WO2011055383A2

WO2011055383A2 - Intranasal delivery to improve the performance of children suffering from dyslexia

Info

Publication number: WO2011055383A2
Application number: PCT/IN2010/000719
Authority: WO
Inventors: Ambikanandan Rajnarayan Misra; Narendra Ishwarlal Gandhi; Mannalal Ramgopal Bajaj; Bharat Babulal Shah; Rajan Shantaram Samant; Hemal Rana
Original assignee: Lyka Labs Limited
Priority date: 2009-11-06
Filing date: 2010-11-01
Publication date: 2011-05-12
Also published as: WO2011055383A3

Abstract

The invention discloses a pharmaceutical composition comprising therapeutically effective amount of stimulants, anti-motion drugs and nootropics, either alone or in combination, administered through, oral, intranasal or intravenous, for the treatment and/or management of dyslexia.

Description

INTRANASAL DELIVERY TO IMPROVE THE PERFORMANCE OF CHILDREN SUFFERING FROM DYSLEXIA"

TECHNICAL FIELD OF THE INVENTION:

The present invention relates to a pharmaceutical composition comprising stimulants, anti-motion drugs and nootropics, either alone or in combination, administered through oral intranasal or intravenously, for the treatment and/or management of dyslexia.

BACKGROUND AND PRIOR ART:

Dyslexia is a learning disability characterized by problems in reading, spelling, writing, speaking and listening. However, the persons with dyslexia frequently display above average to superior intelligence, gifted creativity and genius like Leonardo da Vinci, Albert Einstein, Walt Disney etc. In many cases, dyslexia appears to be inherited. The National Institutes of Health estimates that about 5-10% of school-aged children and total of 15% of the United States population is affected by learning disabilities, mostly with problems in language and reading. The condition appears in all ages, races and income levels.

Dyslexia is not a disease, but describes rather a different kind of mind that learns in a different way from other people. Dyslexia is a major problem of human development. It is a disorder manifested by difficulty in learning to read despite conventional instruction, adequate intelligence and sociocultural opportunities that arises from fundamental cognitive disabilities.

Dyslexic children seem to have trouble learning early reading skills, problems hearing individual sounds in words, analyzing whole words in parts, and blending sounds into words. Often, a person with dyslexia has a problem translating language into thought (such as in listening or reading) or translating thought into language (such as in writing or speaking). The problems with identifying single words, understanding sounds in words, sound order, or rhymes, spelling, transposing letters in words, handwriting, reading comprehension, delayed spoken language, confusion with directions, or right/left handedness, confusion with opposites (up/down, early/late and so on), mathematics are also commonly observed.

Dyslexic children also experience difficulties with 'jumbled spellings'. These are spelling attempts in which all the correct letters are present, but are written in the wrong order, shows that the child is experiencing difficulty with visual memory. Non-dyslexic children and adults often use their visual memory when trying to remember a difficult spelling. They write down two or three possible versions of the word on a spare piece of paper and see which spelling 'looks right'. They are relying on their visual memory to help them, but the visual memory of a dyslexic child may not be adequate for this task. Some children mix up 'b' and 'd'or even 'p' and 'q' and the number 9. These letters are the similar in their mirror image, and cause regular confusion for a dyslexic person.

Research indicates that dyslexia is a chronic and persistent disorder. Dyslexia is a kind of learning disability noted for spatial reversals and shifts and is sometimes described as a neurological disorder. Occasionally, balance, movement and rhythm are also affected.

Although an exact cause has not been identified, studies have identified differences in the way sound and visual information are processed between persons with and without dyslexia. In the dyslexic individual these differences create a "physiologic signature" a unique brain pattern resulting because of emphasized activity along dopamine related neuro-pathways. Dopamine is a neurotransmitter, chemical substance acting in the brain that facilitates certain kinds of messages. When dopamine levels are high, the person with dyslexia experiences time as moving very slowly outside themselves, and very fast inside as if time stands still. It has also been observed that, when the person with dyslexia experiences episodes of disorientation, words or sounds do not create a visual picture for them and their mind continues to try and solve the confusion visually, at that time, dopamine levels also shift and change. This seems to be consistent with some of the symptoms of dyslexia, such as inaccurate perceptions of time and a lot of day dreaming.

