WO2007096902A2

WO2007096902A2 - Solid oral dosage forms of griseofulvin

Info

Publication number: WO2007096902A2
Application number: PCT/IN2007/000061
Authority: WO
Inventors: Subrata Kundu; Sanjay Chhagan Wagh; Makarand Krishnakumar Avachat
Original assignee: Lupin Limited
Priority date: 2006-02-23
Filing date: 2007-02-20
Publication date: 2007-08-30
Also published as: WO2007096902A3

Abstract

A taste masked solid oral discrete dosage form comprising griseofulvin, a pharmaceutical composition comprising the same and a process for the preparation thereof . The taste masked solid oral discrete dosage forms comprises a core and/or one or more coating layers The pharmaceutical suspension composition is in the form of taste masked pellets comprising griseofulvin and one or more coating layers. The process of preparation of the taste masked solid oral discrete dosage forms comprising griseofulvin, comprises the steps of reducing the particle size of griseofulvin, blending with the other excipients, granulation, extrusion- spheronization, drying and screening to obtain discrete dosage forms, said discrete dosage forms are further coated with one or more film coating layers to achieve taste masking.

Description

NOVEL SOLID ORAL DOSAGE FORMS OF GRISEOFULV1N

FIELD OF THE INVENTION

The present invention relates to novel taste masked solid oral discrete dosage form comprising griseofulvin and a process for the preparation thereof.

BACKGROUND OF THE INVENTION

Griseofulvin is chemically 7-chloro-2',4, 6-trimethoxy-6'-methylspiro [benzofuran-2 (3H), 1'-cyclohex-2'-ene]-3,4'-dione. It is fungistatic and is indicated for the treatment of the ringworm infections caused by Tinea species Microsporum, Epidermophyton, and Trichophyton.

Griseofulvin absorption from the gastrointestinal tract varies considerably among individuals mainly because of insolubility of the drug in aqueous media of the upper gastrointestinal tract. Administering the drug along with a meal having a high fat content may increase the serum level.

Griseofulvin is the drug of choice for Tinea species in children where its safety and efficacy is well established. It is available in the form of oral suspension under the brand name of Grifulvin V^® of 125mg/5ml; and tablets of 125mg, 250mg and 500mg strengths. However it is an extremely bitter tasting drug. Various ways of taste masking of bitter drugs have been tried. US 4,725,440 of E. R. Squibb and Sons disclose soft smooth non-adhesive antifungal pastille formulation comprising sweeteners for masking the taste of the antifungal agent.

There is still a need to have a taste-masked solid oral dosage form, which will also ensure satisfactory bioavailability of griseofulvin.

The inventors have now surprisingly found a novel solid oral discrete dosage form comprising griseofulvin, which exhibits adequate taste masking and bioavailability. OBJECTS OF THE INVENTION

An object of the invention is to provide a novel taste masked solid oral discrete dosage forms comprising griseofulvin.

Another object of the invention is to provide a novel taste masked solid oral discrete dosage forms comprising core comprising griseofulvin and one or more pharmaceutical excipients and one or more coating layers.

Another object of the invention is to provide a process of preparation of novel taste masked solid oral discrete dosage form comprising griseofulvin, the said process comprising the steps of reducing the particle size of griseofulvin, blending with the other excipients, granulation, extrusion, spheronization, drying and screening to obtain discrete dosage forms, said discrete dosage forms being further coated with one or more film coating layers to achieve taste masking.

Another object of the invention is to provide a process of preparation of novel taste masked solid oral discrete dosage form, said discrete dosage forms comprising griseofulvin, the said process- comprising the steps of reducing the particle size of griseofulvin; blending with the other excipients; preparation of binder solution; loading of carrier or substrate, blended drug and binder solution in fluidized bed processor; said discrete dosage forms being further coated with one or more film coating layers to achieve taste masking.

