FIELD OF INVENTION

The present invention relates to a transdermal patch for treatment of degenerative neurological disorders like dementia or Alzheimer type dementia.

BACKGROUND

There are certain neurological disorders in which there will be progressive deterioration in cognitive function. Dementia is the one among them and it is a non-specific syndrome in which affected areas of brain function may be affected  such as memory  language  problem solving and attention.Dementia  unlike Alzheimer""s  is not a disease in itself. When dementia appears the higher mental functions of the patient are involved initially. Eventually  in the later stages  the person may not know what day of the week  month or year it is  he may not know where he is  and might not be able to identify the people around him. This dementia is one major symptom associated with Alzheimer""s  Parkinson’s etc.

Certain drugs like Rivastigmine  Donepezil and Galantamine etc.  are known in the prior art to be used in treatment of Alzheimer type dementia.

US Patent 4948807 discloses a compound N-ethyl  N-methyl-3-[1-(dimethylamino)ethyl]-N-methyl-phenyl-carbamate] with common name Rivastigmine for the treatment of senile dementia Alzheimer’s disease and other neurodegenerative disorders.

Rivastigmine is available commercially in the market as oral capsule and solution dosage forms under the brand name EXELON®.

The oral administration of Rivastigmine or other known anti-dementia medicines is generally followed or accomplished by nausea and vomiting. Since  a patient has to take these medicines for a long duration therefore  a strong need was felt for alternate route of administration of these anti-dementia drugs to overcome the associated side effects. Systemic administration of anti-dementia drugs has been found to be very effective alternative in lowering the above specified side effects like nausea and vomiting. In systemic administration the active drug diffuses through the skin in transdermal route.

In recent developments  transdermal patches comprising anti-dementia drugs have been very successful in treatment of these neurodegenerative disorders with less side effects and better patient compliance.

US Patent 5 602 176 discloses (S)-N-ethyl-3-[(1-dimethylamino)ethyl]-N-methyl-phenylcarbamate (Rivastigmine) and a transdermal pharmaceutical composition comprising Rivastigmine and non-swellable acrylate polymer (Durotack 280-2416).

US Patent 6 316 023 claimsa transdermal device comprising a pharmaceutical composition containing 1 to 40 weight percent of Rivastigmine in free base or acid addition salt  0.01 to 0.5 weight percent of an antioxidant and a diluent or carrier wherein the antioxidant is preferably a-tocopherol or ascorbylpalmitate. The composition also comprises 10 to 30 weight percent of polymethacrylate or acid addition salt.

US 2010/0087768 relates to transdermal device containing a drug which is liquid at room temperature  selected from propargylamines and rivastigmine which may be partially volatile at process temperature during manufacture of the device. In this patent acrylic polymer pressure sensitive adhesive is used for formulation.

WO 2011076621 relates to adhesive monolith comprising a drug reservoir (reservoir) on a support (top layer) containing rivastigmine as drug and a polymer matrix and an adhesive layer present on the reservoir comprising a contact adhesive and a removable layer wherein the polymer matrix of the reservoir does not comprise either hydroxyl groups or carboxyl groups

Rivastigmine patch is commercially available (Exelon® patch) in the market. However  this commercially available Rivastigmine patch has complicated multilayer pressure-sensitive adhesive system consisting of acrylic polymer layer containing drug  antioxidant and silicone adhesive layer to control drug release. It contains four layers i.e. backing film followed by drug matrix (drug product in acrylic matrix)  adhesive (silicon) matrix and release liner which will be removed at the time of use.

This multilayer system always increase the production cost and has a more complex manufacture than monolayer systems.The acrylics used in the above discussed prior arts usually have a disadvantage of poor adhesion to low-energy surfaces  such as polyethylene and polypropylene  as well as lower overall adhesion compared to rubber unless the adhesive is highly engineered.

OBJECTS OF THE INVENTION

The primary object of the invention is to provide a transdermal patch for treatment of neurodegenerative disorder like dementia orAlzheimer type dementia.

Another object of the invention is to provide a controlled release transdermal patch of Rivastigmine  which is cost effective  more stable and less complicated for large scale industrial production.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure-1 is graphical representation of in vitro mouse skin permeation test result for examples 1  3 and 5.

Figure-2 is graphical representation of in vitro mouse skin permeation test result for examples 7 and 11.

Figure-3 is graphical representation of in vitro human skin permeation Test result for examples 1 and 7.

