FORM 2
THE PATENTS ACT, J 970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"LIQUID ORAL SPRAY DOSAGE FORM CONTAINING DONEPEZIL"
2. APPLICANT (S):
(a) NAME: Lincoln Pharmaceuticals Limited
(b) NATIONALITY: Indian Company incorporated under
the Companies Act, 1956
(c) ADDRESS: Lincoln House, Science City Road, Sola, Ahmedabad-380 060, Gujarat, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of Invention:
The present invention relates to dosage forms of Donepezil. More specifically, the present invention relates to a liquid oral spray dosage form for donepezil for management of dementia associated with Parkinsonism.
Background of Invention:
Parkinson's disease (also known as Parkinson disease or PD) is a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills, speech, and other functions. PD is the most common cause of chronic progressive Parkinsonism, a term which refers to the syndrome of tremor, rigidity, bradykinesia and postural instability.
The term Parkinsonism is used for symptoms of tremor, stiffness, and slowing of movement caused by loss of dopamine. "Parkinson's disease" is the synonym of "primary parkinsonism", i.e., isolated Parkinsonism due to a neurodegenerative process without any secondary systemic cause. In some cases, it would be inaccurate to say that the cause is "unknown", because a small proportion is caused by genetic mutations. It is possible for a patient to be initially diagnosed with Parkinson's disease but then to develop additional features, requiring revision of the diagnosis.
There are other disorders that are called Parkinson-plus diseases. These include: multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Some include dementia with Lewy bodies (DLB) while idiopathic Parkinson's disease patients also have Lewy bodies in their brain tissue, the distribution is denser and more widespread in DLB. Even so, the relationship between Parkinson disease, Parkinson disease with dementia (PDD), and dementia with Lewy bodies (DLB) might be most accurately conceptualized as a spectrum, with a discrete area of overlap between each of the three disorders.
Donepezil, marketed under the trade name Aricept by its developer Eisai and partner Pfizer, is a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the treatment of Alzheimer's disease where it is used to increase cortical acetylcholine. Its binding to the acetylcholinesterase can be seen at Proteopedia.

Donepezil is a specific non-competitive reversible inhibitor of acetylcholinesterase (AChE), and appears to exert its therapeutic effect by enhancing cholinergic function. By inhibiting the hydrolysis of acetylcholine by AChE, donepezil increases acetylcholine concentrations, thus enhancing cholinergic function. As the dementia progresses, fewer cholinergic neurons are thought to remain functionally intact, and the effects of donepezil may be lessened.
Donepezil is an oral medication used to treat Alzheimer's disease. It belongs to a class of drugs called cholinesterase inhibitors that also includes tacrine (Cognex). Scientists believe that Alzheimer's disease may result from a deficiency in chemicals (neurotransmitters) used by nerves in the brain to communicate with one another. Donepezil inhibits acetylcholinesterase, an enzyme responsible for the destruction of one neurotransmitter, acetylcholine. This leads to increased concentrations of acetylcholine in the brain, and the increased concentrations are believed to be responsible for the improvement seen during treatment with donepezil. Donepezil improves the symptoms but does not slow down the progression of Alzheimer's disease. Donepezil was approved by the FDA in 1996.
Donepezil was first described in US4895841 and WO 98/39000, the structure of which is as below, the empirical formula for donepezil is C24H29NO3 and chemical name is (RS)-2-[(1 -benzyl-4-piperidyl)methyl]- 5,6-dimethoxy-2,3-dihydroinden-l -one hydrochloride

Hitherto, donepezil has been formulated in various formulations such as tablets, solutions syrups, etc. One such formulation was disclosed in WO2005/097124 which discloses a liquid formulation. The said application fails to disclose or describe an oral formulation that can be applied as spray in buccal cavity.

