WO2010103539A2

WO2010103539A2 - Sustained release oral formulation of vinpocetine

Info

Publication number: WO2010103539A2
Application number: PCT/IN2010/000129
Authority: WO
Inventors: Dinesh Shantilal Patel; Sachin Dinesh Patel; Shashikant Prabhudas Kurani
Original assignee: Dinesh Shantilal Patel; Sachin Dinesh Patel; Shashikant Prabhudas Kurani
Priority date: 2009-03-09
Filing date: 2010-03-08
Publication date: 2010-09-16
Also published as: WO2010103539A3

Abstract

A sustained release vinpocetine oral formulation comprising vinpocetine in the range of about 1 % to 25 %; about 30 to 70 percent by weight of cellulose ether; other components that includes a therapeutically inert, pharmaceutically acceptable adjunct material selected from the group consisting of water soluble fillers; from about 10 to about 30 percent by weight of acidifier; conventional ingredients selected from binders, lubricants and disintegrants and coating materials.

Description

SUSTAINED RELEASE ORAL FORMULATION OF VINPOCETINE

FIELD OF INVENTION

The present invention relates to pharmaceutical compositions, useful in the treatment of cerebrovascular disorders, comprising vinpocetine (eburnamenine-14-carboxylic acid ethyl ester) formed with inert additive materials. The present invention also relates to preparation_^ of sustained release tablet dosage form. Even more particularly the present invention relates to matrix type sustained release tablet dosage form for oral drug delivery.

BACKGROUND OF INVENTION Vinpocetine is a semisynthetic derivative alkalloid of vincamine, an extract from the periwinkle vinca minor is used in cerebrovascular disorders. Vinpocetine is used for the treatment of cerebrovascular disorders and is usually available as tablets containing 5 mg/10 mg of active ingredient. Vinpocetine is given as immediate release tablets dosage form 2 -3 times per day. Rapid absorption of vinpocetine released from instant release tablet in gastrointestinal tract and short elimination half life, existing formulations has got the poor patient compliance due to frequent administration of tablets. Vinpocetine is a water insoluble weak base, having a significant pH dependent solubility profile. This property results in decrease in dissolution rate with increase in pH of dissolution media.

There are number of patents appearing as prior art for overcoming the above problems of instant release tablet as formulating it into sustained release formulation. Vinpocetine exhibits properties which makes this drug as good sustainable release member by oral administration. These properties are rapid absorption from gastrointestinal tract, short elimination half life (2.54 ± 0.48 hours ) by renal route among others.

Methods and compositions for preperation of different dosage forms containing vinpocetine are known in the art.

EP0368247 for controlled release preperation, discloses a matrix preperation which is composed of active ingredient and fatty acid ester of polyglycerol and which is solid at room temprature and can be processed into fine granules, capsules, tablets etc. As present investigator found that when an active ingredient is dispersed into a matrix being solid at ambient temperature (15 to 35° C) and consisting of or containing a fatty acid ester of a polyglycerol, which has not been employed in conventional matrix preparations, to produce a matrix preparation for controlled release can be obtained. However there is a limitation of using fatty acid which are difficult to formulate and scale up.

WO/2008/002382 for composition and method for enhancing brain function, discloses a nutritional supplement for enhancing cognitive function comprising huperzine A3, vinpocetine and acetyl -L- carnitine formulated in an enteric coating and this is only for enteric absorption and is available as combination drugs.

US 4794001 for formulation providing three distinct release, discloses a therapeutic composition for oral administration consisiting essentially of a pharmaceutical gelatin capsule in which the first group of spheroids is uncoated and rapidly disintegrates upon ingestion, a second group of spheroids is coated with a pH sensitive coat to provide a second dose and a third group of spheroids is coated with a pH independent coat to provide a third dose. The therapeutic preperation utilised as a mixture of group of spheroids taken as a matrix filled in the capsules.

