KR101964295B1 - Memantine Transdermal Delivery System Having Reduced Skin Irritation - Google Patents

Abstract

The present invention provides a transdermal administration system capable of minimizing skin irritation caused by rapid skin permeation of memantine by controlling the absorption rate of skin through regulation of the release rate of memantine. The patch, which is a transdermal administration system according to the present invention, comprises at least one layer (release control layer) containing (or containing) one or more release modifiers (substances) and capable of controlling the release rate, The skin permeation rate of the skin can be controlled. In addition, the residual amount of memantine in the patch after administration may be about 60 to 50% by weight or less relative to the initial loading amount, thereby minimizing the loss of drug and preventing abuse of the drug.

Description

[0001] The present invention relates to a Memantine transdermal delivery system having reduced skin irritation,

The present invention relates to a percutaneous delivery system for administration of memantine with reduced skin irritation, and more particularly to a patch for administering memantine.

Dementia is causing problems for tens of millions of patients and their families around the world as a result of an increasingly contemporary society as the aging society advances. Among these dementias, Alzheimer's dementia is the most common and occurs at a rate of 1 per 5 out of the elderly people over 80 years old. In Alzheimer's, there are two kinds of systems that are necessary for communication of brain cells. One of them is the reduction of brain neurotransmitter, acetylcholine, while the other transmitter, glutamate, is hyperactively activated, leading to the death of the nerve.

When glutamate is excessive, brain neurons are excessively stimulated to cause damage and death of the cranial nerve. Memantine, an NMDA (N-methyl-D-aspartate) receptor antagonist, prevents glutamate from being transmitted to NMDA receptors, It is effective in preventing damage and death of nerve cells due to excessive inflow of Ca ^{2 +} ions. Because of this effect, memantine has been approved for moderate to severe Alzheimer's treatment. These memantines are expected to be effective not only for Alzheimer's, but also for mental trauma and stroke accompanied by excessive glutamate stimulation.

If memantine is developed for the transdermal delivery of memantine due to the characteristics of patients with dementia who are on the market, for convenience of use, for patient compliance, and for furthermore, they are forbidden to take medication for the administration of memantine, Lt; RTI ID = 0.0 > of drug administration. ≪ / RTI >

In general, the skin is divided into the stratum corneum, the epidermis, and the dermis, and performs a barrier function to protect the human body from the external environment. Therefore, drug delivery through skin is difficult to permeate due to skin barrier function. Therefore, in the conventional technique, permeation enhancer for improving skin permeation of drug is used or skin barrier function is directly or indirectly reduced to improve drug absorption Technology has been developed. However, memantine has a molecular weight of 179.31, a melting point of 10 ° C or less, and is a highly volatile drug. Also, the log P of the drug is 3.28, which is very lipophilic and permeates the skin very easily.

Accordingly, a problem to be solved by the present invention is to develop memantine patches that can be delivered through skin to improve patient compliance and caregiver convenience of memantine, which is approved as a treatment for Alzheimer's disease. The present invention also provides a patch that minimizes skin irritation upon transdermal administration.

In order to solve the above problems, the present invention provides a patch formulation comprising memantine or a pharmaceutically acceptable salt thereof, wherein the patch formulation comprises a release modulating agent and / or a release modulating layer in the patch of memantine Wherein the absorption rate of the skin is lowered to a specific rate or lower by controlling the release rate of the menstrual blood.

Preferably, the menstin patch according to the present invention has a skin absorption rate in humans of about 20 ug / cm ² / hr or less for 24 hours, more preferably 18 ug / cm ² / hr or less, even more preferably 15 ug / cm ² / hr or less. In the case of memantine-containing patches according to the present invention, skin irritation can be drastically reduced while having appropriate blood concentrations when the skin permeation rate is as described above.

In the memantine patch according to the present invention, as a release modifier that controls the skin permeation rate of memantine and improves the skin irritation, specific examples include fatty acids, waxes, lauroyl polyoxyl-32 glycerides -32 glycerides, stearoyl polyoxyl-32 glycerides, silicon oxides, magnesium aluminometasilicates and calcium silicates, polymethacrylates (for example, Eudragit E100, Eudragit EL100, Plastoid B), polyvinyl acetate, polyethylene oxide, high molecular weight polyvinyl pyrrolidone having a molecular weight of 400,000-3,000,000, polyvinyl alcohol, or a mixture thereof. More preferably, useful release modifiers according to the present invention are stearic acid, polymethacrylates, high molecular weight polyvinylpyrrolidone polymers having molecular weights of 400,000-3,000,000, or mixtures thereof in terms of improving skin irritation.