Specifically, a Position Paper on Reading Disabilities In Your Child of the American Association of Ophthalmology presented and distributed at the forum, "The Right To Read" of the White House Conference on Children, Washington, D.C., Dec. 14, 1970, entitled, "Dyslexia" defines the term "Dyslexia" as a difficulty in reading or reading disability because of a poor understanding of printed words. Dyslexia caused by obvious conditions such as prolonged absence from school, psychological problems, or obvious (generally cortical) brain defects is identified as "secondary dyslexia". The dyslexia which is stated to be of unknown origin is referred to as "specific primary dyslexia or developmental dyslexia". The paper continues with the teaching that eye defects do not cause specific primary dyslexia because the dyslexia is based on recognition and not on vision. This view is representative of the widely accepted belief of the medical profession that this form of dyslexia is caused by an inability of the brain to recognize what the eye sees (see, for example: "Reading Disability" edited by John Money, pp. 9-16 and 45-60, The Johns Hopkins Press (1962); and Vol. 20, No. 3, August 1973 issue of "Pediatric Clinics of North America," pp. 587-597 and 599-605).

The first reference of the term dyslexia occurred in 1872 by the physician R. Berlin of Stuttgart, Germany, who used the term to describe the case of an adult with acquired dyslexia, that is, loss of reading ability due to a brain lesion. Short afterwards, Dr. A. Kussmaul (1877) suggested the term "word blindness" to describe an adult aphasic patient who had lost his reading ability. Similarly, Charcot (1887) defined dyslexia as the total loss of reading ability. Finally, Bateman, in 1890, defined dyslexia as a form of verbal amnesia in which the patient has lost the memory of the conventional meaning of graphic symbols (Critchley, 1964). On 21^stDecember 1895, James Hinshelwood, an optic surgeon from Glasgow, Scotland, published an article in the journal "The Lancet" on the issue of visual memory and word blindness. This article inspired W. Pringle Morgan, a general doctor of the seashore town of Seaford, to describe the case of an intelligent fourteen years-old boy who could not learn how to read. His article, published in the British Medical Journal on 7*November 1896, is considered as one of the first reports about congenital word blindness, if not the first. In this sense, Morgan is recognized as the father of developmental dyslexia. As much as Morgan is considered the father, the ultimate founder and sponsor of the study of dyslexia was Hinshelwood, who published a series of reports and articles between 1896 and 191 1 in the medical press describing clinical cases and suggesting its possible congenital nature. Hinshelwood contributed essentially to create a clinical and social awareness necessary to consider dyslexia as a medical issue of greatest importance. In 1917, Hinshelwood published a second treaty on "Congenital Word Blindness", which summarized the current knowledge on the issue. According to him, the defect involved the acquisition and storage in the brain of the visual memories of letters and words. This defect was hereditary, but remediable, and more common in boys. His classification of dyslexics in three groups is also interesting: Alexia, for cases of mental retardation with reading disability; Dyslexia, for common cases of small delays in learning to read; and word blindness, for severe cases of pure reading disability. In his multiple publications, Hinshelwood described the congenital nature of these reading difficulties and tried to find its biological causes. However, Naidoo (1972) observed that dyslexics had memory problems, specifically with storage capacity, claiming that dyslexics could experience other problems besides phonological deficits. Two similar studies (Spring and Capps, 1974; Denckla and Rudel, 1976) showed that dyslexics, in general, have a good vocabulary but they are slow in naming objects. Martha Denckla and Rita Rudel designed a serial rapid naming task (colors, numbers, objects and letters), named "Rapid Automatized Naming," which has become the standard task to measure this skill. Subject's scores on this task are related to phoneme awareness and reading skills, but they are still, to some degree, different cognitive abilities. From this moment on, it became apparent that it was necessary to study all these language and cognitive skills that are related to reading ability. The goal was to find out which of these skills are causally important in the development of reading and the etiology of dyslexia. Vellutino (1979) stated that dyslexics have difficulties establishing verbal associations, perhaps due to phonological decoding problems. Moreover, there exists a relationship between phonological deficits and short-term memory deficits in normal readers. Theories relating dyslexia with memory or visual deficits continued during this decade, although in a lesser amount than in previous decades. Thomson (1984), of the University of Birmingham, England, pointed out that dyslexics have memory deficits, specifically a smaller storage capacity than normal readers. Richard Wagner and Torgesen (1987) claimed that phoneme awareness is essential to learning to read. Margaret Snowling, English psychologist, described during the 1980s and 1990s dyslexics' deficits in phonological tasks and short-term memory.

Current treatment of dyslexia is carried out using a team of neurologist, a pediatrician, and special education instructors. The management for dyslexic patients is life-long. Intervention programs to children must systematically and explicitly teach phonics ensuring a clear understanding of how letters are linked to sounds (phonemes) and spelling. Typically individualized teaching with opportunities for writing, reading, and discussing literature is recommended to provide a balanced remedial program providing systematic instruction on phonemic awareness, phonics, vocabulary fluency and comprehension strategies. Treatment for older persons (high school, college, and graduate school) is accommodation rather than remediation. College students require extra time with examination and reading/writing assignments. Other accommodations include recorded books, tape recorders in the classroom, tutorial services, alternatives to multiple choice questions and computer availability with spelling checkers.

