Patent Application
20140052081
The present invention relates to a transdermal patch, and more particularly to a donepezil transdermal patch having excellent transdermal absorption properties and long-lasting drug effects.
Dementia, especially Alzheimer's disease, is a disease that is more likely to be developed by elderly individuals and requires more medical care and social costs. Progress in medical technology leads to a surge in the elderly population. Therefore, the development of anti-Alzheimer's disease drugs is gradually being demanded.
Donepezil, (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one, is a piperidine compound having acetylcholinesterase inhibiting activity that is used to treat Alzheimer's disease. Currently, most Alzheimer's disease treatment take the form of tablets for oral administration. However, as most Alzheimer's disease patients are elderly individuals, it is hard for them to take the oral agents. Moreover, it is difficult for patients having symptoms of Alzheimer's disease to take the oral agents. In addition, Alzheimer's disease patients usually have the symptoms of memory loss and dementia, and usually forget or refuse to receive medical treatment. Therefore, a donepezil transdermal patch is therefore developed to solve the problems described above.
Generally, a transdermal patch consists of an adhesive matrix layer, a backing layer and a release liner, wherein the adhesive matrix layer comprises drug, adhesive and other additives. However, the stratum corneum layer has a very high fat solubility, skin permeability of drug is generally low and the stratum corneum layer of normal skin has a barrier function to prevent invasion of exogenous materials; therefore, when a conventional transdermal patch is used, in many cases a drug blended therein cannot be sufficiently absorbed transdermally. Therefore, to increase the transdermal absorption properties of a drug in a transdermal patch, various studies have been carried out.
U.S. 2008/0138399 A1 discloses a transdermal absorption patch comprising donepezil hydrochloride in high concentration, adhesive matrix and a (meth)acrylate copolymer having a carboxyl group. However, long-term use of donepezil hydrochloride in high concentration may cause the patients to have side effects such as nausea, vomiting, diarrhea, gastric juice increase, headache, insomnia, dizziness, fatigue, syncope, hot flushes, blood pressure changes, and muscle spasm.
U.S. 2010/0080842 A1 discloses a transdermal extended-delivery donepozil active agent composition comprising a donepozil active agent, a transdermal absorption enhancer, and a pressure sensitive adhesive comprised of carboxylic acid functionalities. Said composition is formulated to provide the donepozil active agent with a skin permeation rate of at least 1.5 μg/cm2/hr. However, the highest skin permeation rate of the donepozil active agent exemplified in the examples of U.S. 2010/0081842 only is only 3.4 μg/cm2/hr.
Therefore, we are still looking for a transdermal patch that is suitable to be used in treating Alzheimer's disease, and that has sufficient transdermal absorption properties and long-lasting drug effect.
Accordingly, a primary objective of the present invention is to solve the problems described above, and to provide a donepezil transdermal patch having excellent trasdermal absorption properties to achieve a satisfying bioavailability.
Another objective of the present invention is to provide a donepezil transdermal patch having long-lasting drug effects, which can be effectively applied to a region on the skin of patients for at least three days.
The other objective of the present invention is to provide a method for treating Alzheimer's disease, which comprises applying the transdermal patch of the present invention to skin of patients.
Hereinafter, preferred embodiments of the present invention are illustrated in detail.
The donepezil transdermal patch of the present invention comprises:
(a) a backing layer, and
(b) a pressure sensitive adhesive matrix layer comprising:
In the present invention, the backing layer is not particularly limited and is well known by persons with ordinary skill in the art. In one embodiment of the present invention, the backing layer is prepared from polyester, nylon, polyvinyl chloride, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ionic polymer resins or other synthetic components.
The donepezil free base included in the transdermal patch of the present invention is well known to persons with ordinary skill in the art and can be prepared by any conventional methods. In the transdermal patch of the present invention, the donepezil free base is preferably in non-crystalline form. That is, the pressure sensitive adhesive matrix layer does not comprise any solid or undissolved donepezil free base.