US 6572899 for memory loss treatment formulation, relates to combination of specific vitamins , minerals, herbs and nutrients. The formulation contains phosphatidylserine, phosphatidylcholine, coenzyme QlO, alpha lipoic acid, vinpocetine, acetyl -L- carnitine, gingko biloba, bulberry and spinach extract. The formulation is preferebly given in capsule form at eight capsules per day. The limitation of this patent is again a capsule form and with combination for various phytochemicals.

EP0689844 for complex of vinpocetine formed with cyclodextrin. Process for preperation and pharmaceutical composition containing them realtes to an inclusion complex of vinpocetine formed with any kind of cyclodextrin , preferebly alpha -cyclodextrin, beta - cyclodextrin, gamma -cyclodextrin and hydroxypropyl- beta -cyclodextrin, a process for its preparation, a pharmaceutical composition containing said complex and a process for preparing said composition. The patent describes the use of conventional cyclodextrin complexes.

US 6964969 for composition and method for treating impaired or deteorating neurological function, which contains various agents such as agent promoting synthesis of Adenosine triphosphate like creatinine monohydrate , antioxidant like vinpocetine, gingko biloba, agent for maintainig brain function like choline, agent comprising pyrodoxine, huperzine where in the method involves orally administering to human for a therapeutically effective peroid of time. The preperation is preferebly taken on daily basis. However there is no emphasis on the sustaining the vinpocetine release or any other component release.

US 4749707 for citrate salt of vinpocetine and a procedure to prepare the salt is disclosed. The citrate salt of vinpocetine is soluble in water increasing in pharmacological action, rapid absorption especially in elder persons. It is easy to formulate oral drop and injectables. The invention does not teach any thing about sustained release dosage and its formulation.

WO/1996/025161 for use of vinpocetine derivatives for inhibiting the production or secretion of amyloid beta protein relates to synthesis of vinpocetine derivatives with different substitutions. The composition comprises pharmaceutically acceptable salts along with a pharmaceutically acceptable excipient, carrier or diluent. The limitation of the composition is the requirement for preparation of salt and then formulating the composition.

It is evident from above that none of the formulation emphasized on reducing the dosing frequency/sustaining the vinpocetine release for 16 to 24 hours. Accordingly there is need to provide a sustained release dosage form which can release the drug at desired rate upto 24 hours in the required therapeutic concentrations. SUMMARY OF INVENTION

Thus according to one aspect there is provided an oral sustained release dosage formulation comprising a homogenous mixture of a therapeutically effective amount of vinpocetine; from about 30 to about 70 percent by weight of one or more cellulose ethers, such as hydroxypropyl methylcellulose; and from about 30 to about 70 percent by weight of a therapeutically inert, pharmaceutically acceptable adjunct material such as lactose.

According to another aspect there is provided a method of manufacturing a sustained release formulation of vinpocetine comprising the steps of dispensing in atmosphere of less than 45 % relative humidity, blending, granulation, sieving through mesh, drying, sifting, lubrication and finally compression. Optionally tablets can be coated if desired to get the elegant appearance.

DETAILED DESCRIPTION OF THE INVENTION

Brief Description of the accompanying drawings

Figure 1 Dissolution study of composition containing drug excipient ratio 1:15

Figure 2: Dissolution study of composition containing drug excipient ratio 1:10

Figure 3: Dissolution profile for drug xitric acid ratio of 1 :1 Figure 4: Dissolution profile for drug xitric acid ratio of 1 :4 Figure 5: Effect of tablet hardness on dissolution profile

Figure 6: Comparative dissolution study of vinpocetine conventional marketed formulation and prepared SR tablets of present invention

The present invention is, directed to a sustained release vinpocetine formulation which takes care of the drawbacks and satisfies the needs. The oral sustained release formulation of the present invention causes a sustained release of vinpocetine over a prolonged period of time. Thus the present invention overcomes the "peak and trough" side effects of the traditional oral vinpocetine formulations to provide more stable therapeutic effects. Furthermore, the sustained release vinpocetine formulation is more convenient to use than the immediate release tablets thereby resulting in improved patient compliance.