US Patent No.7576133 discloses a method of nasal administration of stimulant and Modafinil which are adapted for nasal administration.

US Patent Publication No.2010016437 discloses a pharmacotherapy of cognitive deficits in learning and memory by administering an alpha-am inoamide, particularly safinamide.

Russian Patent No.2212890 relates to infusion solution used for improvement of cerebral circulation comprising Vinpocetine, ascorbic acid, benzyl alcohol, sodium pyrosulfite, sorbitol, tartaric acid and water.

Russian Patent No.2262931 relates to a pharmaceutical composition as a solid medicinal formulation possessing cerebro-vasodilating and nootropic activity and comprising vinpocetin piracetam as active components.

United States Patent 3940485 discloses a pharmacotherapy of dyslexia by treatment and pre-treatment of dysmetric dyslexia by improving sequential scanning and ocular fixation abilities and therapeutic compounds

All these drugs are given orally and by parental route and act on brain neurotransmitter systems. However, the current existing therapies shows potential dose dependent side effects of these drugs especially stimulants which shows nervousness and insomnia, and long-term use of stimulants in children are reported to cause drug dependence, adversely affect growth, may ironically depress the nervous system or lead to loss of consciousness. An important contribution of the present invention is therefore, firstly, the recognition that the aforesaid discovered conditions existing in a dyslexic patient contribute to his poor response to reading instruction, and secondly, devising the within method according to which said patient can be properly prepared for reading so as to significantly improve his reading performance by improving memory.

Accordingly, the primary objective of the current invention is to reduce the drug dosing and enhancing the brain delivery of the drugs through intranasal administration or by other route of administration which may be successfully used in treatment and/or management of dyslexia.

SUMMARY OF THE INVENTION:

In accordance with the above, the present invention provides a pharmaceutical composition comprising stimulants, anti-motion drugs and nootropics either alone or in combination for treatment of dyslexia.

Specifically, the present invention provides a pharmaceutical composition comprising Vinpocetine, Modafmil and Cyclizine either alone or in combination, by nasal, oral or parenteral route for the effective management of Dyslexia.

In another aspect, the present invention provides a pharmaceutical composition in the form of Solution, Suspension, Powder, Liposome, Microemulsion, Microspheres, Tablet and Capsule.

In yet another aspect, the present invention provides a method for administration of a pharmaceutical composition either alone or in combination by nasal, oral or parenteral route for the management of dyslexia.

DESCRIPTION OF FIGURES:

Figure 1: Diffusion studies and the mean cumulative values for % drug release Figure 2: Effects of drug Vinpocetine orally and nasally administered in to mice on the escape latency achieved in the Morris Water Maze Task in Saline treated mice.

Figure 3: Effects of drug Vinpocetine orally and nasally administered in to mice on the escape latency achieved in the Morris Water Maze Task in Scopolamine treated mice.

Figure 4: Effects of drug Modafinil orally and nasally administered in to mice on the escape latency achieved in the Morris Water Maze Task in Saline treated mice.

Figure 5: Effects of drug Modafinil orally and nasally administered in to mice on the escape latency achieved in the Morris Water Maze Task in Scopolamine treated mice.

DETAILED DESCRIPTION OF THE INVENTION:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

"An effective amount of Vinpocetine and/or Modafinil and/or Cyclizine," as used herein, is an amount of the pharmaceutical composition, effective for managing dyslexia, i.e. an amount of Vinpocetine and/or Modafinil and/or Cyclizine of a defined particle size suitable for absorption in the nasal passageway which is able to improve memory or to enhance awareness and to significantly enhances the patient's eye tracking, and thus reading, ability. Also Vinpocetine, Modafinil and Cyclizine is given by any other route like oral or injection in suitable formulation so as to improve bioavailability, reduce dose dependent side effect and reduce frequency of dose.

"A pharmaceutical composition," as used herein, means a medicament for use in treating a mammal that comprises Vinpocetine and/or Modafinil and/or Cyclizine of a defined particle size prepared in a manner that is suitable for nasal administration to a mammal. A pharmaceutical composition according to the invention may also, but does not of necessity, include a non-toxic pharmaceutically acceptable carrier. "A defined particle size," as used herein, means particles having a size sufficiently small so as to be absorbed through the nasal mucous membranes, i.e. smaller than about 100 microns. Preferably, the Vinpocetine and/or Modafinil and/or Cyclizine will have a particle size, measured as microemulsion of 1 to 120 microns.

In accordance with the above objective, the present invention describes a pharmaceutical composition through nasal route or by other route like oral and injection comprising stimulants, anti-motion drugs and nootropics either alone or in combination to improve the performance of children suffering from dyslexia.

