WO2021098791A1

WO2021098791A1 - Transdermal patch containing memantine

Info

Publication number: WO2021098791A1
Application number: PCT/CN2020/130177
Authority: WO
Inventors: 柯潇; 王一茜; 甘泉
Original assignee: 成都康弘药业集团股份有限公司
Priority date: 2019-11-20
Filing date: 2020-11-19
Publication date: 2021-05-27
Also published as: CN112915071A

Abstract

Disclosed is a memantine transdermal patch containing a backing layer, a release liner and a drug-containing matrix layer. The drug-containing matrix layer contains a memantine alkali, an organic acid and an acrylic pressure-sensitive adhesive matrix, wherein the organic acid is a chain organic acid of C8-C18. The patch has less volatilization, does not crystallize, and can realize the long-term stable release of active ingredients.

Description

A transdermal patch containing memantine

Technical field

The invention relates to a transdermal patch containing memantine as an active ingredient, which belongs to the field of pharmaceutical preparations.

Background technique

Alzheimer's disease (Alzheimer disease, AD), commonly known as Alzheimer’s, is a degenerative disease of the central nervous system characterized by progressive cognitive impairment and memory loss. Its clinical manifestations mainly include memory impairment and cognitive impairment And mental behavior disorder. With the development of the global aging process, the incidence of AD continues to increase, which seriously affects human health and quality of life. The "World Alzheimer's Disease Report" pointed out that 36 million people worldwide suffered from Alzheimer's disease in 2010, and this number increased to 44 million in 2013; it almost doubles every 20 years. By 2030, Alzheimer's The prevalence of Hymer's disease will reach 66 million, and it will reach 115 million by 2050. Therefore, Alzheimer's disease has become a major public health issue of common concern to all countries in the world.

Memantine hydrochloride was approved by the FDA in 2013 for the treatment of moderate to severe Alzheimer’s disease. It is an amantadine derivative and is an N-methyl-D-aspartate (NMDA) receptor antagonist. It has a chemical structure of 3,5-dimethyladamantane-1-amine (such as formula I).

In the prior art, memantine hydrochloride has a variety of dosage forms, including tablets, sustained-release capsules, etc. The usage and dosage of the memantine hydrochloride clearly indicate that the patient can start treatment only when there is a caregiver who supervises the patient's medication on time. For patients with Alzheimer's disease, oral medications have problems such as memory difficulties and difficulty swallowing after repeated medications. Therefore, transdermal patches have become the first choice for clinical applications. The drugs in the patch can be absorbed by the body through the skin, which provides good medication convenience for patients with Alzheimer’s disease and avoids the gastrointestinal tract caused by oral drugs. Discomfort and difficulty in swallowing in some patients can effectively improve patient compliance.

For transdermal patches, the higher the transdermal rate, the faster the drug concentration will reach the therapeutic window, which will speed up the onset time. Memantine exists in two drug forms, namely free base and salt. Generally, the free base has higher skin permeability than the salt form, but the free base form of the drug is less stable than the salt form, for example, it is easier to prepare during the preparation process. Crystallize. Most of the prior art uses memantine salt as the active ingredient of transdermal preparations and improves the transdermal rate through various technical means, but the ideal transdermal rate is still not obtained. The inventors found that the free base of memantine is volatile, and a large amount of medicine will be lost during the experiment. In particular, the drying process in the preparation process will accelerate the volatilization of the free base of memantine, which greatly limits the application of memantine. Although the prior art CN107468673A uses memantine to prepare transdermal patches, it does not pay attention to the problem of the volatility of memantine.

Therefore, it is of great significance to prepare a transdermal patch of memantine that has a high transdermal rate, less volatilization of the drug, no crystallization, no irritation, and long-term sustained release of memantine.

Summary of the invention

The purpose of the present invention is to provide a memantine transdermal patch with high transdermal rate, less drug volatilization, good stability, and long-term stable release, and a preparation method thereof.

The first object of the present invention is to provide a transdermal memantine patch, wherein the transdermal patch comprises a backing film, a release film and a drug-containing matrix layer, and the drug-containing matrix layer contains the active ingredient memantine, organic Acid and acrylic pressure-sensitive adhesive matrix, in which the organic acid is a C ₈ -C ₁₈ chain organic acid.

Transdermal in the present invention refers to the delivery of active pharmaceutical ingredients into and through the skin or mucosal tissues. When applied to the skin, its role is to deliver the active pharmaceutical ingredient transdermally.

The release film of the present invention refers to a release liner near the skin in contact with the drug-containing matrix layer, for example, a release liner composed of polyethylene terephthalate, polypropylene, polyester or polyethylene. Common release films are commercially available. For example, the models can be selected from 3M ScotchpakTM Release Liners 1020, 1022, 9748, 9742, 9744, 9755, 9741 and other models.

The backing film of the present invention is a flexible substrate, which provides a barrier that prevents the active pharmaceutical ingredient from migrating away from the intended administration direction and provides physical support for the patch. Any known backing layer that satisfies this purpose can be used in the present invention. Non-limiting examples of substances that can constitute the backing layer can include polyethylene terephthalate, various nylons, polypropylene, polyester, polyester/ethylene-vinyl acetate, metalized polyester film, poly Vinylidene chloride, metal films such as aluminum foil, polyvinylidene fluoride film, and mixtures, copolymers or laminates thereof. Common release films can be obtained commercially. For example, the specific backing layer model can be selected from 3M ScotchpakTM Backings 1109, 9738, 9736, 9730, 9723, 1012, 9680, 9731, 9732, 9733, 9734, 9735, 9754, 9756, 9757, 9758 and other models.