More preferably, the memantine patch according to the present invention comprises a release modulating layer (distinct from the drug layer) for controlling the rate of skin absorption of memantine, which release modulating layer is used to control the release rate of memantine (For example, Duro-tak 87-9301, 87-9088, 87-900A), a silicone adhesive (e.g., BIO-PSA4201, BIO-PSA4301), polyisobutyl (For example, Duro-tak 87-6908), polyvinyl acetate, polyethylene oxide, high molecular weight polyvinyl pyrrolidone having a molecular weight of 400,000-3,000,000, polyvinyl alcohol, hydroxypropylcellulose, hydroxyethylcellulose Or mixtures thereof.

The rate of skin absorption of a drug can affect the rate at which the drug is released in the patch, the skin permeability of the drug, the condition and thickness of the skin, and the concentration of the drug for diffusion. However, the presence of a substance or layer controlling the rate of release of the drug and the absence of a permeation enhancer for enhancing skin permeation are not present, and depending on the diffusion rate of Fick's Law, the drug concentration, drug delivery distance, skin thickness, It is only affected by chemical properties.

The present invention relates to a menstrual patch having good permeability to skin, wherein the skin absorption (permeation) rate is controlled not by adjusting the concentration of the general drug or the thickness of the patch, but by controlling the release of the substance and layer, The rate of permeation was controlled by controlling the rate at which the drug was released. The present invention can be controlled by combining the type and amount of the release modifier, the type of the release modifier layer, and the like. This release control can control the permeation rate of memantine to the skin, and consequently the degree of skin irritation can be controlled.

The memantine patch according to the present invention may further comprise a stabilizer for improving the stability of memantine. The stabilizer is preferably a low molecular weight polyvinylpyrrolidone having a molecular weight of 2,500 to 50,000, a polyvinyl alcohol , Hydroxypropylcellulose, hydroxyethylcellulose and the like, antioxidants such as butylated hydroxytoluene (BHT), tocopherol, ascorbic acid, and alpha-bisabolol, or a mixture thereof.

Preferably, the memantine patch according to the present invention comprises memantine free base, which is not a memantine salt such as memantine hydrochloride, as a pharmaceutical active ingredient, and when such memantine free base is contained, It is possible to exclude the influence on the speed (unforeseeable) and it is more preferable for the purpose of the present invention to keep the skin permeation rate constant.

The menstin patch according to the present invention has a prescription for improving skin irritation and at the same time has a high drug utilization efficiency so that the residual amount of memantine after administration for 24 hours is not more than 60% by weight of the initial content, Is not more than 50% by weight.

Thus, more preferably, the present invention relates to a single layer of memantine patch comprising memantine free base, release modifier, stabilizer and tackifier, or a single layer comprising such memantine and a release layer It provides a memantine patch containing two layers. The memantine patch according to the present invention may further comprise a backing layer which is not permeable to memantine and a release liner which is removed in use.

The present invention specifically encompasses the administration of a drug through controlled release of memantine in patches by including one or more layers (release control layer) which can contain (or contain) and control release rate of one or more release modifiers Provided is a patch preparation which can control skin absorption rate and minimize skin irritation caused by rapid penetration. In addition, the present invention can achieve economical advantages such that the residual amount of memantine in the patch after administration is maintained at about 60 to 50 wt% or less relative to the initial loading amount, thereby minimizing drug loss and preventing misuse of drugs .

BRIEF DESCRIPTION OF THE DRAWINGS The following drawings, which are incorporated herein by reference, illustrate preferred embodiments of the invention. That is, the present invention plays a role of further understanding the technical idea of the present invention together with the contents of the above-mentioned invention, and thus the present invention should not be construed as being limited to the matters described in such drawings.
BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a cross-sectional view showing a schematic structure of a patch capable of controlling the release rate of memantine according to the present invention. Fig.

Hereinafter, embodiments of the present invention will be described in detail to facilitate understanding of the present invention. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. Embodiments of the invention are provided to more fully describe the present invention to those skilled in the art.

≪ Comparative Examples 1 to 3 > [0092] The antioxidant and the stabilizer were included,

Memantine free base-containing patches containing antioxidants and stabilizers in the contents and contents of the following Table 1, but without a release modifier, were prepared as follows.