Of particular importance is the ease with which the matrix tablets can be manufactured. It does not require elaborate and expensive equipment and can be prepared quickly and inexpensively .These and other features, aspects, and advantages of the present invention will become better understood with reference to the following description and appended claims.

Vinpocetine has the formula: C₂₂H₂₆N₂O₂ and has the following characteristics: Molecular weight: 350.43 ; melting point: 149-153 ; it is poorly soluble in water, ethyl ether and hexane but dissolves well in ethanol and 0.1N HCl.

In the present invention, water soluble and swellable polymers are used as release retardants. Hydroxypropyl methylcellulose (HPMC) is a polymer frequently used in the formulation of sustained release dosage forms. Chemically it is 2- Hydroxypropyl methyl ether (9004-65-3). Suitable grades of hydroxypropyl methylcellulose for use in the present invention are the Methocel having a viscosity range of about 3500 to about 5600 cps and preferably a viscosity of about 4000 cps. The mechanisms by which it retards drug release include its ability to form rapidly a gel layer at the matrix periphery exposed to aqueous fluids. The drug is released from the matrix mainly by diffusion through water filled pores. The porosity and tortuosity of a swellable matrix are primarily attributed to polymer swellability. Variables such as the particle size, viscosity and proportion of HPMC modify the characteristics of porosity and tortuosity of the swollen matrix and therefore, modify the release rate of drugs. It is also proposed that rate of drug release decreases with an increasing viscosity grade. Taking this into consideration HPMC K-100 is used in given invention.

HPMC is capable of swelling to significant extent upon contact with release medium. Thus the amount of imbibing bulk fluid is much higher. In case of phosphate buffer pH 6.8 ,this can lead to higher amount of hydroxide ions entering the tablet, which can maintain higher microenvironment pH values within HPMC based devices. Higher microenvironment pH values may lead to higher solubility of the organic acid within the system and thus to higher driving force for diffusion.

Sodium alginate is another polymer used in present invention. Chemically it is alginic acid with anionic nature. At low pH values, sodium alginate will get precipitated in the hydrated gel layer as alginic acid. This gel layer may provide resistance to erosion. At higher pH values, the alginate forms a soluble salt which can provide less resistance to erosion, which leads to changes in release mechanism from diffusion controlled to erosion controlled. The resulting higher permeability of the gel layer at high pH values compensates the lower drug solubility.

Lactose monohydrate is an excipient with pH independent solubility and has been widely used in tablet dosage form as a diluent. Chemically it is O-β-D-galactopyranosyl-(l— »4) - β - D-glucopyranose monohydrate. [64044-51-5]. It is expected that increasing amount of lactose will accelerate rate of drug release. This can be due to the good solubility of lactose in water. Upon contact with release media lactose diffuses out of the device, thereby increasing the porosity of the resulting polymer matrix. Considering that the addition of soluble excipients increase the release rate of HPMC matrices and that the intestinal pH decreases the release rate of weakly basic drugs, both processes could be combined to compensate the decreased drug solubility with increased matrix porosity. Therefore, in this study, HPMC and sodium alginate were used as release retardants. The lactose was used to modify the drug release and it also ensures that most of the drug is released in a period of time comparable to the gastrointestinal residence time.

The active of the present invention has a relatively short elimination half life (2-3 hrs.) that normally would be administered in divided doses two or more times a day. Vinpocetine has a significant pH dependent solubility profile, weak organic acids such as citric, tartaric, fumaric, glutamic, and adipic acids may be added to the tablets formulation to facilitate drug dissolution throughout the gastrointestinal tract. Other suitable pharmaceutical excipients for the powder blend of the medicinal substance include lubricants,glidants and disintegrants.

The drug to excipients ratio is a critical step in the given invention, as the excipients used in the combination help to sustain the drug release up to 24 hours. The ratio of drug to excipients was kept at 1:12. It was observed that increase in the ratio up to 1:15 resulted in the prolonged release of the drug. The total amount of drug released at the end of 24 hours was only 69% where as it was observed that using the drug to excipients ratio of 1:10 released the total drug in 18 hours. The dissolution study of the composition with drug to excipient ratios as 1: 15 and 1:10 are provided in Figures 1 and 2.