Another object of the present invention is to provide a pharmaceutical suspension composition in the form of a novel taste masked pellets comprising griseofulvin and one or more coating layers.

SUMMARY OF THE INVENTION

A novel taste masked solid oral discrete dosage forms comprising a core comprising griseofulvin and one or more coating layers.

A process of preparation of novel taste masked solid oral discrete dosage forms comprising griseofulvin, the said process comprising the steps of reducing the particle size of griseofulvin, blending with the other excipients, granulation, extrusion- spheronization, drying and screening to obtain discrete dosage forms, said discrete dosage forms being further coated with one or more film coating layers to achieve taste masking.

DETAILED DESCRIPTION OF THE INVENTION

The invention pertains to a novel taste masked solid oral discrete dosage form comprising griseofulvin and a process for its preparation.

In a preferred embodiment the invention relates to a novel taste masked solid oral discrete dosage form comprising a core comprising griseofulvin and pharmaceutical excipients and one or more coating layers.

The term "core" as used herein includes the active ingredient and one or more pharmaceutically acceptable excipient or carriers/substrates.

The term "carrier/substrates" as used herein includes sugar spheres, microcrystalline cellulose spheres, beads or pharmaceutical carriers well known in the art, with or without active ingredient.

The term "discrete dosage form" comprises granules, spheroids, pellets, beads, microspheres, microcapsules, ion-exchange resins, tablets, etc.

The term "pellets" comprises spherical as well as non-spherical particles prepared by extrusion and spheronization. The latter are also referred to as spheroids.

The core of these discrete dosage forms comprises griseofulvin and one or more excipients selected from the group comprising diluents, stabilizers, binders, disintegrants, glidants, lubricants or flow aids, wetting agents and the like. One excipient can perform more than one function.

While griseofulvin of any particle size can be used in the present invention, in a preferred embodiment, the particle size of griseofulvin is such that 90% of the particles are below 25 μ. The term "90 % particles below 25μ" as used herein can also be represented as dgo of the griseofulvin particles below 25μ. It is noted that the notation d_x means that X % of particles have a diameter less than the specified diameter D. The particle size of the griseofulvin particles is measured for the purpose of this invention using light scattering technique (Malvern Mastersizer Hydro 2000S) by wet dispersion method.

This particle size can be achieved by methods commonly known to those skilled in the art and can include methods like dry milling, wet milling, controlled crystallization and micronization.

Diluents include, but are not limited to mannitol, sucrose, starch, lactose, dicalcium phosphate, xylitol, sorbitol, microcrystalline cellulose and mixtures thereof.

One or more organic acids can be used in the pellet composition as a stabilizer. The stabilizer reduces the impurity levels of the compositions and thus contributes to the stability of these compositions. Examples of suitable organic acids include, but are not limited to oxalic acid, citric acid, tartaric acid, maleic acid and the like. While any amount of the one or more organic acids can be used, provided it stabilizes griseofulvin, in a preferred embodiment, 1-10% w/w of one or more organic acids can be included in the compositions.

Binders include, but are not limited to, alkyl celluloses such as methylcellulose, ethyl cellulose; hydroxyalkylcelluloses such as hydroxypropylcellulose, low substituted hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; starches such as pregelatinised starch, maize starch, dried starch; sugars or polyvinylpyrrolidone and combinations thereof can be used.

Disintegrants include, but are not limited to, crospovidone, sodium starch glycolate; starches such as maize starch, dried starch; croscarmellose sodium, cellulose products such as microcrystalline cellulose, microfine cellulose, low substituted hydroxypropylcellulose and combinations thereof. Glidants include, but are not limited to colloidal silica, powdered cellulose, talc, tribasic calcium phosphate and mixtures thereof.

Lubricants and flow aids include, but not limited to, stearic acid, its salts and its derivatives, calcium silicate, colloidal silicon dioxide and mixtures thereof.

Wetting agents include, but are not limited to, surfactants either singly or in admixture. Examples of surfactants include, but are not limited to, the polysorbates, sodium lauryl sulphate, poloxamers and the like.