SUMMARY OF THE INVENTION

Accordingly  the present invention provides a transdermal patch of Rivastigmine for treatment of neurodegenerative disorder like dementia or Alzheimer type dementia by controlled systemic administration of Rivastigmine to the subject under treatment.

In one embodiment of the invention  the transdermal patch comprises a backing film  an adhesive monolayer containing Rivastigmine in free base form or its pharmaceutically acceptable salts and release liner.

In one preferred embodiment of the invention  the transdermal patch comprises an adhesive monolayer which contains Rivastigmine  styrene block copolymer  a tackifier  and an anti-oxidant  wherein total polystyrene units are in an amount of 4% w/w or more of said adhesive monolayer.

DETAILED DESCRIPTION

Detailed embodiments of the present invention are disclosed herein with reference to the examples and drawings. However  it is to be understood that the disclosed embodiments are merely exemplary of the invention  which can be embodied in various forms. Therefore  specific structural and functional details disclosed herein are not to be interpreted as limiting  but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriately detailed structure. Further  the terms and phrases used herein are not intended to be limiting but rather to provide an understandable description of the invention.

The term "controlled release" as used herein refers to the drug release. Typically  the controlled release refers to the release of the drug at a controlled rate over an extended period of time longer induration compared to the conventional release.
In the preferred embodiment  Rivastigmine may be in the form of free base or its pharmaceutically available salts in the adhesive monolayer.

In one embodiment of the invention  the amount of Rivastigmine in free base form is preferably 10-25%  more preferably 15-21% w/w of the adhesive monolayer.

It was found that styrene block copolymer is suitable as a synthetic rubber polymer in preparing the transdermal patch with Rivastigmine as active anti-dementia drug. In the preferred embodiment  styrene block copolymer is at least one selected from the group consisting of styrene-butadiene-styrene  Styrene-ethylene/butylene-styrene  Styrene-ethylene/propylene  Styrene-isoprene-styrene. In more preferred embodiment  Styrene-isoprene-styrene is used.

In one embodiment of the invention  the amount of styrene block copolymer is preferably 10 - 35%w/w  more preferably 15 - 30% w/w  still more preferably 20 - 30% w/w of the adhesive monolayer.

In above monolayer  total amount of polystyrene unit may be preferably 4- 6% w/w  more preferably 4.5-5.5% w/w  of said adhesive monolayer. Such amount of polystyrene content is advantageous for the good physicochemical property of softness (hardness)  drug holding without having cold flow  and enable higher adhesiveness on skin.

Tackifiers are chemical compounds used in formulating adhesives to increase the tack  the stickiness of the surface of the adhesive. Tackifiers are usually resins (e.g. rosins and their derivates  terpenes and modified terpenes  aliphatic  cycloaliphatic and aromatic resins (C5 aliphatic resins  C9 aromatic resins  and C5/C9 aliphatic/aromatic resins)  hydrogenated hydrocarbon resins  and their mixtures  terpene-phenol resins (TPR  used often with ethylene-vinyl acetate adhesives)).

Many pressure sensitive adhesives are a blend of styrene block copolymer and a tackifier resin. Some acrylic adhesives also include an additional tackifier. Rosin esters impart excellent specific adhesion to a wide range of substrates due to their polarity and polymer compatibility. Their low molecular weight and narrow molecular weight distribution  combined with their cycloaliphatic – aromatic structure  make rosin esters the most broadly compatible of all adhesive tackifiers. They are used in a wide range of polymers including high and low vinyl acetate EVA  acrylics  polyurethanes.

Further  the amount of the tackifier is preferably 30-70% w/w  more preferably 45-70% w/w  still more preferably 54-65% w/w of the monolayer.The ratio of total tackifier: styrene block copolymer is preferably 2:1 to 3:1  more preferably 2.1:1 to 2.6:1.

In onespecific embodiment of the invention  the tackifier in the monolayer comprises rosin ester and petroleum resin. Preferred example of rosin ester and petroleum resininclude rosins and their derivatives  terpenes and modified terpenes  aliphatic  cycloaliphatic and aromatic resins  hydrogenated hydrocarbon resins and their mixtures and terpene-phenol resins. The ratio of petroleum resin: rosin ester is preferably 1:1 to 3:1  more preferably 1.9:1 to 3:1  still more preferably 1.9:1 to 2.7:1.