The drug and citric acid ratio is also another important parameter in formulation for the better release of desired drug dissolution pattern.

The used ratio in formulation was approximately 1 :2 (drug: citric acid).

Reducing this ratio to 1:1 resulted in poor dissolution profile of drug as shown in figure 3. Increasing the ratio up to 1:4 caused the immediate release of vinpocetine from the tablets as depicted in Figure 4 and showed yellow coloration of the tablets.

Metalic stearates include zinc stearate, calcium stearate and magnesium stearate may be used as lubricants.

Ac-Di-SoI is a trade name for carboxymethylcellulose sodium. It is the sodium salt of polycarboxymethyl ether of cellulose. Other disintegrants such as Amberlite can also be used instead of Explotab and AcDiSoI.

Materials used as glidants are talc, corn starch and aerosil. Aerosil is chemically colloidal silicone dioxide. Various batches were prepared and evaluated with selected excipients so as to get optimum drug release pattern for 24 hrs. from sustained release tablet dosage forms. Initially tablets were formulated by aqueous -wet granulation technique. In accordance with the present invention, a formulation for the sustained release of vinpocetine is provided. The sustained release formulation of the present invention is preferably an oral tablet dosage form comprising a homogenous mixture of vinpocetine, one or more cellulose ethers, and one or more therapeutically inert, pharmaceutically accepted fillers, binders, lubricants, disintegrants, glidant, adsorbent. Tablets may be manufactured using standard tablet processing procedures and equipment. One method for forming tablets is by direct compression of a powdered, crystalline or granular composition containing the active agent(s), alone or in combination with one or more carriers, additives, or the like. As an alternative to direct compression, tablets can be prepared using wet-granulation or dry- granulation processes. Tablets may also be molded rather than compressed, starting with a moist or otherwise tractable material; however, compression and granulation techniques are preferred. After compression tablets can be coated optionally using aqueous or non aqueous means.

The present invention uses water insoluble and swellable polymers to retard the distribution.

The present invention further uses organic acids, which provides acidic micro-environment in the matrix formulation.

The tablet hardness also plays a significant role in finished formulation. The range of tablet hardness maintained in the range of 3 to 7 kg/Cm2 shows acceptable drug release profile. The same is not achieved, if, other range of hardness is given to the tablets in the formulation. It fails in the test of friability and also shows lamination. This is depicted in Figure 5

The process for preparing sustained release tablets of vinpocetine according to present invention uses polymers and organic acids that provide gradual release of the drug over a sustained period of time, and that preferably results in substantially constant blood levels of drug over sustained time period. The present invention also provides the convenience of not requiring the administration of divided doses during a 24 hour period and results in better patient compliance.

These compositions have a cerebrovascular vasodilatatory effect and contain a therapeutically effective amount of active substance with polymer and the usual non-toxic inert additive materials which are commonly used in such formulation and are useful for enteral administration.

The pharmaceutical compositions according to the invention contain 1.0 to 100 mg, preferably 15.0 to 45.0 mg of active ingredient. The compositions preferably are finished as formulations suitable for enteral administration. The final object of the invention is a process for the preparation of the above pharmaceutical composition, which comprises the well- known methods viz wet granulation, dry granulation, or direct compression of active substance, with pharmaceutically acceptable inert additive materials. Coating can be done optionally to improve the appearance using suitable FDA approved (GRAS) colors.