All these excipients can be used at levels well known to the persons skilled in the art.

The cores of the invention may be produced by the method of granulation using Griseofulvin together with one or more excipients using conventional techniques. Such granulation techniques include the use of conventional granulators e.g. spray granulators, rotary granulators, centrifugal fluidized bed granulators, highspeed mixer granulators.

In a preferred embodiment, granules are prepared by wet granulation. The wet granules are then extruded and subjected to a process of spheronization. Drying may be carried out by conventional techniques, for example in the tray drier, fluidized bed dryer or in a drying oven or hot air drier.

It is, of course, desirable that the pellets should be prepared by a method, which is convenient and ensures reproducibility of pellet size distribution, surface area, its smoothness and density of the pellet in addition to reproducibility of morphological properties of the pellets. This may generally be achieved by conventional adjustment of the conditions of granulation and, if necessary, by screening of the pellets thus produced. Compaction, surface layering and agglomeration are the pellatisation techniques used in pharmaceutical industries. Of the compaction techniques, extrusion and spheronization is the most popular method as narrower particle size with high capacity output and less cost can be achieved. Recently, however, melt polarization has been used to make compaction pellets using a different types of equipment e.g. high-shear mixer. Other pelletisation methods such as globulation, balling and compression are also used but in limited scale. One of the oldest processes for manufacturing spherical pellets is the agglomeration granulation in coating pans i.e., which involves layering process. Layering involves the deposition of successive layers of an active compound on to the seeds. However the coating-pan technique, which is an outdated process, had various disadvantages: such as considerable drug loss, having a high noise pollution, high labor dependence and a very time consuming process. Besides uniform coating of the pellets does not take place. Centrifugal granulator can also be used for pelletisation. The Extrusion Spheronization (compaction) and fluid bed processing are most preferred.

In a preferred embodiment, the pellets can be formed by a process of extrusion through a suitable screen followed by spheronization at an optimum speed. The resulting pellets are then dried in a fluid bed dryer and then screened to get the pellets of the desired shape and size.

In other embodiment, the pellets can be formed by a process of layering which involves spraying the binder solution on the pellets or beads followed by addition of the powdered drug or drug blend in a fluid bed processor. The pellets could be non-pareil seeds, dummy beads or could be the beads made of the drug itself, or beads of microcrystalline cellulose or sugar. The resulting pellets are then dried and screened to get the pellets of the desired shape and size.

The pellets can further be coated through processes well known to the persons skilled in the art to provide one or more coating layers for the purposes of taste masking and ease of further processing and sipping. Conventional coating techniques, for example, spray coating using a fluidized bed granulator, a centrifugal fluidized bed coater or a spray drier or coating with a rotary granulator can be used.

Film-forming agents, which are useful in the coating process, include, but are not limited to, polysaccharides such as maltodextrin; alkyl celluloses such as methyl or ethyl cellulose, hydroxyalkylcelluloses such as hydroxypropylcellulose, hydroxypropylmethylcelluloses e.g. those marketed under the trade name of Methocel^®; polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinylpyrrolidone and vinyl acetate (e.g. marketed under the brand name of Plasdone) and polymers based on methacrylic acid such as those marketed under the brand name of Eudragit (herein after referred as Eudragit E); alginate based coatings and combinations of these. These may be applied from aqueous or non-aqueous systems or combinations of aqueous and non - aqueous systems as appropriate.

Additives can be included along with the film formers to obtain satisfactory films. These additives include plasticizers such as dibutyl phthalate, triethyl citrate, polyethylene glycol and the like;, antitacking agents such as talc, stearic acid and its salts as well as its derivatives and colloidal silicon dioxide and the like; surfactants such as polysorbates and sodium lauryl sulphate; coloring agents and opacifying agents such as titanium dioxide and the like. All these excipients can be used at levels well known to the persons skilled in the art.