The drug-containing matrix layer of the present invention refers to an adhesive layer capable of providing stable drug release, and includes a memantine, organic acid, and acrylic pressure-sensitive adhesive matrix. After the release film is removed, the drug-containing matrix layer contacts and adheres to the skin.

The inventors of the present invention have found through experiments that due to the poor stability of memantine free base, the drug-containing matrix layer cannot effectively inhibit crystallization without adding organic acids and low-carbon chain organic acids, and memantine is easy to volatilize . The inventors unexpectedly discovered that _{the transdermal patch prepared by adding organic acids with C 8} or more can not only inhibit crystallization, but also inhibit the volatilization of memantine.

C ₈ -C ₁₈ chain organic acids are straight or branched fatty acids with 8-18 carbon atoms, examples include but are not limited to myristic acid, palmitic acid, oleic acid, linoleic acid, caprylic acid, capric acid, Stearic acid, dodecenoic acid, palmitic acid, lauric acid, etc. Preference is given to myristic acid, palmitic acid, caprylic acid or oleic acid. Caprylic acid and oleic acid are more preferred.

The acrylic pressure-sensitive adhesive of the present invention is preferably a pressure-sensitive adhesive without carboxyl end groups, for example, an acrylic pressure-sensitive adhesive matrix without end groups and/or an acrylic pressure-sensitive adhesive matrix with hydroxyl end groups. The research of the present invention found that white flocs appear when the pressure-sensitive adhesives with carboxyl end groups are mixed with memantine, which leads to uneven mixing. However, when acrylic pressure-sensitive adhesives with no end groups or hydroxyl end groups are used, the acrylic pressure-sensitive adhesive matrix is The above situation will not occur. Exemplarily, the acrylic pressure-sensitive adhesive model without end groups can be selected from DURO-TAK 87-4098, DURO-TAK 87-900A, DURO-TAK 87-9301, DURO-TAK 87-6908, GELVA GMS 3083, GELVA GMS 3253. Exemplarily, the acrylic pressure-sensitive adhesive model at the hydroxyl end can be selected from DURO-TAK 387-2287/87-2287, DURO-TAK 387-2510/87-2510, DURO-TAK 87-4287, DURO-TAK 387-2516 /87-2516, GELVA GMS 788. It is well known in the art that the pressure-sensitive adhesive used in the use process is usually a wet glue with a certain solid content of acrylic pressure-sensitive adhesive (for example, DURO-TAK 87-4098 solid content is 38.5%), so the acrylic pressure-sensitive adhesive of the present invention The glue content is calculated based on the solid content of acrylic pressure-sensitive adhesive.

Further, in some embodiments, the molar ratio of memantine to organic acid is 10:1 to 1:2. The research of the present invention found that when the molar ratio of the two is greater than 10:1, the effect of suppressing volatilization is weakened due to the decrease of the organic acid content. When the molar ratio of memantine to organic acid is greater than 1:3, due to the increase of organic acid, the entire drug-containing matrix layer is in a semi-solid state and has certain fluidity, which accelerates the volatilization of the drug. Therefore, the molar ratio of memantine and organic acid of the present invention is preferably 10:1 to 1:2, more preferably 3:1 to 1:2; most preferably 2:1 to 1:2.

In some embodiments, the drug-containing matrix layer of the present invention further includes a matrix modifier. The matrix modifier of the present invention refers to a substance that can interact with other components of the drug-containing matrix layer to jointly affect the properties of the patch (such as volatility, crystallization, and skin penetration rate). For example, the matrix modifier of the present invention is selected from one or more of silica or sodium polyacrylate, pyrrolidone, cellulose, and povidone polymer matrix modifier. Exemplarily, the silica may be gel-process silica or colloidal silica. The present invention has unexpectedly discovered through research that proper addition of silica or polymer matrix regulator has a certain effect on inhibiting the volatilization of the drug.

In some preferred embodiments, the sodium polyacrylate in the polymer matrix modifier is partially neutralized sodium polyacrylate; the pyrrolidone is selected from polyvinylpyrrolidone, polypropylene pyrrolidone, and nitromethylpyrrolidone; the cellulose is selected from hydroxy Propyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose; povidones are copovidone, polyvinyl acetate povidone.

In other preferred embodiments, the polymer matrix modifier is selected from partially neutralized sodium polyacrylate, polyvinylpyrrolidone, polyvinyl acetate povidone or hypromellose.

In some embodiments, the composition of the memantine transdermal patch of the present invention contains the drug-containing matrix layer, in terms of mass percentage:

Memantine 10-30%

Organic acid 1-35%

Acrylic pressure sensitive adhesive 30-90%

Matrix modifier 0-50%.

In some preferred embodiments, the composition of the memantine transdermal patch drug-containing matrix layer of the present invention comprises in terms of mass percentage:

Memantine 10-25%

Organic acid 3-35％

Acrylic pressure sensitive adhesive 35-87%

Matrix modifier 0-30%.

In some other preferred embodiments, the composition of the memantine transdermal patch of the present invention contains the drug-containing matrix layer in terms of mass percentage:

Memantine 10-25%

Organic acid 3-20%

Acrylic pressure sensitive adhesive 51-72%

Matrix regulator 3-30%.