Polymeric compositions have been widely used as a matrix for sustained or sustained drug release formulations. For such applications, a highly hydrophilic polymeric composition is suitably employed. Cellulose ethers such as hydroxypropyl methylcellulose and hydroxy propyl cellulose are among the polymeric compositions which have been most widely used in this manner. They exhibit fast hydration forming a protective initial gel layer quickly through which the drug is released to the system. Once the initial gel layer is formed, it continues to allow additional water to penetrate into the mass. Soluble materials will wet, dissolve, and diffuse out of the matrix while insoluble materials will be held in place until the surrounding complex erodes or dissolves away. As the outer gel layer begins to fully hydrate and be dissolved, a new layer replaces it that is tight and strong enough to retard diffusion and sustained uniform drug release. Factors affecting the rate of hydration of the polymeric composition, and thereby the drug release rate, include its viscosity, concentration, particle size, and chemical makeup. Another factor affecting the rate of gel formation or hydration of the polymeric composition used as a sustained drug release matrix is the chemical characteristics of the drug employed. Certain polymers can be employed effectively for some drugs but not for others. The degree of water solubility of the drug, molecular weight of the drug, and the diffusion coefficient of the drug in hydrated polymer are critical.

In addition to the active agent, the tablets prepared for oral administration using the method of the invention will generally contain other materials such as binders, diluents, lubricants, disintegrants, fillers, acidifiers and the like. Binders are used to impart cohesive qualities to the tablet, and thus ensure that the tablet remains intact after compression. Suitable binder materials include, but are not limited to, sodium alginate, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, and the like). Diluents are typically necessary to increase bulk so that a practical size of a tablet is ultimately provided. Suitable diluent include from water soluble and insoluble fillers like lactose, calcium phosphates, starch, and mannitol. Lubricants are used to facilitate tablet manufacture; examples of suitable lubricants include stearate salts and talc. Disintegrants are used to facilitate disintegration of the tablet, and are generally, celluloses and starches. Glidants include, for example, materials such as silicon dioxide, talc etc. Acidifiers viz organic acids which either increase the permeability of the drug delivery system by leaching out at higher pH values or which keep the pH within the system in the intestinal pH range low and thus the solubility of the drug high. Independent of the pH value of the dissolution medium, the pH inside the tablet matrix is expected to be acidic and thus the solubility of the weakly basic drug to be high. In this case drug release should be pH independent. For this purpose, substances with high acidic strength and relatively low solubility in pH 1.2 are suitable which include citric acid, tartaric acid, succinic acid, fumaric acid, adipic acid etc.

An aspect of the present invention is the process of preparing the sustained release matrix composition of vinpocetine which comprises the steps of dispensing the ingradients in atmosphere of less than 45 % relative humidity, blending, granulation, sieving through mesh, drying, sifting, lubrication and finally compression. Optionally tablets can be coated to get the elegant appearance by using suitable coating material using aqueous or nonaqueous means with suitable FDA approved colorants like titanium dioxide or other inorganic ferric compounds or GRAS colorants.

Tablets can be prepared as bilayered tablet dosage form by incorporating one immediate release layer of another drug belonging to the category of vinpocetine or alike or drugs from other categories. Upon administration, the drug present in the immediate release layer will start dissolving rapidly to provide its desired therapeutic effect and vinpocetine present in the matrix layer will give its prolonged therapeutic effects upto 24 hours.

Further, the tablets can also be encapulated into a matrix of another drug which may have beneficial effects for therapeutic use in neurological disorders or mucoskeletal disorders or for the therapeutic treatment for other ailments in mammals.

An important aspect of the present invention is that the sustained release profile of vinpocetine can be specified by the types or amounts of cellulose ethers used. The invention is thus very adaptable and versatile to each particular use.

The comparative results of the drug dissolution profile is described in Figure 6. It is noted that compared to the conventional formulation the product if the present invention provides a sustained release profile.

A functionally effective amount of the cellulose ether composition was employed. Such an amount is an amount sufficient to extend the release of vinpocetine for up to 24 hours. Such an amount can vary and typically ranges from about 30 to 70 weight percent, and preferably from about 30 to about 40 weight percent based on the weight of the tablets, although any functionally effective amount can be employed.