Comparative Example 1 Comparative Example 2 Comparative Example 3 Memantine 12% 17% 23% BHT 0.1% 0.1% 0.1% α-Bisabolol 0.5% 0.5% 0.5% Polyvinylpyrrolidone 12PF
(PVP 12PF) 2.5% 2.5% 2.5% Acrylate polymer
(87-9301, 87-9088) 84.9% 79.9% 73.9% Content of drug (mg / cm ² ) 0.52 0.75 0.92

Specifically, Comparative Example 1 was prepared as follows. 0.02 g of BHT and 0.5 g of PVP 12PF were dissolved in 1 g of ethanol and 2.4 g of memantine, 0.1 g of? -Bisabolol and 47.5 g of an acrylate polymer (87-9301: 23 g, 87-9088: 24.5 g) Acrylate drug-in-adhesive acrylate. The adhesive acrylate drug was coated on a backing membrane (Scotchpak 1109, 3M Corp., USA) using a coating coater. After being manufactured to a constant thickness, the laminate was dried at room temperature for 10 minutes and then at 70 ° C for 20 minutes. The polyester release liner was laminated onto the dried drug. The concentration of memantine in the patch was 0.52 mg / cm ² .

Comparative Examples 2 and 3 were prepared in the same manner as in Comparative Example 1 in the ratio shown in the above table. The concentration of memantine in the patch was 0.75 mg / cm ² and 0.92 mg / cm ² , respectively.

Comparative Examples 1 to 3 were evaluated as follows. Using a modified drage method, NZW rabbits were exposed to 2.5 × 2.5 cm ² patches for 24 h, followed by 24 h, 48 h, and 72 h of skin erythema and edema. In addition, the amount of residual drug was analyzed in the patches removed from the site of anastomosis to estimate the uptake. In a similar manner, 1 × 1 cm ² patches were applied on human skin for approximately 2 hours, and the rate of absorption and the Primary Irritation Index (PII) were evaluated. The results are summarized in Table 2 below.

Comparative Example 1 Comparative Example 2 Comparative Example 3 rabbit
(24hr, n = 4) Absorption rate
(ug / cm ² / hr) 14.5 ± 1.8 20.7 ± 1.5 31.1 ± 2.3 P.I.I 0.6 0.8 1.5 (edema) Person
(2 hr, n = 3) Absorption rate
(ug / cm ² / hr) 46.9 ± 20.4 75.1 ± 36.0 111.9 ± 28.1 P.I.I 2.2 (edema) 3.0 (severe edema) 3.5 (severe edema)

As shown in Table 2, the rate of absorption of the drug increases in proportion to the content of the drug, and the skin irritation also increases to a similar degree. In particular, the initial rate of absorption in rabbits was not clearly determined, but it was confirmed that the initial rate of absorption was very rapid when applied to humans, and that the rate of absorption over time within 2 hours after administration and afterwards could be different can do. It can also be deduced that the absorption profile varies with the rate of absorption and time in humans and rabbits when compared to the degree of stimulation. Even in Comparative Examples 1 and 2 in which skin irritation hardly occurred in rabbits after 24 hours of administration, it was found that moderate irritation occurred in humans administered for 2 hours.

Therefore, if the drug is released from the patch at a uniform rate within a certain time range by controlling the rate of release of the drug from the patch, regardless of the content, overcoming the absorption rate difference due to the drug content, It was assumed that there would be.

≪ Examples 1-4 > A single-layer patch containing a release modifier

Memantine-containing patches containing release modifiers were prepared with the ingredients and contents shown in Table 3 below.

Example 1 Example 2 Example 3 Example 4 Memantine 13% 10% 9.2% 10% BHT 0.1% 0.1% 0.1% 0.1% Stearic acid 5% 8% 8% 5% PVP 12PF 5% 5% - - PVP 90F - - - 5% Polymethacrylate
(Eudragit E100 or Eudragit EL100 or Plastoid B) - - 10% - Acrylate polymer
(87-9301, 87-9088, 87-900A) 76.9% 76.9% 72.7% 79.9% Content of drug (mg / cm ² ) 0.69 0.55 0.53 0.48

Specifically, Example 1 was prepared as follows. 0.02 g of BHT, 1 g of PVP 12PF and 1 g of stearic acid are dissolved in 2 g of ethanol, and 2.6 g of memantine and 42.1 g of an acrylate polymer (87-9301) are added to form an adhesive-type acrylate drug -adhesive acrylate. This adhesive acrylate drug was coated on a backing membrane (Scotchpak 1109, 3M Corp., USA) using a coating coater. After being manufactured to a constant thickness, it was dried at room temperature for 10 minutes and then dried at 70 ° C for 20 minutes. The polyester release liner was laminated onto the dried drug. The concentration of memantine in the patch was 0.69 mg / cm ² .