Memantine 10-20%

Organic acid 4-17%

Acrylic pressure sensitive adhesive 51-63%

Matrix regulator 3-15%.

Memantine 20%

Caprylic acid 8-17%

Acrylic pressure sensitive adhesive 51-63%

Polyvinylpyrrolidone 3-15%.

In other embodiments, the drug-containing matrix layer of the present invention further contains a penetration enhancer. The penetration enhancer of the present invention refers to a substance that can be used to adjust/improve the skin penetration rate of the patch. Exemplary penetration enhancers are selected from surfactants, lower alcohols, amino acids, fatty acid esters, and bicarbonates. One or more. In some preferred embodiments, the surfactants in the penetration enhancer are selected from poloxamers, sorbitan fatty acid esters, polysorbates, polyoxyethylene fatty alcohol ethers, lecithin; lower alcohols are selected From one or more of propylene glycol and glycerol; amino acids are selected from arginine, histidine, glycine, and alanine; fatty acid esters are selected from isopropyl myristate, fatty acid methyl ester, fatty acid ethyl Ester; bicarbonate is selected from sodium bicarbonate, ammonium bicarbonate, potassium bicarbonate, calcium bicarbonate. In other preferred embodiments, the penetration enhancer is selected from arginine or sodium bicarbonate. In some embodiments, the content of the penetration enhancer is 5-20% by weight, preferably 10-20% by weight, more preferably 10% by weight.

In other embodiments, the matrix drug-containing layer of the present invention may further include auxiliary agents such as antioxidants, solvents, colorants and/or preservatives. For example, the drug-containing matrix layer of the present invention further contains an antioxidant. Illustratively, antioxidants include, but are not limited to, ascorbic acid, palmitate, sulfites (such as sodium sulfite, sodium metasulfite), BHT, and the like.

In other embodiments, the transdermal patch of the present invention includes a three to five layer structure. In the three-layer transdermal patch, only one drug-containing matrix layer is located between the release film and the backing film. In such an embodiment, after the release film is removed, the drug-containing matrix layer contacts and adheres to the skin.

In other embodiments, the transdermal patch of the present invention contains a four-layer or five-layer structure. In a four-layer or five-layer transdermal patch, a barrier layer and/or an adhesive layer are further included on the drug-containing matrix layer. For example, in the five-layer structure, the transdermal patch also includes an adhesive layer and an isolation layer located below the backing film in sequence, and the order of the structure is the backing film layer, the adhesive layer, the isolation layer, and the drug-containing matrix layer. And release film. The isolation layer separates the drug-containing matrix layer and the adhesive layer. Examples of specific isolation layer models that can be used are 3M ScotchpakTM Backings 1109, 9738, 9736, 9730, 9723, 1012, 9680, 9731, 9732, 9733, 9734 , 9735, 9754, 9756, 9757, 9758 and other models. Suitable for manufacturing the adhesive layer is acrylic or polyisobutylene pressure sensitive adhesive, which can be selected from Henkel's DURO-TAK 87-4098, 387-2287, 87-6908, 87-235A, 87-2852, 387- 2516, 387-2510, 387-2074, 87-235A, can also be selected from silicone pressure-sensitive adhesives, can be selected from Dow Corning's BIO-PSA AC7-4301, AC7-4302, AC7-4201, AC7-4202, 7- 4301, 7-4302, 7-4201, 7-4202.

Another aspect of the present invention is to provide a method for preparing a transdermal patch, the steps include:

(1) Mixing: first stir and dissolve the memantine, organic acid, and acrylic pressure-sensitive adhesive matrix to obtain a drug-containing glue;

(2) Coating and drying: coating the drug-containing glue on the release film under heating, and drying for 2 to 3 hours;

(3) After the sample is dried, the backing film is used to press the drug-containing glue layer, and die cut into a certain area and shape.

(1) Mixing: Mix the memantine, organic acid, acrylic pressure-sensitive adhesive matrix, and matrix regulator in an alcohol solvent to obtain a drug-containing glue;

(2) Coating and drying: After the drug-containing glue is allowed to stand for defoaming, it is coated on the release film and dried;

(3) Use the backing film to press the drug-containing glue layer, and punch it into a certain area and shape.

In other preferred preparation embodiments, in step 1), first weigh the matrix regulator, add alcohol solvent and mix well, then add memantine, organic acid and acrylic pressure-sensitive adhesive matrix, stir and mix Evenly, get medicated glue liquid. The alcohol solvent is preferably one or more of ethanol, propylene glycol and glycerol.

After step 4): Cut the sample obtained in step 3) into wafers, remove the wafer release film, stick it on the new release film, and then evenly coat the pressure-sensitive adhesive on it and dry it, Press the backing film and cut out the disc.

Description of the drawings

Figure 1 Three-layer transdermal patch structure in Example 2;

Figure 2-1 is a sample diagram of the transdermal patch in prescription 4-8 in Example 3;

Figure 2-2 shows the visual field of the transdermal patch sample of prescription 4-8 in Example 3 as observed under a microscope;

Figure 2-3 is a sample diagram of the transdermal patch of prescription 9 in Example 3;

Figure 3 is a diagram showing the cumulative permeation volume of transdermal patches in prescriptions 4-8 in Example 3 in 48 hours in vitro;

Figure 4 is a diagram showing the cumulative permeation volume of transdermal patches in prescriptions 10-15 in Example 4 in 48 hours in vitro;

Fig. 5 is a graph showing the cumulative permeation volume of the transdermal patch in the prescription 16-20 in Example 5 in 48 hours in vitro;

Figure 6 is a graph showing the cumulative permeation volume of transdermal patches in prescription 30 in Example 7 in 48 hours in vitro;

Fig. 7 is a graph showing the cumulative permeation volume of transdermal patches in prescriptions 35-41 in Example 9 in vitro for 48 hours;

Figure 8 is a five-layer transdermal patch structure in Example 11;

Figure 9 is a sample diagram of transdermal patches in prescriptions 51-53 in Example 12;

Detailed ways

The present invention further describes the content of the present invention in detail through the following examples, which cannot be used to limit the protection scope of the present invention.

