosine, L-tyrosine, phenylalanine, arginine, polyvinylpyrrolidone, mannitol, gelatin, tween 80, pluronic, brij, sodium dodecylsulfonate, ascorbic acid, ethylene glycol, phosphate, acetate, citrate, 2-hydroxypropyl-propylcyclodextrin, collagen, polyethylene glycol, gelatin, polyethyleneimine;

preferably, the drug protective agent is any one or a combination of at least two of 2-hydroxypropyl-propylene cyclodextrin, collagen, polyethylene glycol, gelatin or polyethyleneimine.

5. The drug-loaded microneedle patch according to any one of claims 1-4, wherein said film-forming process is: injecting the matrix solution into a microneedle mould, and drying to obtain a needle body;

preferably, the drying is natural drying or freeze drying.

6. The drug-loaded microneedle patch according to any one of claims 1-5, wherein said backing is prepared from a solution of a backing material via film formation;

preferably, the backing material comprises any one or a combination of at least two of polyvinylpyrrolidone, polyvinyl alcohol, hyaluronic acid, sucrose, carbomer, polyvinyl acid, polyethylene oxide, polyacrylic acid, polyacrylamide, poly (methyl vinyl ether/maleic acid) half ester copolymer, polyethylene glycol, pullulan, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, or carboxymethyl cellulose;

preferably, the mass percentage of the backing material in the solution of the backing material is 5-60%.

7. The drug-loaded microneedle patch according to any one of claims 1-6, wherein said film-forming process is: injecting a solution of a backing material into a backing mould, and drying to obtain the backing;

preferably, the drying is natural drying or freeze drying.

8. The drug-loaded microneedle patch of any one of claims 1-7, wherein said backing has a thickness of 0.5-5 mm.

9. The drug-loaded microneedle patch according to any one of claims 1 to 8, wherein a method of injecting the matrix solution into the microneedle mold is any one of a vacuum method, a centrifugal method or a spray method;

preferably, the method for injecting the solution of the backing material into the backing mold is any one of a vacuum method, a centrifugal method or a spraying method.

10. Use of a drug-loaded microneedle patch according to any one of claims 1-9 for the preparation of a pharmaceutical formulation for the treatment of psoriasis and atopic dermatitis.

Images