In an embodiment, the active drugs of the present invention are typically selected from stimulants such as Amphetamine, Methamphetamine, Dextroamphetamine, Pimoline, Methylphenidate and Modafinil (for enhancing self-esteem, and reduce restlessness, and distractibility); anti-motion drugs such as Meclizine, Cyclizine, cinnarizine, buclizine(for symptomatic relief of balance and coordination occurring because of visual perception alterations), and nootropic drugs such as Piracetam, Oxiracetam, Amiracetam, Nefiracetam, Picamoline, Vinpocetine, Pyritinol; and chemical precursors of dopamine such as Livodopa(to improve cognitive function). These drugs are used either alone or in combination.

The preferred embodiment of the current invention describes a pharmaceutical composition comprising an effective amount of Vinpocetine and/or Modafinil and/or Cyclizine of a defined particle size, along with pharmaceutically acceptable excipients, administered through oral, injection and nasal route, to improve the performance of children suffering from dyslexia.One preferred route of administration is intranasal.

In an embodiment, the present invention provides a pharmaceutical composition wherein the excipients used for nasal delivery is typically selected to formulate a nasal solution, gels, sprays, ointments, lotion creams, suspension, powder and carrier based systems such as microemulsion, microspheres and liposomes. The excipients are typically selected from nasal mucoadhesives such as chitosan lactate, chitosan glutamate, chitosan, and other salts of Chitosan, gelatine, HPMC and other cellulose derivatives, polycarbophils, sodium alginate and other derivatives in the range of 0.5 -2%, drug solubilizers as polyethylene glycol, polypropylene glycol, ethanol, a surfactant as acconon, powdered sugar alcohols for powder formulation, phospholipids and cholesterols, and synthetic oils to form microemulsions. Since Vinpocetine is having low solubility in water and Modafinil is practically insoluble in water and only slightly soluble in lower alcohols, solubility enhancers such as oil, surfactant and co-surfactant may be included.

Further, the active ingredient must be compatible with the excipients used in the formulation and should not aggregate in a manner which would result in a loss of accurate dose delivery. The pH of the composition is maintained in the range of 4-10. The pH is suitably maintained with a physiologically acceptable buffer, suitably acetate, phosphate, phthalate or borate buffer. Acetate buffers are preferred for convenience and economy.

The desired isotonicity of Vinpocetine and/or Modafinil and/or Cyclizine containing composition may be accomplished using sodium chloride or other pharmaceutically acceptable agents such as dextrose, boric acid, sodium tartrate, propylene glycol or other inorganic or organic solute. Sodium chloride is preferred particularly for buffers containing sodium ions.

The viscosity of the compositions is maintained at the selected level using a therapeutically acceptable thickening agent selected from xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, acacia, bentonite, carboxymethylcellulose sodium, gelatin, guar gum, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, tragacanth, and the like, preferably, methyl cellulose.

In addition to the above exicipients, the pharmaceutical composition may contain a humectant such as sorbitol, propylene glycol, or glycerol, surfactants selected from polyoxyethylenederivatives of fatty acid, partial esters of sorbitol, anhydrides such as Tween 80, Polyoxyl 40 Stearate, Polyoxyethylene 50 Stearate, sorbitan esters (e.g., Span 80), and Octoxynol (concentration varies from 1 % to 10% based on the total weight), preservatives such as benzalkonium chloride and phenylethylalcohol, benzyl alcohol, Parabens, chlorobutanol(0.02% to 2%), absorption enhancers, flavoring agents and sweetening agents (e.g., saccharin).

In another preferred embodiment, the present invention discloses the pharmaceutical composition for nasal administration at lower dosage level to elicit a systemic therapeutic response and to provide enhanced bioavailability, minimize variations in blood levels, provide more rapid onset of activity, ease of administration, and reduced side effects.

The dosage of Vinpocetine and/or Modafiniland/or Cyclizine may vary appreciably with the age and mass of the patient and other factors readily evaluated by the physician. Therapeutically effective amounts of Vinpocetine and/or Modafinil and/or Cyclizine may vary appreciably if other physiologically active agents are present.

In an embodiment, the compositions of the invention in bulk or unit dosage form typically contain Vinpocetine (l-50mg) and/or Modafinil (5-400mg) and/or Cyclizine (5-50mg). The volume of a dosage unit is from about 0.05 to 0.3 ml for nasal application. Vinpocetin is administered once/twice a day in amount 1 -50 mg, Modafinil is preferably administered in an amount 5-400 mg once/twice in a day and Cyclizine administered 5-50 mg once/twice in a day.