Further  anti-oxidant is preferably a phenolic anti-oxidant  more preferably Butylatedhydroxytoluene.

The amount of the anti-oxidant is in preferably0.5% to 1.2%w/w of the monolayer.

The transdermal patch of the present invention may include a simple three layer laminate structure of an outer backing film  an adhesive monolayer and a release liner wherein said monolayer maybe a matrix structure as mentioned above.

The backing film is  without being limited to  selected from polyester film  polyester/polyethylene lamination film  or polyester/ethylene vinyl acetate lamination film.

The release liner film is  without being limited to  selected from silicon surface coated polyester film  fluoropolymer coated polyester  or fluoropolymer coated polypropylene. This release liner is removed at the time of usage.

The backing layer and the adjacent adhesive monolayer may have strong cohesive force between them which keeps the backing layer and matrix layer intact with each other when patch is applied on the body of the substrate whereas  the monolayer and the release liner may have weak cohesive force between them therefore  release liner can be easily removed before applying the patch on the body. Removal of release liner exposes the monolayer of the patch for application on the body wherein Rivastigmine is systemically administered into the body.

The transdermal patch of the invention may provide a device for control release of Rivastigmine for treatment of dementia or Alzheimer type dementia.

In another embodiment  the present invention also provides a process for preparing a pharmaceutical composition for use as the adhesive monolayer of the present invention wherein the process comprises:
a). dissolving styrene block copolymer in an organic solvent  preferably toluene;
b). adding tackifier such as Rosin ester and Petroleum resinand obtaining a clear semisolid mixture;
c). optionally adding other required excipients such as polybutene into the above mixture andthoroughly mixing the mixture contents;
d). adding Rivastigmine into the mixtureand mixing;
e). obtaining the pharmaceutical composition for use as the adhesive monolayer.

The process may further involves uniformly coatingviscous solution on the silicone coated polyester film and drying in oven to remove solvent and it was laminated by polyesterbacking film  and cut by punching for required patch size.The transdermal patch of the invention can be easily produced and has good stability properties and sufficient stickiness forlong lasting effect for once a daily application patch. The transdermal patch is also useful to simplify the manufacturing process and decreases the cost of production.

According to another embodiment  the present invention provides a method for treating neurodegenerative disorder comprising plastering on the skin of a living body with the transdermal patch of the present invention.

The amount of Rivastigmine may be appropriately determined by those skilled in the art depending on the kinds of symptoms of patients  dosage periods  the sizes of preparations  and the like.

Also  the application period is preferably one day or 24 hours.

Further  the living body described above includes  for example  rabbit  dog  or human  preferably human.

EXAMPLES
The invention is further explained with the help of following examples. However  given examples are only for understanding the invention and not for limiting the scope of the claims.
In the example  “percentage” wherever used would mean “weight percentage”  unless otherwise specified.

Preparation of transdermal patch formulation:

Total 13different formulations of pharmaceutical composition with variation in the ingredients and concentrations of the ingredients were prepared as shown in following table 1. Below given general process was used for preparation of all 13formulations. After preparation  all 13formulations were evaluated fordifferent parameters described herein after and the best formulation was identified with the combination and concentration of ingredients giving the best desired result.

Preparation of transdermal patch with synthetic rubber:

Synthetic rubber was dissolved in an organic solvent preferably toluene  tackfier materials such as Rosin ester and Petroleum resin were added and clear semisolid mixture was obtained. Polybutene was added as required as shown in the table-1. Other required materials as shown in table-1were added and mixed. Rivastigmine base was added and well mixed. The viscous solution was uniformly coated on the silicone coated polyester film and dried in an oven to remove solvent  and it was laminated by polyesterbacking film  and cut by punching for required patch size.

Preparation of transdermal patch with acrylic and silicone polymers:

Pre dissolved polymer solution in ethylacetate  hexane or other solvent was mixed with required materials  and followed by Rivastigmine base and well mixed. The viscous solution wasuniformly coated on the silicone coated polyester film and dried in oven to remove solvent  and it was laminated by polyester backing film  and cut by punching for required patch size.