With a view of increasing bioavailability and bypass hepatic metabolism, the inventors propose a novel dosage formulation for donepezil which can be administered as a spray to buccal cavity.
Summary of Invention:
Accordingly, the present invention provides an oral spray formulation for administration of donepezil hydrochloride with improved bioavailability.
Detailed Description of Invention:
The current invention describes a unique liquid oral spray dosage form containing Donepezil for the treatment of dementia associated with Parkinsonism. The said dosage form remains palatable even at higher concentrations. It gives relatively uniform dose dispensing than other oral liquid formulation, thereby improving bioavailability.
For purposes of this invention the phraseology and terminology used herein should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein are meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
For purposes of this invention, as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise.
In an embodiment the invention provides an oral spray formulation comprising a therapeutically effective amount of donepezil hydrochloride alongwith pharmaceutically acceptable excipients.
The formulation as described herein gives relatively better effect than available oral liquid/solid dosage forms. The same is dispensed in convenient container that can administer the formulation in form of fine droplets, resulting in easy delivery of formulation even to the pediatrics. The formulation is palatable eventhough the drug concentration is relatively large.

The formulation as described herein is used for management of dementia associated with Parkinsonism. Said formulation remains palatable even at a very high concentration of active, that is, Donepezil Hydrochloride by effectively masking the bitter taste of active.
As such, the formulation is directly applied to oral cavity through a device which dispenses the formulation in form of fine droplets. Since, the formulation is delivered in form of very fine droplets, it forms a mist. The formulation, by virtue of being dispensed as a fine mist, covers a larger area as compared to solid of liquid dosage form resulting in better and uniform absorption which enhances bioavailability of drug.
Further, since formulation is dispensed in mist form it covers large area of oral cavity and very small amount of dispensed volume reaches the gut and thus major portion of donepezil is absorbed in oral mucosa only. Hence, chances of hepatic metabolism are low.
In a preferred embodiment, the formulation of invention comprises Donepezil in an amount form 5 mg to 10 mg per spray along with sweeteners and flavors to mask the bitter taste.
The formulation further comprises solubilizer such as propylene glycol in ratio of 3 parts propylene glycol for 1 part of donepezil.
The formulation further comprises a polyhydric alcohol, preferably sorbitol 70% solution in concentration of 5mg/spray.
The formulation further comprises at least on sweetener selected from sucralose and/or neotame. Preferably sucralose in concentration of about lmg/spray and neotame in concentration of about 0.5 mg/spray.
The formulation further comprises menthol in an amount of 0.1 mg/spray. The formulation also comprises at least one flavoring agent such as mixed fruit flavor at a concentration of 0.25 mg/spray. A suitable preservative such as, sodium benzoate in concentration of 0.10mg/spray is also incorporated in formulation.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically exemplified by the preferred embodiments and optional features and examples, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art and such modifications and variations are considered to be falling within the scope of the invention.
Examples Example I:

Sr. No. Ingredients Label Claim
(mg/spray)
1. Donepezil 5
2. Propylene Glycol 15
3. Sorbitol 70% solution 5
4. Sucralose 1
5. Neotame 0.5
6. Menthol 0.1
7. Flavor mixed fruit 0.25
8. Sodium benzoate 0.10
9. Purified water q.S.
The formulation of example I above is manufactured by process comprising:
Step 1. Take small amount of purified water in to manufacturing vessel and
dissolve Donepezil in it. Step 2. Add mixture of Propylene glycol and Sorbitol 70% in to step: I and stir for
5 minutes. Step 3. Dissolve separately Sucralose, Neotame and Sodium benzoate in small
amount of purified water and add to Step 1 (manufacturing vessel) Step 4. Dissolving Menthol in flavor mixed fruit and add to step-1 (manufacturing
vessel)

Step 5. Make up the final volume with purified water. Example II:

Sr. No. Ingredients Label Claim (mg/spray)
1. Donepezil 10
2. Propylene Glycol 30
3. Sorbitol 70% solution 5
4. Sucralose 1
5. Neotame 0.5
6. Menthol 0.1
7. Flavor mixed fruit 0.25
8. Sodium benzoate 0.10
9. Purified water q. s.
The formulation of example II above is manufactured by process comprising:
Step 1. Take small amount of purified water in to manufacturing vessel and
dissolve Donepezil in it. Step 2. Add mixture of Propylene glycol and Sorbitol 70% in to step: 1 and stir for
5 minutes. Step 3. Dissolve separately Sucralose, Neotame and Sodium benzoate in small
amount of purified water and add to Step 1 (manufacturing vessel) Step 4. Dissolve Menthol in flavor mixed fruit and to step-1 (manufacturing vessel) Step 5. Make up the final volume with purified water.
Example III:

Sr. No. Ingredients Label Claim (mg/spray)
1. Donepezil 10
2. Polyethylene Glycol 400 20
3. Sorbitol 70% solution 10
4. Sucralose 1

5. Neotame 0.5
6. Menthol 0.1
7. Ess. Pipermint 0.20
8. Sodium benzoate 0.10
9. Purified water q. s.
Manufacturing process:
Step 1. Take small amount of purified water in to manufacturing vessel and
dissolve Donepezil in it. Step 2. Add mixture of Polyethylene glycol 400 and sorbitol 70% in to step: 1 and
stir for 5 minutes Step 3. Dissolve separately Sucralose, Neotame and Sodium benzoate in small
amount of purified water and add to Step 1 (manufacturing vessel) Step 4. Dissolve Menthol in Ess. Pipermint fruit and add to step-1 (manufacturing
vessel) Step 5. Make up the final volume with purified water
Example IV:

Sr. No. Ingredients Label Claim
(mg/spray)
1. Donepezil 5
2. Polyethylene Glycol 400 16
3. Glycerine 6
4. Sucralose 1
5. Neotame 0.4
6. Menthol 0.12
7. Ess. Spearmint 0.15
8. Sodium benzoate 0.10
9. Purified water q. s.

Manufacturing Process:
Step 1. Take small amount of purified water in to manufacturing vessel and
dissolve Donepezil in it. Step 2. Add mixture of Polyethylene glycol 400 and Glycerin in to step: 1 and stir
for 5 minutes. Step 3. Dissolve separately Sucralose, Neotame and Sodium benzoate in small
amount of purified water and add to Step I (manufacturing vessel) Step 4. Dissolve Menthol in Ess. Spearmint fruit and add to step-1 (manufacturing
vessel). Step 5. Make up the final volume with purified water. Example V:

Sr. No. Ingredients Label Claim (mg/spray)
10. Donepezil 10
11. Propylene Glycol 25
12. Glycerine 15
13. Sucralose 0.5
14. Neotame 1.0
15. Menthol 0.15
16. Ess. Orange Flavour 0.25
17. Sodium benzoate 0.10
18. Purified water q.S-
Step 1. Take small amount of purified water in to manufacturing vessel and
dissolve Donepezil rn it. Step 2. Add mixture of Propylene glycol and Glycerin in to step: 1 and stir for 5
minutes. Step 3. Dissolve separately Sucralose, Neotame and Sodium benzoate in small
amount of purified water and add to Step 1 (manufacturing vessel) Step 4. Dissolving Menthol in Ess. Orange flavour and add to step-1
(manufacturing vessel). Step 5. Make up the final volume with purified water

We claim,
1. A oral spray composition comprising donepezil hydrochloride in an amount of 5 mg to 10 mg; a solubilizer such as propylene glycol in ratio of 3 parts propylene glycol for 1 part of donepezil; sorbitol 70% solution alongwith one or more pharmaceutical acceptable excipients.
2. The oral spray composition according to claim1, wherein the one or more pharmaceutical acceptable excipients are selected from flavoring agent, sweetener, preservative and menthol.
3. The oral spray composition according to claiml, wherein the menthol is present in an amount of 0.1 mg/spray.
4. The oral spray composition according to claiml, wherein the flavoring agent is present in an amount of 0.25 mg/spray.
5. The oral spray composition according to claiml, wherein the preservative such as sodium benzoate is present in an amount of 0.10mg/spray.
6. The oral spray composition according to claiml, wherein the sweetener is selected from sucralose or neotame, present in an amount of 0.5 to lmg per spray.
7. The oral spray composition according to any one of the preceding claims is intend to increase the oral bioavailability and to bypass hepatic metabolism.