The sustained release formulation of the present invention may be incorporated with other drugs like tolperisone, eperisone or other therapeutically useful mukoskeletal agents in the available dosage to form bilayer tablet dosage form. Further Such sustained release formulation may to be encapsulated in the matrix of another drug having beneficial therapeutic application in neurological or mukoskeletal disorders for mammals.

Following are non limiting illustrative examples which show the formulation of sustained release dosage of vinpocetine.

Example 1

Hydroxy propyl methyl cellulose (25%), lactose (61%) and vinpocetine (7.5%) were mixed together. Granules were formulated using aqueous wet granulation method i.e. HPC (5.25%) solution was added to form granules, after drying other ingredient like magnesium stearate (0.5%), silicon dioxide (0.75%) were mixed in their relative percent concentrations. Granules were compressed using conventional tablet press to get tablets. The tablets were evaluated for the parameters required to meet the desired specifications. The tablets were found to meet the desired specifications in terms of hardness, weight variation, friability, assay and dissolution profile.

Example 2

Non aqueous wet granulation method was followed using isopropyl alcohol as solvent, vinpocetine (7.5%) and hydroxy propyl cellulose (5.25%) were separately blended with isopropyl alcohol. Then hydroxy propyl methyl cellulose and lactose were mixed in concentration range of 25 to 37.5 % and 48.5 to 61 % respectively and granules were formulated. Other ingredients like magnesium stearate (0.5%) and silicon dioxide (0.75%) were mixed. Granules were compressed. The tablets were evaluated for the parameters required to meet the desired specifications. The tablets were found to meet the desired specifications in terms of hardness, weight variation, friability, assay and dissolution profile.

Example 3:

Tablets were prepared using same ingredients in same quantities used in example.2 but with slight modification of above procedure. Hydroxyl propyl methyl cellulose, hydroxy propyl cellulose, lactose and vinpocetine were mixed with iso-propyl alcohol in the same concentration range as example.2 and mixed together, granulated and dried. The granules were mixed with lubricants as same quantity used in example. 2 and finally compressed into tablets.

Example 4:

Hydroxy propyl methyl cellulose (25%) and lactose (48.5%), vinpocetine (7.5%) and citric acid (12.5%) were mixed in accurately weighed respective concentrations. These were then mixed together in geometric form and were granulated by using hydroxyl propyl cellulose solution (5.25%) formed in isopropyl alcohol. The granules were dried and other materials such as magnesium stearate (0.5%), SiO₂ (0.75%) mixed and then allowed for compression to get tablets. Various parameters of tablets were determined like tablet hardness, weight variation, friability, assay and dissolution profile.

Example 5: The tablets can also be manufactured by changing the hydroxy propyl methyl cellulose to citric acid ratio and by modifying the quantum of lactose in the appropriate quantity. The hydroxypropylmethylcellulose concentration was varied from 25 to 37.5 % and the citric acid was also varied from 11.25tol3.75%. Vinocetine (7.5%), hydroxypropylcellulose (5.25%), were mixed and granules were formed with non aqueous wet granulation which were lubricated with magnesium stearate (0.5%), and silicon dioxide (0.75%). The granules were compressed into tablets.. The tablets were evaluated for the parameters required to meet the desired specifications. The tablets were found to meet the desired specifications in terms of hardness, weight variation, friability, assay and dissolution profile.

Example 6

Another approach used was varying the concentration of lactose and citric acid. The hydroxy propyl methyl cellulose concentration was kept constant i.e. 25% and the lactose and citric acid concentrations were varied from 36 to 44.75 % and 16.25 to 25 % respectively. Vinpocetine was added in 7.5% concentration. Tablets were prepared by wet granulation using hydroxyl propyl cellulose (5.25%) in isoproyl alcohol. Finally tablets were compressed and evaluated for parameters like tablet hardness, weight variation, friability, assay and dissolution profile.