Examples 2 to 4 were prepared in the same manner as in Example 1 according to the contents and contents of Table 3, and the concentration of memantine in the patch was 0.55 mg / cm ² , 0.53 mg / cm ² and 0.48 mg / cm ² .

≪ Examples 5 to 8 >

Memantine-containing patches containing a release-controlling layer were prepared as follows. Namely, the release control layer (Examples 5 to 8) of the following Table 4 was laminated on the above-mentioned Examples 1 to 4 to prepare a memantine-containing patch with a release control layer.

Example 5 Example 6 Example 7 Example 8 Silicone adhesive
(BIO-PSA4201, BIO-PSA4301) 97.9% 87.9% - - BHT 0.1% 0.1% 0.1% 0.1% Polymethacrylate
(Eudragit E100 or Eudragit EL100 or Plastoid B) - 10.0% - - Silicon oil 12,500 cst 2.0% 2.0% - - PVP90F - - 5.0% - Acrylate polymer
(87-900A) - - 94.9% Polyisobutylene
(87-6908) - - - 99.9%

≪ Examples 9 and 10 > >

A multilayer patch comprising a drug and a release modifier was prepared as shown in Table 5 below.

Example 9 Example 10 A Memantine 51% 96.9% BHT 2% 0.1% Stearic acid 47% - Hydroxypropylcellulose - 3% B BHT 0.1% Eudragit E100 10% 10% Acrylate polymer
(87-9301, 87-9088) 89.1% 72.7% Content of drug (mg / cm ² ) 0.5 0.9

Specifically, the B layer containing the pressure-sensitive adhesive was prepared by mixing BHT, Eudragit E100 and acrylate polymer uniformly and then coating a coating coater on a polyester liner. After being manufactured to a constant thickness, it was dried at room temperature for 10 minutes, and then dried at 100 ° C for 10 minutes. Example 9 was prepared by dissolving stearic acid and BHT in a warmed state and then mixing the drug with the drug. Example 10 was prepared by dissolving the drug, BHT and hydroxypropyl cellulose together while stirring.

Multilayer patches were prepared by coating or spraying A layer containing the drug between two B layers that were dried after coating to a certain thickness.

On the other hand, in Examples 9 and 10, the emission control layers, Examples 5 to 8, were laminated to fabricate new embodiments.

≪ Evaluation of Examples &

The degree of controlled release of the drug through the drug release rate modifier and / or control layer was determined using the USP Apparatus 5 (Paddle over disk) method. The results are shown in Table 6 (n = 3).

Time (hr) Comparative Example 1 (%) Example 2 Example 3 Example 3+ Example 5 0.25 4.32 + 0.14 0.85 ± 1.47 0.00 ± 0.00 0.00 ± 0.00 0.5 7.46 ± 0.60 5.50 + - 0.37 0.00 ± 0.00 5.37 + - 1.27 One 12.53 + - 0.42 9.78 + - 0.52 4.14 + 0.26 9.79 ± 1.25 2 19.25 + - 0.98 16.42 ± 0.29 8.27 ± 0.17 14.32 ± 1.37 4 26.25 ± 1.02 21.67 + - 0.80 12.23 + - 0.86 16.70 ± 0.98 8 37.97 ± 0.92 29.82 + 0.75 17.31 ± 0.59 21.18 ± 0.85 12 47.32 ± 1.65 34.93 + - 0.84 21.47 ± 0.50 25.38 ± 2.19 18 57.48 ± 0.55 40.90 + - 1.01 25.80 ± 0.80 28.45 + - 0.67 24 63.75 ± 1.67 42.44 + 1.46 28.40 +/- 0.39 30.09 ± 0.29

As shown in Table 6 above, the release rate of memantine decreased when the release modifier and / or release modulating layer was included.