In the present invention, the donepezil free base is present in an amount of preferably about 1% to about 15%, more preferably about 3% to about 12%, about 5% to about 12%, about 8% to about 12%, about 3% to about 5%, about 3% to about 8%, about 5% to about 8%, about 6% to about 11%, about 7% to about 12% or about 9% to about 12%, and most preferably about 10% based on the total weight of the pressure sensitive adhesive matrix layer.
In the transdermal patch of the present invention, the acrylic pressure sensitive adhesive agent included in the pressure sensitive adhesive matrix layer is selected from the group consisting of a copolymer of 2-ethylhexyl acrylate and vinyl acetate and a copolymer of 2-ethylhexyl acrylate, vinyl acetate, and hydroxyl-containing monomers, wherein 2-ethylhexylacrylate is present in an amount of about 65% to about 75% and preferably about 67% to 72%, vinyl acetate is present in an amount of about 25% to about 35% and preferably about 28% to about 30%, and the hydroxyl-containing monomers are in an amount of about 0% to about 10% and preferably about 5% to 8%, based on the total weight of the copolymer.
In a preferred embodiment of the present invention, the pressure sensitive adhesive agent is selected from the group consisting of Gelva®GMS 737 (where its weight is made up of about 72% of 2-ethylhexyl acrylate and about 28% of vinyl acetate, and was purchased from Cytec Industries, Inc.), Gelva®GMS 788 (where its weight is made up of about 70% of 2-ethylhexyl acrylate and about 30% of vinyl acetate, and was purchased from Cytec Industries, Inc.), and Duro-tak®2516 (where its weight is made up of about 67% of 2-ethylhexyl acrylate, about 28% of vinyl acetate, and about 5% of the hydroxyl-containing monomers, and was purchased from Henkel Corporation).
In one embodiment of the present invention, the hydroxyl-containing monomers are not particularly restricted; for example, but not limited to, hydroxymethyl acrylate, methyl hydroxymethyl acrylate, hydroxyethyl acrylate, hydroxyethyl methacrylate, hydroxypropyl acrylate, hydroxypropyl methacrylate, hydroxybutyl acrylate, hydroxybutyl methacrylate, hydroxypentyl acrylate, hydroxypentyl methacrylate, hydroxyhexyl acrylate, and hydroxyhexyl methacrylate.
In the present invention, the acrylic pressure sensitive adhesive agent is present in an amount of about 50% to about 99%, preferably about 50% to about 95%, about 50% to about 90%, about 50% to about 85%, about 50% to about 80%, about 60% to about 95%, about 60% to about 90%, about 60% to about 85%, about 60% to about 80%, about 70% to about 95%, about 70% to about 90%, about 70% to about 88%, about 80% to about 95% or about 80% to about 90%, more preferably about 85% to about 92.5%, based on the total weight of the pressure sensitive adhesive matrix layer.
In the donepezil transdermal patch of the present invention, the pressure sensitive adhesive matrix layer may additionally comprise a suitable skin permeation enhancer, which is, for example but not limited to, lauryl lactate, isopropyl myristate, oleic alcohol, or N-methylpyrrolidone.
According to the present invention, the permeation enhancer is present in an amount of about 1% to about 10%, preferably about 3% to about 8% or about 3% to about 6%, and more preferably about 5%, based on the total weight of the pressure sensitive adhesive matrix layer.
As long as not reducing the therapeutic effects of Alzheimer's disease, the donepezil transdermal patch of the present invention can additionally comprise, if needed, suitable plasticizers, stabilizers, or other additives.
In the present invention, the thickness of the pressure sensitive adhesive matrix layer is not particularly restricted, and is preferably about 40 micrometers to about 200 micrometers, more preferably about 80 micrometers to about 120 micrometers, and most preferably about 90 micrometers to about 100 micrometers.
The transdermal patch of the present invention preferably comprises a release liner. Suitable release liners are well known in this field, and are comprised of but not limited to those prepared from polymers, such as polyethylene, polypropylene, and polyesters, or comprised of paper sources, preferably of polyethylene terephthalate (PET). In one embodiment of the present invention, the release liner has a partition line, so that the release liner can be easily removed from the transdermal patch without contacting the pressure sensitive adhesive matrix layer by fingers, and then the transdermal patch can be applied onto the skin. The partition line can be a straight line or a curved line; for example but not limited to, a horizontal line, a vertical line, a wavy line, and a jagged line.