This multiparticulate formulation can be dosed directly into the mouth of the patient or by mixing the prescribed dose with a small amount of soft food or with a drink prior to administration. The pellets can be provided in a bottle with dosing scoop or in single dose e.g. from sachets or can further be formulated, along with

^{• ■} i one or more excipients well known to persons skilled in the art, as a pharmaceutical composition for oral administration such as, but not limited to, tablets, including dispersible tablets, orally disintegrating tablets, hard and soft gelatin capsules or as a suspension composition and the like.

In order to avoid agglomeration of the pellets when administered along with liquids another coating layer was provided on the taste-mask coat.

In other embodiment, the coated pellets can be formulated as a suspension composition along with one or more excipients.

The term "suspension composition" includes within its scope but is not limited to compositions selected from the group of a unit dose packet (sometimes referred to in the art as a "sachet"), in the form of a suspension made from a unit dose packet, in the form of a product for oral suspension for constitution with water or other suitable vehicle before use, in the form of a dose sipping device and in the form of an oral suspension per se. It is noted that when a unit dose packet is constituted, it is probably mainly in the form of a suspension if reconstituted according to directions, although the extent of suspension versus solution depends on a number of factors such as pH. The use of the term "suspension" herein is intended to embrace liquids comprising griseofulvin partially in suspension and partially in solution.

The excipients useful for the suspension composition can be selected from the group comprising wetting agents, sweeteners, thickening agents, dispersing agents, pH-stabilizing agents, flavouring agents, taste - enhancing agents, preservatives, coloring agents, lubricants and flow aids, antifoaming agents. One excipient can perform more than one function.

Wetting agents include, but are not limited to, surfactants, either singly or in admixture. Examples of surfactants include, but are not limited to, the polysorbates, sodium lauryl sulphate, poloxamers and mixtures thereof.

Suitable sweeteners include, but are not limited to, natural sweeteners such as sugars e.g. fructose, glucose, sucrose; sugar alcohols such as mannitol, sorbitol; artificial sweeteners such as sodium saccharine, sodium cyclamate, aspartame.

Suitable thickening agents function as suspending agents and include, but are not limited to, hydrocolloid gums known for such purpose, examples of which include xanthan gum, guar gum, locust bean gum, gum tragacanth and mixtures thereof. Alternatively, synthetic suspending agents may be used such as sodium carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose and mixtures thereof.

Dispersing agents include, but are not limited to, colloidal silicon dioxide and surfactants such as sodium lauryl sulphate, polysorbates or mixtures thereof. The composition may also contain a pH stabilizing agent to maintain a desired pH upon reconstitution, as discussed above. The term "pH stabilizing agent" encompasses buffers and pH altering agents. Suitable pH stabilizing agents include, but are not limited to, tribasic sodium phosphate, anhydrous sodium carbonate, glycine, citric acid and mixtures thereof.

Flavoring agents are selected from those well known to persons skilled in the art and include, but are not limited to, one or more fruity flavors.

Taste enhancing agents include, but are not limited to, sodium chloride, glycine, citric acid and mixtures thereof.

Suitable preservatives include, but are not limited to, benzoic acid and sorbic acid and their salts, methyl paraben, butylparaben, propylparaben and mixtures thereof.

Suitable coloring agents include, but are not limited to, titanium dioxide pigments, lake colors and iron oxide pigments.

Lubricants and flow aids such as, but not limited to, talc, calcium silicate, colloidal silicon dioxide, stearic acid, its salts and its derivatives

Antifoaming agents include, but are not limited to simethicone, dimethyl polysiloxane.

The following example is given to demonstrate the invention and is in no way a limitation to the same. EXAMPLES

Example 1

Brief manufacturing procedure:

1. Griseofulvin, microcrystalline cellulose, croscarmellose sodium and sodium starch glycolate were sifted and mixed.

2. The blend of step (1) was granulated using hydroxypropyl cellulose solution in water comprising sodium lauryl sulfate. 3. The wet mass was extruded using extruder through a suitable screen and the extruded pellets were spheronized at a suitable rpm in an spheronizer using talc as an antiadherant.