In the following specific embodiments, the medicines, reagents and instruments used are as follows:

equipment:

仪器名称equipment name	型号/规格Model/Specification	公司the company
气相色谱仪Gas Chromatograph	6890N6890N	AgilentAgilent
电子天平Electronic balance	BS224S/BP211DBS224S/BP211D	SartoriusSartorius
搅拌器Stirrer	JB-2JB-2	上海雷磁新泾仪器有限公司Shanghai Leici Xinjing Instrument Co., Ltd.
加热型自动涂膜机Heating type automatic film coating machine	BEVS1811/3BEVS1811/3	BEVS INDUSTRIAL CO.,LTDBEVS INDUSTRIAL CO.,LTD
透皮扩散试验仪Transdermal Diffusion Tester	TK-12HTK-12H	上海锴凯科技贸易有限公司Shanghai Kaikai Technology Trading Co., Ltd.

Constant temperature sink

SC-15

Shanghai Bilang Instrument Manufacturing Co., Ltd.

Medicines, excipients and reagents:

In vitro transdermal experiment:

The in vitro transdermal experiment of the present invention refers to the literature Latheeshjlal L, Phanitejaswini P, Soujanya Y, et al. Transdermal drug delivery systems: an overview [J]. International Journal of PharmTech Research, 2011, 3(4): 2140-2148. In vitro skin permeation studies part of the method; wherein the skin used in the present invention is pig skin, and the skin preparation method refers to Guideline P B T. OECD guideline for the testing of chemicals [J]. The Hershberger, 2001, 601: 858. Part of skin preparations.

Content detection:

The amount of loss of the drug content of the drug is determined with reference to the method in the United States Pharmacopoeia USP38. Three parallel samples were taken for each sample, and the results were averaged.

Example 1 Preparation of Memantine

The memantine of the present invention can be obtained commercially, or it can be prepared by neutralizing memantine salt and alkali in a manner known in the art, for example, by the following method: Preparation of memantine free base: Weigh 67g of sodium hydroxide and add 335ml of water, stir to dissolve and add to the dropping funnel; weigh 68g of memantine hydrochloride, add 335ml of water and n-hexane and stir at room temperature, slowly add sodium hydroxide solution dropwise and continue stirring. The organic phase was obtained by extracting the reaction liquid, dried with anhydrous magnesium sulfate, filtered in a funnel and rotary evaporated to remove the solvent to obtain 55 g of memantine (purity>98%) with a yield of 82%.

Example 2

In this example, the influence of the type of pressure-sensitive adhesive matrix is investigated, and the prescription is shown in Table 1.

Table 1 Prescriptions 1-3

Preparation Process

In a suitable container, weigh the memantine, oleic acid and acrylic pressure-sensitive adhesive bases in sequence according to the prescription in Table 1, and stir to dissolve them. After stirring uniformly, use a heated automatic film coating machine to evenly coat it on a polyester film (SCOTCHPAK 1022) (as a release film), and dry the above sample at 30°C for 2 hours to remove volatile solvents. After the sample is dried, the adhesive layer is laminated with a polyester film (SCOTCHPAK 9733) (as a backing film), and finally punched into a suitable area and shape. The transdermal patch has a three-layer structure, including a backing layer (Backing Layer), a drug-containing matrix layer (Drug/Polymer Adhesive Matrix), and a release film layer (Peel-off Release Liner). The structure is shown in Figure 1. .

Experimental results

The inventors investigated the types of acrylic pressure-sensitive adhesive substrates and found that DURO-TAK87-4098 without end groups and other similar substrates, DURO-TAK 387-2287 with hydroxyl end groups, and other similar substrates are useful for memantine stickers. The effect of the agent is the same, but when the pressure-sensitive adhesive with carboxyl end group is mixed with memantine, white flocs will appear, resulting in uneven mixing. Therefore, acrylic pressure-sensitive adhesive bases without end groups and/or hydroxyl end groups are preferred for preparing transdermal patches in which the active ingredient is memantine.

Example 3

In this example, the influence of the types of organic acids on the patch is investigated, and the prescription is shown in Table 2.

Table 2 Prescription 4-9

Preparation Process

In a suitable container, weigh memantine, organic acid, and acrylic pressure-sensitive adhesive matrix (DURO-TAK 87-4098, solid content 38.5%) in sequence according to the prescription in Table 2, and fully stir to dissolve. After stirring uniformly, use a heated automatic film coating machine to evenly coat it on the polyester film (SCOTCHPAK 1022), and dry the above sample at 30°C for 2 hours to remove volatile solvents. After the sample is dried, the adhesive layer is laminated with a polyester film (SCOTCHPAK 9733), and finally punched into a certain area and shape.