In addition, skin permeability was measured using an artificial membrane (Strat-M ^™ Membrane, Millipore) and Human cadaver skin using Frantz diffusion cell, and the drug release rate control was evaluated using this. The results are shown in Table 7 (artificial membrane, n = 3) and 8 (human cadaver skin, n = 3).

Time (hr) Comparative Example 1 (%) Example 1 (%) Example 2 (%) Example 1+ Example 5 (%) One 20.00 9.74 11.37 8.08 2 28.03 14.81 16.75 12.33 4 36.95 20.68 23.84 17.27 8 49.21 31.96 30.49 25.92 24 71.72 46.17 44.32 36.79

Time (hr) Comparative Example 1 (%) Example 1 (%) Example 1+ Example 5 (%) One 0.23 2.29 0.18 2 0.78 4.67 0.75 4 4.94 9.60 2.61 6 10.35 14.20 4.79 8 15.26 16.83 6.74 12 24.51 20.85 10.52 18 35.99 26.78 15.62 24 45.65 33.31 21.03 32 54.91 37.71 26.48 48 68.89 45.70 34.43 72 78.37 52.06 43.60

As shown in Tables 6, 7 and 8, in the case of the release-controlling agent and the release-controlling layer according to the present invention, the absorption rate of the skin was affected by controlling the release rate of memantine in the patch, .

The effect of this rate of absorption on skin irritation was directly assessed and the results are shown in Table 9 (artificial membrane) and 10 (human cadaver skin).

Comparative Example 1 ^* Example 2+ Example 5 ^** Example 3+ Example 5 ^** in vitro absorption rate
(Artificial membrane, ug / cm ² / hr) 15.87 6.44 8.07 Person in vivo
Absorption rate
(ug / cm ² / hr) 46.9 17.5 15.6 Skin irritation
(Erythema / edema) Erythema
Edema - Yes Erythema
Edema - no Erythema
Edema - no  Residual amount in patches (%) - 31.0% 30.7%

*: Removal after about 2 to 4 hours due to edema and itching

**: Remove after 24 hours without stimulation

Comparative Example 1 * Example 4 ** Example 4+ Example 5 ** in vitro absorption rate
(human cadaver, ug / cm ² / hr) 10.1 6.67 5.90 Person in vivo
Absorption rate
(ug / cm ² / hr) 46.9 7.8 13.2 Skin irritation
(Erythema / edema) Erythema
Edema - Yes Erythema
Edema - no Erythema
Edema - no Residual amount in patches (%) - 47.7% 34.2%

*: Removal after about 2 to 4 hours due to edema and itching

**: Remove after 24 hours without stimulation

As shown in Tables 9 and 10, the present invention is characterized by controlling the rate of absorption of the drug through the release-controlling agent (substance) and the release-controlling layer of the drug to control the absorption rate of the skin, Thereby minimizing skin irritation. In addition, the present invention confirms that the residual amount in the patch after administration is about 60 to 50% by weight or less with respect to the drug amount before administration, and it can be deduced that the drug is continuously released at a constant rate even though the release rate of the drug is controlled. By designing to minimize the amount of residual drug, economic benefits such as minimizing loss of drug and preventing abuse of drug are realized.

Claims (11)

In a patch formulation comprising memantine free base,
Wherein the patch formulation comprises an release modulating agent to control the rate of absorption by regulating the release rate of memantine free base,
Wherein the release modifier is stearic acid, polymethacrylate, a polyvinylpyrrolidone polymer having a molecular weight of 400,000-3,000,000, or a mixture thereof. delete delete delete delete The memantine free base patch of claim 1, wherein the patch further comprises a stabilizer. 7. The composition of claim 6, wherein the stabilizer is selected from the group consisting of polyvinylpyrrolidone of molecular weight 2,500-50,000, polyvinyl alcohol, hydroxypropylcellulose, hydroxyethylcellulose, butylated hydroxytoluene (BHT), tocopherol, ascorbic acid, ≪ / RTI > alpha-bisabolol or mixtures thereof. delete delete The memantine free base patch of claim 1, wherein the patch further comprises a release control layer distinct from a drug layer containing memantine free base. 11. The method of claim 10, wherein the release control layer is selected from the group consisting of an acrylate polymer, a silicone tackifier, a polyisobutylene tackifier, a wax, a fatty acid, silica gel, polymethacrylate, polyvinylacetate, polyethylene oxide, A maleimine free base patch comprising polyvinyl pyrrolidone, polyvinyl alcohol, or a mixture thereof.

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