In another embodiment, the present invention provides a method of treatment and/or management of dyslexia comprising administering the subject the pharmaceutical composition of the present invention, through nasal, oral or parental route. The subject for the present invention is human.

Accordingly, the present invention provides Vinpocetine and/or Modafinil and/or Cyclizine containing compositions, in the form of gels, sprays, solutions, suspensions, ointment, cream, dry powders or drops, for effective administration through the nasal mucous membrane. Dry powders and suspensions are applied directly to the nasal cavity by conventional means like dropper, pipette or spray. The formulations may be provided for administration in single or multidose form. In the case of a dropper or pipette this may be achieved by administering appropriate, predetermined volume of the suspension to the patient. In the case of a spray, this may be achieved, by means of a metering atomizing spray pump.

Further, intranasal administration is achieved by means of an aerosol formulation in which the compound is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC),for example, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, a hydrofluorocarbon (HFC), for example, 1 , 1 ,1 ,2- tetrafluoroethane or 1,1 , 1 ,2,3,3,3-heptafluoropropane, carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve. The administration of a nasal composition containing Vinpocetine and/or Modafinil may also be effected by using a nasal tampon or nasal sponge.

For satisfactory intranasal administration, the active ingredient of the pharmaceutical composition has a defined particle size and form which is readily absorbed through the nasal mucosa but which is unassociated with any adverse effects such as irritancy. Further the formulations must be sufficiently stable, chemically and physically, to be consistently dispensed in accurate metered doses, even after prolonged storage under wide temperature fluctuations.

In another embodiment, the pharmaceutical composition of the present invention may be administered in the form of microemulsion or isotonic aqueous suspensions or viscous compositions such as gel, lotion, oils, ointments and cream. Accordingly, Microemulsions or isotonic aqueous suspensions or viscous compositions containing Vinpocetine and/or Modafinil is prepared by addition of an appropriate amount of a surfactant, co-surfactant and oil and buffered to a selected pH. The viscosity is maintained in the range of 1000 to 5000 cps.

In yet another embodiment, the pharmaceutical composition of the present invention may be administered orally such as tablets, capsules, liquid formulations or parentally such as injections. The therapeutically effective compositions of the present invention are prepared by mixing the ingredients following the procedures known in the art. For example, the selected components may be simply mixed in a blender or other standard device to produce a concentrated mixture which may then be adjusted to the final concentration and viscosity by the addition of water or thickening agent.

Use of the pharmaceutical composition of the present invention in preparing the medicament intended to treatment and/or in the management of dyslexia.

The use of the pharmaceutical composition comprising Vinpocetine and/or Modafinil and/or Cyclizine along with pharmaceutically acceptable excipients through nasal delivery provides several advantages. For one, the administration through nasal delivery bypasses absorption from the intestinal track. Thus, compositions can be usefully administered to mammals at low dosage levels to elicit a systemic therapeutic response and to provide enhanced bioavailability, minimize variations in blood levels, and achieve more rapid onset of activity, ease of administration, and reduced side effects compared to most current methods of administration.

Also, it produces desirably high blood levels in a desirably short period of time, resulting in an increase in the amount of desired active product being absorbed as it is not subject to the higher levels of metabolism or excretion.

The intranasal dosing of the present invention is also found to bypass the blood brain barrier and also bypassed the hepatic and gut wall metabolism and showed significant brain uptake than oral and parentral administration and thus is found to be a better administration route in efficient management of dyslexia.

The studies with respect to pharmacokinetics and pharmacodynamics to support our findings are as follows:-

In-vitro diffusion study of Vinpocetine and Modafinil formulations:-

Preparation of membrane: The freshly excised sheep nasal mucosa was collected from the slaughter house in PBS pH 6.4. The membrane was kept in PBS pH 6.4 for 15 min to equilibrate. The superior nasal conche was identified and separated from the nasal membrane. The excised superior nasal membrane was then mounted on Franz diffusion cell. The tissue was stabilized using phosphate buffer pH 6.4 in both the compartments and allowed to stir for 15 min on a magnetic stirrer. After 15 min, solution from both the compartments was removed and fresh phosphate buffer pH 6.4 was filled in the acceptor compartment. The mounting of the nasal membrane was done using Fevi-quick glue at the brim of the donor compartment to avoid leakage of the test sample and supported with thread crossover the cell. The temperature of the receiver chamber, containing 12 ml of diffusion media was controlled at 37°±1°C under continuous stirring with Teflon coated magnetic bar at a constant rate, in a way that the nasal membrane surface just flushes the diffusion fluid.