Experimental results

During the experiment, the inventor found that if organic acid is not added, memantine will be completely volatilized during the preparation process, and the drug loss rate can reach 100%. Therefore, the inventors added organic acids to the prescription, and screened the types of organic acids, and investigated the appearance, drug loss, and skin penetration rate of the prepared patches. The drug loss and skin penetration rate are shown in Table 2. From the appearance of the prepared patch, it is obvious that the backing layer is in an opaque state after the patch prepared with levulinic acid (prescription 8) is dried and laminated (as shown in Figure 2-1 and Figure 2). -2). A large number of drug crystals can be observed under the microscope (as shown in Figure 2-2). Similarly, in the patch prepared with acetic acid (prescription 9), the backing layer is also observed to be in a clear opaque state, and there is a drug precipitation (As shown in Figure 2-3), and other patches prepared by acids have no such phenomenon.

From the perspective of drug loss, myristic acid, palmitic acid, oleic acid, caprylic acid, levulinic acid and acetic acid all have a certain effect on reducing the volatility of memantine and reducing the loss of drugs. Among them, drugs used when oleic acid and caprylic acid are used The loss is minimal.

Figure 3 shows the in vitro skin penetration of prescriptions 4-8. From the perspective of skin penetration rate, when caprylic acid is used, the skin penetration rate is as high as 38.42μg/cm ² /h; the penetration rate of patches prepared with oleic acid, levulinic acid and acetic acid is greater than 18μg/cm ² /h, but when acetyl The patch will crystallize when propionic acid and acetic acid are used.

Example 4

In this example, the effect of the ratio of oleic acid on the patch was investigated. The prescription is shown in Table 3.

Table 3 Prescription 10-15

Preparation Process

In a suitable container, weigh memantine, oleic acid, and acrylic pressure-sensitive adhesive matrix (DURO-TAK 87-4098, solid content 38.5%) in sequence according to the prescription in Table 3, and fully stir to dissolve. After stirring uniformly, use a heated automatic film coating machine to evenly coat it on the polyester film (SCOTCHPAK 1022), and dry the above sample at 30°C for 2 hours to remove volatile solvents. After the sample is dried, the adhesive layer is laminated with a polyester film (SCOTCHPAK 9733), and finally punched into a certain area and shape.

Experimental results

All samples were transparent in appearance after the preparation was completed, no crystallization phenomenon was observed, and there was basically no change in appearance after being left for 3 months. The loss of the drug and the skin penetration rate are shown in Table 3. The in vitro transdermal release curve is shown in Figure 4.

Example 5

In this example, the effect of the ratio of caprylic acid on the patch was investigated. The prescription is shown in Table 4.

Table 4 Prescription 16-20

Preparation Process

In a suitable container, weigh memantine, caprylic acid, and acrylic pressure-sensitive adhesive base (DURO-TAK 87-4098, solid content 38.5%) in sequence according to the prescription in Table 4, and fully stir to dissolve. After stirring uniformly, use a heated automatic film coating machine to evenly coat it on the polyester film (SCOTCHPAK 1022), and dry the above sample at 30°C for 2 hours to remove volatile solvents. After the sample is dried, the adhesive layer is laminated with a polyester film (SCOTCHPAK 9733), and finally punched into a certain area and shape.

Experimental results

All samples were transparent in appearance after the preparation was completed, no crystallization phenomenon was observed, and there was basically no change in appearance after being left for 3 months. The loss of the drug and the skin penetration rate are shown in Table 4. The in vitro transdermal release curve is shown in Figure 5.

Example 6

The prescription of this example is shown in Table 5.

Table 5 Prescription 21-29

Preparation Process

In a suitable container, weigh memantine, caprylic acid, and acrylic pressure-sensitive adhesive matrix (DURO-TAK 87-4098, solid content 38.5%) in sequence according to the prescription in Table 5, and fully stir to dissolve. After stirring uniformly, use a heated automatic film coating machine to evenly coat it on the polyester film (SCOTCHPAK 1022), and dry the above sample at 30°C for 2 hours to remove volatile solvents. After the sample is dried, the adhesive layer is laminated with a polyester film (SCOTCHPAK 9733), and finally punched into a certain area and shape.

Experimental results

All samples appeared transparent after preparation, and no crystallization was observed. The loss of the drug and the skin penetration rate are shown in Table 5.

Example 7

Weigh the prescription according to Table 6.

Table 6 Prescription 30

Preparation process: Weigh memantine, oleic acid, and acrylic pressure-sensitive adhesive matrix (DURO-TAK 87-4098, solid content 38.5%) in a suitable container according to the prescription in Table 6, and fully stir to dissolve. After stirring uniformly, use a heated automatic film coating machine to evenly coat it on the polyester film (SCOTCHPAK 1022), and dry the above sample at 30°C for 2 hours to remove volatile solvents. After the sample is dried, the adhesive layer is laminated with a polyester film (SCOTCHPAK 9733), and finally punched into a certain area and shape.

Experimental results:

The drug loss and skin penetration rate are shown in Table 6. The in vitro release behavior is shown in Figure 6.

Example 8

This example examines the influence of the memantine preparation process on the patch. The prescription is shown in Table 7, wherein the memantine of the prescription 31-32 forms an alkali in the patch in situ, and the memantine of the prescription 33-34 is commercially available or Prepare in advance as in Example 1.