In the transdermal patch of the present invention, a backside treating agent, such as a silicone backside treating agent, a fluorine backside treating agent and wax, can be coated on the backing layer so that the patch can be rolled up and does not need any release liner.
In one embodiment of the present invention, the transdermal patch may comprise a water-proof moisture permeable film on the other side of the backing layer.
The donepezil transdermal patch of the present invention is suitable for the use of treating general dementia, such as Alzheimer's disease, and can also be used in other diseases, such as anti-cerebrovascular dementia or prevention of migraines.
The donepezil transdermal patch of the present invention can be applied to suitable sites on patient's body; for example but not limited to, breast, back, upper arm, thigh, and forehead. The patch can be applied to the patient for at least 3 to 5 days so as to obtain the best treatment effect.
The method for producing the donepezil transdermal patch of the present invention is not particularly restricted as long as it is a conventional method. One example of the method comprises the steps of dissolving a composition comprising donepezil free base and an acrylic pressure sensitive adhesive agent in a solvent such as toluene, hexane, and ethyl acetate; coating the solution on a release liner or a backing layer; removing the solvent by drying; and then binding the laminate coated with the solution to a backing layer or a release liner.
The embodiments given below are intended for demonstrating the present invention, not limiting the scope of the present invention. Any modifications and variations that can be easily made by those skilled in the art fall within the scope of the disclosure of the specification and the appended claims of the present invention.
The donepezil transdermal patches in which the acrylic pressure sensitive adhesive matrix layer comprises the components shown in Tables 1 and 2 are to be prepared. First, the donepezil free base, the acrylic pressure sensitive adhesive agents, and the permeation enhancers (if used) are mixed in ethyl acetate at room temperature. Then, the solution is coated on a PET release liner to form a pressure sensitive adhesive matrix layer having a thickness of about 95 micrometers. Ethyl acetate is removed by drying. Thereafter, the liner is bound to a polyester backing layer, so as to produce a donepezil transdermal patch. In Tables 1 and 2, Samples A1 to A3 and B1 to B4 are the examples of the present invention while Samples C1 to C5 are the comparative examples.
As shown in Table 3, at steady state, the donepezil transdermal patch of the present invention has an excellent skin permeation capability, which is at least two-fold than that of the patch of U.S. 2010/0080842 A1.
Four pieces of relatively the same size (approximately 20 mg/20 cm2) of Sample B1 in Table 2 were applied to the breast of four human subjects, and four tablets with 5 mg/tablet donepezil were orally administrated to another set of four human subjects. Then, the skin permeation rates of donepezil were tested by measuring the donepezil concentrations in blood samples that were drawn from the subjects at different time intervals.
The simulated test of multi-dosage on human subjects is carried out by using the donepezil transdermal patch, Sample B 1. This simulation test is carried out on the basis of the human subject test of Example 3.
Given the above, the donepezil transdermal patch of the present invention is characterized by comprising a specific acrylic pressure sensitive adhesive agent and, if needed, using a specific skin permeation enhancer. The patch of the present invention can provide an excellent skin permeation amount and a better treatment effect without using a high concentration of the active ingredients. Moreover, solid or undissolved donepezil active agents are not generated in the pressure sensitive adhesive matrix layer so the patch does not need to use a solubilizing agent. The donepezil transdermal patch of the present invention provides long-term effects, sustains steadiness and lasting drug concentration in the blood, and can be applied continuously to a skin site of patients for at least 3 days. Given the above, when compared with conventional patches, the donepezil transdermal patch of the present invention have excellent transdermal absorption properties and long-lasting drug effects.
It will be apparent to those skilled in the art that various modifications and variations can be made to the structure of the present invention without departing from the scope or spirit of the present invention. In view of the foregoing, it is intended that the present invention covers modifications and variations of this invention, provided they fall within the scope of the following claims and their equivalents.
| Number | Date | Country | Kind |
|---|---|---|---|
| 100101169 | Jan 2011 | TW | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US12/21145 | 1/12/2012 | WO | 00 | 11/5/2013 |