Experimental Procedure: In this study the in-vitro drug diffusion study was performed using Franz diffusion cell with a diameter of 10 mm and mucosa thickness 0.2 mm-0.6 mm was placed in the donor compartment of Franz diffusion cell along with 1.4 ml of acetate buffer pH 5 added additionally. Recipient compartment containing 12 ml of acetate buffer pH 5 was stirred with Teflon coated magnetic stirrer. Samples from the receptor compartment were withdrawn at predetermined time intervals and analyzed. Each sample removed was replaced by an equal volume of acetate buffer pH 5.

Each study was carried for a period of 5 hrs, during which the drug in receiver chamber ^g/ml) across the sheep nasal membrane calculated at each sampling point. The formulations were studied in triplicate for diffusion studies and the mean cumulative values for % drug release are shown in table 1 and shown graphically in Figure- 1. Result shows that the formulations successfully diffused through nasal mucosa.

Table 1 : In-vitro diffusion study data for Vinpocetine and Modafinil containing formulations:-

Time (min) Percentage Drug Diffused (%W/W)

Vinpocetine Modafinil

5 16.73 + 0.719 17.30+ 0.654 15 28.39 ± 0.726 37.09 ± 0.687

30 33.79 ± 0.766 46.28 ± 0.666

45 41.88 ± 0.596 50.8 ± 0.486

60 51.80 ± 0.987 57.51 ± 0.962

90 54.40± 0.1 19 58.65 ± 0.698

120 66.30 ± 0.989 59.57 ± 0.39

150 68.13 ± 0.976 60.18 ± 2.109

180 70.38 ± 1.134 62.50 ± 1.243

210 75.62 ± 0.961 64.57 ± 0.753

240 82.84 ± 0.901 73.98 ± 1.186

270 90.70 ± 1.545 96.56 ± 1 .681

300 99.03 ± 2.030 97.42 ± 1.766

Values are expressed as mean ± SEM of three estimations.

Figure-2 and Figure-3 shows effects of drug Vinpocetine orally and nasally administered in to mice on the escape latency achieved in the Morris water maze task in saline and scopolamine treated mice. Saline treated mice rapidly acquired the spatial task, as escape latency. When Vinpocetine solution and microemulsion are administered orally and through intranasal the same did not affect the escape latencies. However, the escape latencies of scopolamine treated mice were significantly longer than those of saline treated mice from days 3 to 5, the Vinpocetine microemulsion given orally tend to reduce the escape latencies achieved on days 3 to 4, and significantly reduce the escape latency achieved on days 5. The effect of the Vinpocetine microemulsion administered intranasal tend to be stronger than those of the Vinpocetine orally in this task and it significantly reduced the escape latencies achieved on day 3-5. In contrast, the Vinpocetine solution had very less effect on the escape latencies. The data represented demonstrate that a nasal administration of a Vinpocetine microemulsion improves scopolamine induced amnesia at both 24 and 48 hr after the acquisition trial in mice. The inventors investigated the effects of Vinpocetine solution and microemulsion orally and intranasal. Although the Vinpocetine solution given orally did not affected the step through latency 24 hour after the acquition trial, it tend to extend the step-through latency 48 hr after the trial. The Vinpocetine given nasally significantly improved spatial impairment in the scopolamine induced amnesic mice in the Morris water-maze test. These results suggest that nasally administered Vinpocetine microemulsion significantly improves scopolamine induced amnesia in the water maze task and that these antiamnesic effects are attributable, at least in part, to the Vinpocetine nasally, but not to the Vinpocetine microemulsion orally. These results suggest that novel Vinpocetine formulation of Vinpocetine as microemulsion given intranasally to the mice significantly improve memory. This study aptly demonstrated the effectiveness of intranasal delivery of Vinpocetin emicroemulsion.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Example 1: Solution

The solution comprises stimulant such as Amphetamine, Methamphetamine, Dextroamphetamine, Pimoline, Methylphenidate, Modafinil, antimotion drug such as Meclizine, Cyclizine and nootropic such as Piracetam, Oxiracetam, Amiracetam, Nefiracetam, Picamoline, Vinpocetine, Pyritinol and chemical precursor of Dopamine such as Livodopa alone or in combination, atleast one solubilizer selected from propylene glycol, Polyethylene glycol 400, ethanol or combinations, atleast, one surfactant, such as, Acconon, atleast one solvent selected such as Chitosan acetate in a aqueous base.

Sr. No. Ingredients Composition

1. Vinpocetine/Modafinil/Cyclizine 2 - 20 %

2. Propylene glycol 5 - 20 %

3. Polyethylene glycol 400 10 - 25 %

4. Ethanol upto 15 %

5. Acconon upto 2 %

6. Chitosan Acetate 0.5 - 1%

7. Citric acid q.s. to adjust pH 4 - 8

8. Water upto 100 % Manufacturing method:

Solution is prepared by solubilizing active ingredients in suitable mixture of vehicle followed by addition of surfactant. Mucoadhesive agent may or may not be added in the preparation. Adjust the pH and filter it by suitable filter media.