Table 7 Prescription 31-34

Prescription 31-32 Preparation method: Weigh 0.62g sodium hydroxide and dissolve it in 10mL methanol, dissolve it ultrasonically, and set aside. Weigh the methanol solution of memantine hydrochloride and sodium hydroxide according to the prescription in Table 7, and stir and mix for about 20 minutes. Then add the caprylic acid according to the prescription amount to the aforementioned mixed solution, and stir for about 20 minutes. Finally, weigh DURO-TAK 87-4287 according to the prescribed amount and add it to the mixture, stir for 40 minutes, let stand for 20 minutes, and use a heated automatic coating machine to evenly coat it on the polyester film (SCOTCHPAK 1022) (as a release film ), the above samples were dried at 50°C for 10 minutes to remove volatile solvents. After the sample is dried, a polyester film (SCOTCHPAK 9733) is used to press the adhesive layer (as a backing film), and finally die cut into a certain area and shape.

Prescription 33 preparation method: Weigh PVP according to the prescription amount, add an appropriate amount of absolute ethanol and stir for about 20 minutes to dissolve it for later use. Weigh memantine, caprylic acid, and glycerin according to the prescription amount and add them to the PVP ethanol solution and stir for about 20 minutes. Finally, weigh the DURO-TAK 87-4098 according to the prescription and add it to the above mixture, stir for 40 minutes, let it stand for 20 minutes, and use a heated automatic coating machine to evenly coat it on the polyester film (SCOTCHPAK 1022) (as a release Membrane), the above sample was dried at 50°C for 10 minutes to remove volatile solvents. After the sample is dried, a polyester film (SCOTCHPAK 9733) is used to press the adhesive layer (as a backing film), and finally die cut into a certain area and shape.

Prescription 34 preparation method: Weigh memantine and caprylic acid in order according to the prescription amount and stir for about 20 minutes. Then weigh DURO-TAK 87-4098 according to the prescribed amount and add it, stir for 40 minutes, let stand for 20 minutes, and use a heated automatic coating machine to evenly coat it on the polyester film (SCOTCHPAK 1022) (as a release film) , The above samples were dried at 50°C for 10 minutes to remove volatile solvents. After the sample is dried, a polyester film (SCOTCHPAK 9733) is used to press the adhesive layer (as a backing film), and finally die cut into a certain area and shape.

Experimental results: The patch prepared according to the above prescription and process was tested for the content of the drug within one week after the preparation was completed, and the results showed that the loss of each prescription was ≤1%. In addition, the skin penetration rate and appearance of the patch under high temperature (40° C.) and light conditions for 5 days were investigated. The results are shown in Table 7. The results showed that all prescriptions 31-32 devitrified under the conditions of high temperature or light for 5 days, and the patch was covered with dendritic crystals and appeared white and opaque, while prescription 33-34 had no obvious devitrification.

Table 7

Example 9

This example examines the effect of adding different types of polymers in the prescription on the patch. The fixed molar ratio of memantine to caprylic acid in the prescription is 2:1, and the other ingredients in the prescription are shown in Table 8.

Table 8 Prescription 35-41

Preparation Process

In a suitable container, weigh the amount of polymer prescribed in Table 8, add an appropriate amount of ethanol solution, and stir to dissolve the polymer. Then weigh the memantine, caprylic acid and acrylic pressure-sensitive adhesive base (DURO-TAK87-4098) in the above container according to the prescription in Table 8, and stir to dissolve them. After stirring uniformly, use a heated automatic film coating machine to evenly coat it on the polyester film (SCOTCHPAK 1022), and dry the above sample at 30°C for 2 hours to remove volatile solvents. After the sample is dried, the adhesive layer is laminated with a polyester film (SCOTCHPAK 9733), and finally punched into a certain area and shape.

Experimental results

All samples were transparent in appearance after the preparation was completed, no crystallization phenomenon was observed, and there was no obvious change in appearance after being left for 3 months and 6 months. In addition, the inventors found that adding sodium polyacrylate, polyvinylpyrrolidone, cellulose, povidone and other high molecular polymers can further reduce the loss of drug content, while maintaining a higher penetration rate of the patch ( As shown in Figure 7).

Example 10

This example investigates the influence of the content of the polymer matrix modifier on the patch. The ingredients and contents in the prescription are shown in Table 9.

Table 9 Prescription 42-47

Preparation Process

Weigh memantine in accordance with the prescription in Table 9, add glycerin, mix well, add caprylic acid to make it evenly mixed, then add PVP K90, stir well until PVP K90 is completely dispersed, and then add the pressure-sensitive adhesive DURO-TAK 87- 4098, fully agitate for 2 hours; after standing for defoaming, apply uniformly on 9755YDS film (as a release film), dry the sample at 40°C for 40 minutes, and press the backing 9754YDS Film (backing film) to obtain a patch.

Experimental results

The transdermal patch prepared according to the above-mentioned prescription and process is in a transparent state after preparation, no crystallization phenomenon occurs, and there is no obvious change in appearance after being placed at room temperature for 3 months and 6 months. The drug loss and skin penetration rate are shown in Table 10. Each prescription patch was released steadily within 48 hours.

Table 10

Example 11

The reservoir transdermal patch was prepared with the prescription in Table 11. The matrix modifier was colloidal silica or polyvinylpyrrolidone, the molar ratio of memantine to caprylic acid was fixed at 2:1, and the other ingredients and contents in the prescription As shown in Table 11.