Table-1 (Number: weight percentage in adhesive)
INGREDIENTS Ex-1 Ex-2 Ex-3 Ex-4 Ex-5 Ex-6 Ex-7 Ex-8 Ex-9 Ex-10 Ex-11 Ex-12 Ex-13
Rivastigmine base 20.1 20.0 19.8 20.0 19.9 10.2 15.0 10.0 19.8 19.9 15.0 15.0 18.0
Butylatedhydroxytoluene 0.5 0.5 0.5 0.5 0.5 0.5 0.8 0.8 0.6 0.6 0.8 0.8 1.0
Styrene-Isoprene-Styrene copolymer
(Polystyrene 22%) 25.0 - - - - - 25.0 25.0 14.9 15.1 - - -
Styrene-Isoprene-Styrene copolymer
(Polystyrene 20%) - - - - - - - - - - 25.0 - 25.0
Styrene-Isoprene-Styrene copolymer
(Polystyrene 15%) - - - - - - - - - - - 25.0 -
Rosin ester 15.0 - - - - - 20.0 25.0 - 9.9 20.0 20.0 17.0
Petroleum resin 39.4 - - - - - 39.2 39.2 49.6 40.1 39.2 39.2 39.0
Polybutene - - - - - - - - 15.2 14.8 - - -
Acrylates Copolymer Durotak-2353 - - 40.1 - - - - - - - - - -
Acrylates Copolymer Durotak-2510 - 79.5 39.5 - - - - - - - - - -
Acrylates Copolymer
Cytec-9083 - - - - 39.8 - - - - - - - -
Acrylates Copolymer Cytec-7883 - - - 79.5 39.8 - - - - - - - -
Silicone Adhesive
Dowcorning-4602 - - - - - 89.3 - - - - - - -

Evaluation

Physical observation of adhesive
The physical property of adhesive was evaluated by thumb tack feeling. The evaluation score was indicated as below in table-2.

Table-2
Score
A Excellent adhesion  no pithy nature  no remaining adhesive on thumb
B Good adhesion  minor pithy nature  minor remaining adhesive on thumb
C Fair adhesion  pithy nature  the adhesive remains on thumb
D Poor adhesion  pithy nature  majority of adhesive remains on thumb
Peel Test

The test sample was cut 1 cm width x 2.5 cm long and placed on stainless steel plate and peeled with the angle of 180°Cat 300mm/min speed. The peeling force was measured as adhesive test.

In vitro mouse skin permeation Test

The nude mouse (7-11 weeks old) skin was taken out surgically  and a 3 cm2 of circled shape test sample was attached to thestratum corneumside of nude mouse skin and set on to Franz diffusion cells. The receiver compartment was filled with phosphate buffered saline  pH=7.4  at 32ºC  and the receiver solution was taken at each predetermined sampling time point and measured by HPLC. The drug amount permeated was calculated as per the chromatographic peak area.
In vitro human skin permeation Test

Human cadaver skin was used to evaluate drug permeability of Example-1 and Example-2. A5cm2 of circled shape test sample was attached to the horney side of human cadaver skin  and set on to flow-through type diffusion cells. The receiver compartment was filled with phosphate buffered saline  pH=7.4  at 32ºC  and the receiver solution was taken at each predetermined sampling time point  and measured by HPLC. The drug amount permeated was calculated as per the chromatographic peak area.
Figure-1in the accompanying drawings illustrates a graphical representation of in vitro mouse skin permeation test result for examples 1  3 and 5.

Figure-2in the accompanying drawings illustrates graphical representation of in vitro mouse skin permeation test result for examples 7 and 11.

Whereas  Figure-3 of the accompanying drawings represents in vitro human skin permeation Test result for examples 1 and 7.
The observed results were summarized in table-3 below.
Table-3
Drug (%) Styrene-Isoprene-Styrene copolymer
(%) Tackifier (%) Ratio of Tackifier/ Styrene-Isoprene-Styrene copolymer Ratio of Petroleum resin /Rosin ester Total Polystyrene units content (%) Physical Observation Score Peel Test (kg/cm) Skin permeation
Ex-1 20.1 25.0 54.4 2.18 2.63 5.5 A 0.86 A
Ex-2 20.0 - - - - - C 1.03 -
Ex-3 19.8 - - - - - B 1.01 B
Ex-4 20.0 - - - - - C - -
Ex-5 19.9 - - - - - B 0.67 C
Ex-6 10.2 - - - - - D - -
Ex-7 15.0 25.0 59.2 2.37 1.96 5.5 A 0.81 A
Ex-8 10.0 25.0 64.2 2.57 1.96 5.5 A 1.63 -
Ex-9 19.8 14.9 49.6 3.31 - 3.3 C - -
Ex-10 19.9 15.1 50.0 3.33 4.05 3.3 C - -
Ex-11 15.0 25.0 59.2 2.37 1.96 5.0 A 1.45 A
Ex-12 15.0 25.0 59.2 2.37 1.96 3.75 C - -
Ex-13 18.0 25.0 56.0 2.24 2.29 5.0 A 1.04 -