Example 2: Suspension

The formulation will be in suspension form which comprises of stimulant such as Amphetamine, Methamphetamine, Dextroamphetamine, Pimoline, Methylphenidate, Modafinil, antimotion drug such as Meclizine, Cyclizine and nootropic such as Piracetam, Oxiracetam, Amiracetam, Nefiracetam, Picamoline, Vinpocetine, Pyritinol and chemical precursor of Dopamine such as Levodopa, either alone or in combination, in a carrier solution comprising 1 % chitosan acetate or chitosan derivatives as a carrier.

Manufacturing method:

Suspension is prepared by dispersing active ingredients in suitable vehicle followed by addition of proper suspending agent. Mucoadhesive agent may or may not be added in the preparation. Adjust the pH with using suitable weak acid or base.

Example 3: Powder for Insufflation

The formulation is in powder form for insufflation which comprises of micronized drug such as Vinpocetine and/or Modafinil with carrier such as sugars and sugar alcohols selected from lactose, trehalose, mannitol etc. and a mucoadhesive agent as Hydroxy propylmethyl cellulose or may be insufflated as a mixture of drugs encapsulated in carrier systems as liposomes and then freeze drying it with carrier sugars or sugar alcohols to form a free flowing powder and then mixing with HPMC. 2010/000719

17

Manufacturing method:

Micronized drug such as Vinpocetine and/or Modafinil mixed with lactose thoroughly followed by Hydroxypropyl methyl cellulose.

Example 4: Liposome

The formulation can be provided in the form of liposomes which comprises stimulants such as Amphetamine, Modafinil and/or nootropics drugs like Vinpocetine, and/or antimotion drug like Cyclizine alone or in combination.

Manufacturing method:

Liposome is prepared by thin film hydration method. The drug is mixed with liposome forming-lipids such as HSPC/DSPG/Steryl Amine and cholesterol in pharmaceutically acceptable molar ratio of 1 :5 to 1 : 25 (Drug: Lipid ratio) or Phosphatidyl cholines/cholesterol in ratio 10:0.1 to 10:5 and a solvent comprising of Chloroform/Methanol. The liposomes are further formed by removing the chloroform/methanol under vacuum and hydrating the lipids by water. Example 5: Microspheres

Manufacturing method:

The preparation method of the drug such as Vinpocetine and/or Modafiil and/or Cyclizine loaded PLGA microspheres was based on emulsion solvent evaporation technique. For the single emulsion technique, 25 mg of PLGA was dissolved in 1 -3 ml of chloroform in order to study the effect of internal phase volume on the microsphere characteristics. Then 5 mg of drug (particle size of the drug crystal was around 30 μηι) was dispersed in the polymer solution. The mixture was poured into 10 ml of 2% w/v PVA aqueous solution and emulsified with a high speed homogenizer at 10,000 rpm for 1 min. The organic solvent was allowed to evaporate by stirring the mixture at 700 rpm for 18 h under ambient temperature.

Example 6: Microemulsion

The formulation is in microemulsion form which comprise oil such as Capmul MCM, Ethyl oleate,Ethyl laurate, Maisine,Labrafil, or triglyceride or its other derivatives,surfactants such as acconon cc6,cremophore RH- 40, Octoxynol, Labrasol, Polyoxyl 40 stearate,Polyethylene 50 Stearate and Tween, Span, Brij, Polyoxyethylene- 35-ricinoleate, co-surfactants like ethanol, transcutol and distilled water,and polycarbophil or chitosan as mucoadhesive agents.

Formulation 1:

Sr. No. Ingredients Qty

1. Vinpocetine 1-50 mg/ 5ml

2. Capmul MCM C8 4 -6% v/v

3. Tween 80 15 - 40 % v/v

4. Polyethylene glycol 400(PEG 400) 6 - 20% v/v

5. 50%w/w PG in doubled distilled water Q.s to make 100% v/v Formulation 2:

Formulation 3:

Formulation 4:

Manufacturing Procedure for Formulation 1, 2 and 3:

Vinpocetine microemulsion containing 1-20 mg / 5 ml Vinpocetine(drug) were prepared by using Capmul MCM C8 oil as oily phase(4-6%v/v), Tween 80 (15 - 40%v/v) as a surfactant and PEG 400/ Transcutol HP (6 - 20% v/v) used as cosurfactant and 50% w/w PG in double distilled water as aqueous phase while in formulation 3 instead of 50% PG as aqueous phase, used distilled water and adjust the pH between 4-7 by using any acid. Formulation was prepared by dissolving Vinpocetine in the oil phase, followed by addition of surfactant and cosurfactant, and finally the 50% PG in the double distilled water was added gradually with continuous stirring, which resulted in transparent and homogenous vinpocetine microemulsion (% transmittance of (10 times dilution) at 630 nm, 96 - 100%). Manufacturing Procedure for Formulation 4:

Modafinil microemulsion containing 5-50 mg/5 ml Modafinil (drug) were prepared by using Capmul MCM C8 oil as oily phase (4 - 6%v/v), Tween 80 (15 - 40 %v/v) as a surfactant and PEG 400 (6 - 15% v/v) used as cosurfactant and in distilled water form the aqueous phase. Formulation was prepared by dissolving Modafinil in the oil phase, followed by addition of surfactant and co-surfactant, and finally the in the distilled water was added gradually with continuous stirring, which resulted in transparent and homogenous Modafinil microemulsion [% transmittance of (100 times dilution) at 630 nm, 96% - 100%].

Example 7: Tablet

Manufacturing Procedure for Tablet:

Tablet can be made by wet granulation method and compress as per the pharmaceutical procedure known in the art.

Example 8: Capsule

Sr. No. Ingredients Qty.

1. Vinpocetine 1-50 mg

2. Modafinil 50 - 400 mg

3. Cyclizine 5-50 mg

4. Starch 5 - 20%

5. Microcrystalline cellulose 6 - 20%

6. Surfactant such as Sodium 1- 5 %

lauryl sulphate

7. Magnesium stearate 1 %

8. Talc 1 % Manufacturing Procedure for Capsule:

Mix all the ingredients in blender till homogeneity is achieved and fill the capsule in suitable size capsules.

Stability Data:

The products have found to be stable at room, temperature upto 3 months and accelerated stability studies are under investigation.

Claims

We claim,

1. A pharmaceutical composition comprising therapeutically effective amount of stimulants, anti-motion drugs and nootropics either alone or in combinations, along with pharmaceutically acceptable excipients, for treatment and/or management of dyslexia.

2. The pharmaceutical composition as claimed in claim 1 , wherein the stimulants are selected from Amphetamine, Methamphetamine, Dextroamphetamine, Pimoline, Methylphenidate and Modafinil.

3. The pharmaceutical composition as claimed in claim 1 , wherein the anti- motion drugs are selected from Meclizine, Cyclizine, Buclizine, Cinnarizine.

4. The pharmaceutical composition as claimed in claim 1 , wherein the nootropic drugs are selected from Piracetam, Oxiracetam, Amiracetam, Nefiracetam, Picamoline, Vinpocetine, Pyritinol.

5. The pharmaceutical composition as claimed in claim 1, wherein the composition comprises Vinpocetine/Modafinil/Cyclizine either alone or in combinations, along with pharmaceutically acceptable excipients.

6. The pharmaceutical composition as claimed in claim 5, wherein the Vinpocetine is present in an amount of 1 -50 mg.

7. The pharmaceutical composition as claimed in claim 5, wherein the Modafinil is present in an amount of 5-400 mg.

8. The pharmaceutical composition as claimed in claim 5, wherein the Cyclizine is present in an amount of 5-50 mg.

9. The pharmaceutical composition as claimed in claim 1 and 5, wherein the composition is administered through oral, intranasal and parental.

10. The pharmaceutical composition as claimed in claim 1 and 5, wherein the said composition is in the form of Solution, Suspension, Powder, Liposome, Microemulsion, Microspheres, Tablet and Capsule.

1 1. The pharmaceutical composition as claimed in claim 5, wherein the Vinpocetine is administered in an amount 1 -50 mg, once/twice in a day.

12. The pharmaceutical composition as claimed in claim 5, wherein Modafinil is administered in an amount 5-400 mg, once/twice in a day.

13. The pharmaceutical composition as claimed in claim 5, wherein Cyclizine is administered in an amount 5-50 mg, once/twice in a day.

14. Method of treating dyslexia comprises administering 'an effective amount' of the pharmaceutical composition as claimed in claim 1, to the subject suffering from dyslexia.

15. The method as claimed in claim 14, wherein the subject is human.

16. Use of the pharmaceutical composition as claimed in claim 1 in preparing the medicament useful to treat dyslexia.

17. A method of obviating learning difficulties for a dyslexic patient by administering to said patient participating in learning and memory related activity, the 'composition of the present invention' as claimed in claim 1 , which method is based on the improved drug action and enhanced bioavailability of the drugs and lead subsequent reduction in dose and frequency of dosing, and are useful in the treatment of various mental, learning and memory related condition and disorders as well as for maintenance of normal functions of brain.