Table 11 Prescription 48-50

Preparation Process

Weigh memantine, add solvent glycerol and/or glycerol + propylene glycol, mix well, add caprylic acid to make it evenly mixed, add polyvinylpyrrolidone (PVP K90), stir well until PVP K90 is completely dispersed, add pressure Sensitive glue DURO-TAK 87-4098, stir well for 2h; after standing for defoaming, evenly coat on 9755YDS film (as a release layer), dry the sample at 40℃ for 40min, and press the backing 9754YDS Film (as Isolation layer), that is, patch.

Cut the above sample into 1.13cm ² size discs, remove the disc release film, stick it on the new 9755YDS film release film, and then evenly coat DURO-TAK 87-4098 pressure sensitive adhesive ( As the adhesive layer), dry at 60°C for 10 minutes, press the backing 9754YDS Film (as the backing layer), and cut out a disc with a diameter of 20mm to obtain a reservoir type transdermal sticker, which has a five-layer structure The order of structure is Backing Layer, Overlapping Adhesive Film, Separating Layer, Drug/Polymer Adhesive Matrix and Peel- off Reease Liner), the structure is shown in Figure 8.

Experimental results

The transdermal patch prepared according to the above-mentioned prescription and process is in a transparent state after preparation, no crystallization phenomenon occurs, and there is no obvious change in appearance after being left for 3 months and 6 months. The drug loss and transdermal rate are shown in Table 11. Each prescription was released steadily within 48 hours.

Example 12

This example examines the effect of penetration enhancers on the patch, and the specific prescription is shown in Table 12.

Table 12 Prescription 51-53

Preparation Process

In a suitable container, weigh memantine, organic acid, penetration enhancer, and acrylic pressure-sensitive adhesive base (DURO-TAK 87-4098) with a solid content of 38.5% in sequence according to the prescription in Table 12, and stir to dissolve. After stirring uniformly, use a heated automatic film coating machine to evenly coat it on the polyester film (SCOTCHPAK 1022), and dry the above sample at 30°C for 2 hours to remove volatile solvents. After the sample is dried, the adhesive layer is laminated with a polyester film (SCOTCHPAK 9733), and finally punched into a certain area and shape.

Experimental results

The transdermal patch prepared according to the above-mentioned prescription and process did not show crystallization after preparation. The inventors screened the types of penetration enhancers and found that the amino acid arginine, fatty acid ester isopropyl myristate (IPM), and sodium bicarbonate can all increase the penetration rate. Among them, sodium bicarbonate and arginine can enhance the penetration rate. The penetration effect is better (Figure 9).

Example 13

Experimental purpose: To investigate the skin irritation of the patch of the present invention through rabbit skin irritation experiments.

Experimental animals: 6 male rabbits aged 2-5 months, weighing 1.8-2.5 kg, Chengdu Dashuo Experimental Animal Co., Ltd.

Reference substance: blank patch, except that it does not contain memantine, the rest of the components are the same as the memantine patch of the present invention.

Test product: Memantine patch, prepared in accordance with prescription 12, prescription 17, and prescription 23.

Experimental method: The experiment adopts the self-comparison between the left and right sides of the back spine of the same body. About 24 hours before the first administration, the left and right sides of the experimental animal's back spine are depilated without any damage to the epidermis. The depilation range is about 8cm×8cm on the left and right sides. Before administration, check whether the depilated skin is damaged due to depilation. The damaged skin should not be tested. The transdermal patch was applied to the administration site, and the effective application area of the test substance was a circle with a diameter of 25 mm.

Take the sample to be tested directly on the skin that has been depilated on one side, then cover it with medical gauze, and then fix it with non-irritating tape and bandage; on the other side, the depilated skin is given a blank patch, and then covered with medical gauze. Then use non-irritating tape and bandage to fix it. The initial retention time of the patch application is 6 hours, after which the covering is removed, 15-60 minutes after the drug is removed, 24, 48, and 72 hours are visually observed and recorded for erythema and edema at the application site, according to Table 13. The skin irritation response was scored, and the irritation intensity was evaluated according to Table 14.

Table 13 Scoring criteria for skin irritation

Table 14 Evaluation Criteria for Skin Irritation Intensity

Experimental results: The six rabbits showed no erythema or edema at 60 minutes after the patch was removed, and at 24, 48, and 72 hours on either the experimental side or the control side, indicating a single administration of memantine transdermal patch No irritation to rabbit skin. The specific results are shown in Table 15 below.