Example 7

The use of disintegrant i.e. carboxy methyl cellulose sodium (0.75 %). in the formula was another approach. Tablets were prepared using wet granulation method. Vinpocetine (7.5%) lactose 45.25 %, citric acid (15%), hydroxypropylmethylcellulose (25%) were blended and binded with hydroxypropylcellulose (5.25%) solution using isopropyl alcohol. Magnesium stearate 0.5% silicon dioxide (0.75%) were added to the granules and finally compressed to get the tablets.

Example 8

The modification of example.7 was done by replacing citric acid with tartaric acid in the same quantity. Remaining other ingredients and procedure used were same as example.7.

The tablets were evaluated for the parameters required to meet the desired specifications. The tablets were found to meet the desired specifications in terms of hardness, weight variation, friability, assay and dissolution profile.

Example 9

Another approach involves use of increased amount of silicon dioxide. Hydroxy propyl methyl cellulose (25%), lactose (43.5%), vinpocetine (7.5%), citric acid (13.75%), and sodium carboxymethylcellulose (0.75%) were mixed in accurately weighed respective concentrations. These were then mixed together in geometric form and were granulated by using hydroxyl propyl cellulose solution (5.25%) using isopropyl alcohol as a solvent. The granules were dried and other materials such as magnesium stearate (0.5%) and silicon dioxide (3.75%) were added for lubrication and granules were compressed into tablets and evaluated for tablet hardness, weight variation, friability, assay and dissolution profile. Example 10

The amount of vinpocetine and citric acid was decreased in this procedure. Vinpocetine (3.75%), Hydroxypropyl methylcellulose (30%), lactose (49.57%), citric acid (8.43%), and carboxymethylcellulose (0.75%) were blended and granulated with hydroxypropylcellulose (6.25%) solution, magnesium stearate (0.5%) and silicon dioxide (0.75%) were mixed with formed granules and compressed into tablets. The tablets were compressed and evaluated for tablet hardness, weight variation friability, assay and dissolution profile.

Example 11 The decreased amount of citric acid and use of talc for direct compression was another approach. Ingredients which were used are vinpocetine (7.5%), hydroxyl propyl methyl cellulose (25%), hydroxyl propyl cellulose (5.25%), lactose (37.75%), citric acid (13.75%), carboxy methyl cellulose sodium (0.75%), magnesium stearate (1.25%), silicon dioxide (3.75%), talc (5%) in respective concentrations and granules were directly compressed using conventional tablet compression machine. The tablets were evaluated for tablet hardness, weight variation, friability, assay and dissolution profile.

Example 12

The application of non aqueous wet granulation technique for ingredients used in example 11 was another approach. The binding solvent used was iso-propyl alcohol. Other ingredients like magnesium stearate (1.25%), silicon dioxide (3.75%), and talc (5%) were added extragranularly. The formed granules were finally compressed into tablets.

Example 13 The example involves the same approach as that was used for example no.l with some modifications. The concentration of therapeutic active substance was increased 12.5%. Accurately weighed drug (12.5%), hydroxy propyl methyl cellulose (25%), lactose (51%) were mixed together. Granules were prepared using aqueous wet granulation using hydroxypropylcellulose (5.25%) as a binder. Granules were mixed with magnesium stearate (0.5%), silicon dioxide (0.75%) and talc (5%) and finally compressed in to tablets. The compressed tablets were evaluated for physical properties and drug dissolution profile.

Example 14 The same formula from example.12 was employed in this example but the difference was that the compressed tablets were further coated with isopropyl alcohol and some FDA approved colors to impart the elegance to the tablets.

Table no.l The overall dissolution pattern for the batches prepared:

The effect of tablet hardness or tablet curing on the in vitro dissolution rate was assessed. The compression force during tabletting of vinpocetine was varied so as to get tablet hardness between 3-7 Kg/Cm²