Observation
From the results  Example-1  7  8 11 and 13 showed good score of physical observation  peel force value and higher skin permeability.
The composition of Example 1  7  8 11 and 13 is further described herein below in table-4.
Table-4
Ex-1 Ex-7 Ex-8 Ex-11 Ex-13 Observed range
Drug (Rivastigmine base) 20.1 15.0 10.0 15.0 18.0 15 – 20.1% w/w
Anti-oxidant 0.5 0.8 0.8 0.8 1.0 0.5 – 1.0% w/w
Styrene-isoprene-styrene 25.0 25.0 25. 25.0 25.0 -
Total tackifier (Rosin ester + Petroleum resin) 54.4 59.2 64.2 59.2 56.0 54.4 – 64.2% w/w
Ratio of total tackifier / Styrene-isoprene-styrene 2.18 2.37 2.57 2.37 2.24 2.18 – 2.57
Ratio of Petroleum resin / Rosin ester 2.63 1.96 1.96 1.96 2.29 1.96 – 2.63
Total polystyrene units content (%) 5.5 5.5 5.5 5.0 5.0 5.0 - 5.5%

We Claim:
1. A transdermal patch for treatment of neurodegenerative disorder  comprising a backing film an adhesive monolayer containingRivastigmine in free base form or its pharmaceutically acceptable salts and a release liner.

2. The transdermal patch as claimed in claim 1  wherein the adhesive monolayer further comprises  styrene block copolymer  a tackifier  and an anti-oxidant  and wherein total polystyreneunitsare in an amount of 4% w/w or more of said adhesive monolayer.

3. The transdermal patch as claimed in claim 1 or 2  wherein said Rivastigmine in free base form is in an amount of 10-25%.

4. The transdermal patch as claimed in claim 2 or 3  wherein said styrene block copolymer is in an amount of 10 - 35% w/w of said adhesive monolayer.

5. The transdermal patch as claimed in any one of claims2 to 4  wherein total polystyrene units are in an amount of 4- 6% w/w of said adhesive monolayer.

6. The transdermal patch as claimed in any one of claims2 to 5  wherein said styrene block copolymer is at least one selected from the group consisting of styrene-butadiene-styrene  Styrene-ethylene/butylene-styrene  Styrene-ethylene/propylene  Styrene-isoprene-styrene  preferably Styrene-isoprene-styrene.

7. The transdermal patch as claimed in any one of claims2 to 6  wherein said tackifier is combination of rosin ester and petroleum resin.

8. The transdermal patch as claimed in claim 7  wherein ratio of petroleum resin: rosin ester is 1:1 to 3:1.

9. The transdermal patch as claimed in any one of claims2 to 8  wherein said tackifier is in an amount of 30-70% w/w  preferably 45-70% of said adhesive monolayer.
10. The transdermal patch as claimed in any one of claims2 to 9  wherein the ratio of total tackifier: styrene block copolymer is 2:1 to 3:1.

11. The transdermal patch as claimed in any one of claims2 to 10  wherein said anti-oxidant is a phenolic anti-oxidant.

12. The transdermal patch as claimed in any one of claims2 to 11  wherein said anti-oxidant is Butylatedhydroxytoluene.

13. The transdermal patch as claimed in any one of claims2 to 12  wherein said anti-oxidant is in an amount of 0.5% to 1.2% w/wof said adhesive monolayer.

14. The transdermal patchas claimed in any one of claims2 to 13  wherein said neurodegenerative disorder is dementia or Alzheimer type dementia.

15. The transdermal patch as claimed in any one of claims1 to 14  wherein said backing film is selected from polyester film  polyester/polyethylene lamination film  or polyester/ethylene vinyl acetate lamination film.

16. The transdermal patchas claimed in any one of claims1 to 14  further comprising a removable release liner which is selected from silicon surface coated polyester film  fluoropolymer coated polyester and fluoropolymer coated polypropylene.

17. A transdermal patch for treatment of neurodegenerative disorder such as herein described in the description with reference to the accompanying examples and drawings.