Table 15

Claims

A transdermal memantine patch, comprising a backing film, a release film and a drug-containing matrix layer, characterized in that the drug-containing matrix layer contains an active ingredient memantine, an organic acid and an acrylic pressure-sensitive adhesive matrix, wherein the organic acid is C 8 -C 18 chain organic acid.
The patch according to claim 1, wherein the organic acid is myristic acid, palmitic acid, oleic acid or caprylic acid.
The patch according to claim 2, wherein the organic acid is oleic acid or caprylic acid.
The patch according to claim 3, wherein the organic acid is caprylic acid.
The patch according to claim 1, wherein the acrylic pressure-sensitive adhesive matrix does not contain carboxyl terminal groups.
The patch according to claim 5, wherein the acrylic pressure-sensitive adhesive matrix is an acrylic pressure-sensitive adhesive matrix without end groups and/or an acrylic pressure-sensitive adhesive matrix with hydroxyl end groups.
The patch according to claim 1, wherein the molar ratio of memantine and organic acid is 10:1 to 1:2.
The patch according to claim 7, wherein the molar ratio of memantine and organic acid is 3:1 to 1:2.
The patch according to claim 8, wherein the molar ratio of memantine and organic acid is 2:1 to 1:2.
The patch according to any one of the foregoing, characterized in that the patch further contains a matrix modifier selected from the group consisting of silicon dioxide or sodium polyacrylate, pyrrolidone, cellulose, and povidone One or more of polymer matrix modifiers.
The patch according to claim 10, wherein the sodium polyacrylate in the polymer matrix modifier is partially neutralized sodium polyacrylate; the pyrrolidone is selected from polyvinylpyrrolidone, polypropylene pyrrolidone, nitromethylpyrrolidone; cellulose The class is selected from hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and ethyl cellulose; povidones are copovidone and polyvinyl acetate povidone.
The patch according to claim 11, wherein the polymer matrix modifier is selected from partially neutralized sodium polyacrylate, polyvinylpyrrolidone, polyvinylacetate povidone or hypromellose.
The patch according to claim 12, wherein the polymer matrix modifier is selected from partially neutralized sodium polyacrylate, polyvinylpyrrolidone or hypromellose.
The patch according to any one of claims 1-13, wherein the composition of the drug-containing matrix layer comprises in mass percentage:

Memantine 10-30%

Organic acid 1-35%

Acrylic pressure sensitive adhesive 30-90%

Matrix modifier 0-50%.
The patch according to claim 14, characterized in that the composition of the drug-containing matrix layer comprises in mass percentage:

Memantine 10-25%

Organic acid 3-35％

Acrylic pressure sensitive adhesive 35-87%

Matrix modifier 0-30%.
The patch according to claim 15, characterized in that the composition of the drug-containing matrix layer comprises in mass percentage:

Memantine 10-25%

Organic acid 3-20%

Acrylic pressure sensitive adhesive 51-72%

Matrix regulator 3-30%.
The patch according to claim 16, characterized in that the composition of the drug-containing matrix layer comprises in mass percentage:

Memantine 10-20%

Organic acid 4-17%

Acrylic pressure sensitive adhesive 51-63%

Matrix regulator 3-15%.
The patch according to claim 17, characterized in that the composition of the drug-containing matrix layer comprises in mass percentage:

Memantine 20%

Caprylic acid 8-17%

Acrylic pressure sensitive adhesive 51-63%

Polyvinylpyrrolidone 3-15%.
The patch according to any one of the foregoing, characterized in that the patch further contains a penetration enhancer, wherein the penetration enhancer is selected from surfactants, lower alcohols, amino acids, fatty acid esters, and bicarbonate. One or more.
The patch according to claim 19, wherein the surfactant in the penetration enhancer is selected from the group consisting of poloxamers, sorbitan fatty acid esters, polysorbates, polyoxyethylene fatty alcohol ethers, lecithin ; Lower alcohols are selected from one or more of propylene glycol and glycerol; amino acids are selected from arginine, histidine, glycine, and alanine; fatty acid esters are selected from isopropyl myristate, fatty acids Methyl ester, fatty acid ethyl ester; bicarbonate is selected from sodium bicarbonate, ammonium bicarbonate, potassium bicarbonate, calcium bicarbonate.
The patch according to claim 20, wherein the penetration enhancer is selected from arginine or sodium bicarbonate.
The patch according to any one of claims 19-21, wherein the content of the penetration enhancer is 5-20% by weight.
The patch according to any one of claims 22, wherein the content of the penetration enhancer is 10-20% by weight.
The patch according to any one of claims 23, wherein the content of the penetration enhancer is 10% by weight.
The patch according to any one of the foregoing, characterized in that the patch further includes an antioxidant.
The patch according to any one of the foregoing, characterized in that the patch further comprises an adhesive layer and an isolation layer located below the backing film in sequence, and the isolation layer is composed of a drug-containing matrix layer and an adhesive layer. isolation.
A method for preparing the transdermal memantine patch of any one of claims 1-26, comprising the following steps:

(1) Mixing: first stir and dissolve the memantine, organic acid, and acrylic pressure-sensitive adhesive matrix to obtain a drug-containing glue;

(2) Coating and drying: coating the drug-containing glue on the release film under heating, and drying for 2 to 3 hours;

(3) After the sample is dried, the backing film is used to press the drug-containing glue layer, and die cut into a certain area and shape.
A method for preparing the memantine transdermal patch of claims 1-26, comprising the following steps:

(1) Mixing: Mix the memantine, organic acid, acrylic pressure-sensitive adhesive matrix, and matrix regulator in an alcohol solvent to obtain a drug-containing glue;

(2) Coating and drying: After the drug-containing glue is allowed to stand for defoaming, it is coated on the release film and dried;

(3) Use the backing film to press the drug-containing glue layer, and punch it into a certain area and shape.
The preparation method according to claim 28, characterized in that, in step 1), first weigh the matrix regulator, add alcohol solvent and mix well, then add memantine, organic acid and acrylic pressure-sensitive adhesive matrix , Stir, the mixer is uniform, and the medicated glue is obtained.
The preparation method according to claim 29, wherein the alcohol solvent is one or more of ethanol, propylene glycol and glycerol.
The preparation method according to any one of claims 27-30, further comprising after step 4): cutting the sample obtained in step 3) into wafers, removing the wafer release film, and attaching it to The new release film is then evenly coated with pressure-sensitive adhesive, dried, and the backing film is pressed, and the wafer is cut out.