The drug dissolution pattern may be changed by carrying out the necessary changes in the ratios of drug to the excipients with the acceptable limits. The above limits are not exhaustive and changes are anticipated by a person skilled in the art of pharmaceutics. Procedure Drug dissolution studies were performed in USP XXII Standard (Basket) apparatus 1 for delayed -release in 900 ml buffers at 37 ± 0.5⁰C Temperature and 100 RPM. Initially tablets were kept in 900 ml of Simulated gastric fluid (SGF) for first 2 hr after which tablets were transferred to 900 ml of Buffer pH 4.5 for 1 hr and finally tablets were transferred to 900 ml Simulated intestinal fluid (SIF) containing 1% SLS and kept for remaining study period. Aliquots of 10 ml Samples were withdrawn after 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, and after 24 hours. Every time samples were filtered and replaced with an equal volume of fresh dissolution medium. Sample was analyzed for drug content by using an UV-vis spectrophotometer at 269 nm.

Drug content (%) was analysed by following method:

Twenty tablets were weighed and powdered. The powder weight equivalent to 10 mg of vinpocetine was transferred into 100 ml volumetric flask containing 4 ml of acetone and 50 ml of methanol; the solution was ultrasonicated for about 40 min, diluted to volume with methanol and filtered. Aliquot of 0.3 ml was withdrawn from stock solution and diluted to 10 ml with methanol. Absorbance of resulting solution was determined at 274nm, the wavelength of maximum absorbance of vinpocetine, by UV spectrophotometer against a blank solution. The same may be determined using at conventional method of HPLC.

Table no. 2 CDR (Cumulative drug release) profiles of different the batches observed during the initial stage.

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Table no. 3 Three month stability data for Vinpocetine tablet, 25±1° C/60% ±5 RH

Table no. 4 Three month stability data for Vinpocetine tablet, 40° C/ 75% ±5 RH

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Claims

1. A sustained release vinpocetine oral formulation comprising a. vinpocetine in the range of about 1% to 25% b. about 30 to 70 percent by weight of cellulose ether; c. other components that includes a therapeutically inert, pharmaceutically acceptable adjunct material selected from the group consisting of water soluble fillers; d. from about 10 to about 30 percent by weight of acidifier; e. conventional ingredients selected from binders, lubricants and disintegrants and coating materials.

2. The sustained release vinpocetine formulation according to claim 1 wherein the concentration of vinpocetine is 15 mg and 30 mg.

3. The sustained release vinpocetine formulation according to claim 1, comprising from about 30 to about 40 percent by weight of the cellulose ether.

4. The sustained release formulation accoridng to claim 1 wherein the ratio of vinpocetine to the excipients is preferably 1:12

5. The sustained release vinpocetine formulation according to claim 1, wherein the cellulose ether is selected from the group consisting of hydroxypropyl .cellulose, hydroxypropyl methylcellulose, and mixtures thereof or containing the same.

6. The sustained release vinpocetine formulation according to claim 1, comprising from about 10 to about 30 percent by weight of the acidifiers.

7. The sustained release vinpocetine formulation according to claim 6 wherein the acidifiers are seleected from citric acid, tartaric acid and similar acids.

8. The sustained release vinpocetine formulation according to claim 1, wherein the binders are selected from hydroxypropyl cellulose, starch, acacia.

9. The sustained release vinpocetine formulation according to claim 1 wherein the lubricants are selected from magnesium stearate. talc.

10. The sustained release vinpocetine formulation according to claim 1 wherein the disintegrants are selected from crosscarmilose sodium, sodium starch glycolate, glidant aerosil, and adsorbent talc.

11. The sustained release vinpocetine formulation according to claim 1, wherein the release period is from about 16 to about 24 hours.

12. A process of preparing the sustained release matrix composition of vinpocetine which comprises the steps of dispensing in atmosphere of less than 45 % relative humidity, blending, granulation, sieving through mesh, drying, sifting, lubrication and finally compression.

13. Sustained release formulation according to claim 1 adapted to be incorporated with other drugs like tolperisone, eperisone or other therapeutically useful mukoskeletal agents in the available dosage to form bilayer tablet dosage form.

14. Such sustained release formulation according to claim 1 adapted to be encapsulated in the matrix of another drug having beneficial therapeutic application in neurological or mukoskeletal disorders for mammals.