4. The pellets were dried in a fluid bed processor at 40-50⁰C till LOD was less than 3% w/w. 5. Coat step (4) pellets with coating solution (A) in fluidized bed coater (bottom spray).

6. Coat step (5) coated pellets with coating solution (B) in fluidized bed coater (bottom spray).

Example 2

Brief manufacturing procedure

1. Griseofulvin and Talc are sifted and mixed in blender.

2. Hydroxypropylmethylcellulose solution in water comprising sodium lauryl sulfate was prepared.

3. MCC/Sugar spheres are loaded in Fluidized Bed Processor and blend of step (1) is loaded on MCC/sugar spheres (Tangential spray unit) using step (2) solution.

4. Coat step (3) pellets with coating solution (A) in fluidized bed coater (bottom spray). 5. Coat step (4) coated pellets with coating solution (B) in fluidized bed coater (bottom spray).

Bioequivalence Study

A bioequivalence study was carried out using griseofulvin pellets, equivalent to griseofulvin 250mg prepared according to Example 1, as the test product and Grifulvin V^® (griseofulvin oral suspension) manufactured by Ortho Dermatological, USA of strength 125mg/5ml as reference product.

The study was carried out in 6 healthy volunteers receiving single dose of griseofulvin equivalent to 250mg in fed state for 96 hrs. The study was monitored in terms of the AUCs and C_max. AUCs are plots of serum concentrations of griseofulvin along the ordinate (Y-axis) against time on the abscissa (X-axis). Generally, the values for AUC represent a number of values taken from all the subjects in a population and are, therefore, mean values averaged over the entire population. C_max, the observed maximum in a plot of serum level concentration of griseofulvin (Y-axis) versus time (X-axis) is likewise an average value. ^f<

The ratios of the log transformed mean values for C_maχ and AUC for the test and reference product (T/R ratio) is a measure of the bioequivalence between the test and reference product. Values between 80 and 125 % of these ratios indicate bioequivalence as recommended by the USFDA.

Table 1: Fed BE study data of Griseofulvin pellets (Example 1) against commercially available suspension formulation "GRIFULVIN V^®" n = 6

Cmax = Maximum plasma concentration

AUC (o-t) = Area under the plasma concentration time curve from time 0 to t As can be seen from the data above in Table 1, test product shows comparable bioavailability with reference product. The T/R ratio, in case of C_max and AUC were within the limits of 80-125 %, as established by the USFDA for claiming bioequivalence between a test and reference product.

Claims

1. A novel taste masked solid oral discrete dosage forms comprising a core comprising griseofulvin and one or more coating layers.

2. A novel taste masked solid oral discrete dosage form of claim 1 , wherein the core further comprises one or more excipients selected from the group comprising diluents, binders, disintegrants, glidants, lubricants or flow aids and wetting agents.

3. A novel taste masked oral discrete dosage form of claim 2, wherein the diluent is one or more selected from the group comprising mannitol, sucrose, starch, lactose, dicalcium phosphate, xylitol, sorbitol and microcrystalline cellulose.

4. A novel taste masked oral discrete dosage form of claim 2, wherein the binder is one or more selected from the group comprising alkyl celluloses, hydroxyalkylcelluloses, sodium carboxymethylcellulose, starches, pregelatinised maize starch, sugars, polyethylene oxide, gums and polyvinylpyrrolidone.

5. A novel taste masked oral discrete dosage form of claim 2, wherein the disintegrant is one or more selected from the group comprising crospovidone, sodium starch glycolate, starches, croscarmellose sodium and cellulose products.

6. A novel taste masked oral discrete dosage form of claim 2, wherein the glidant is one or more selected from the group comprising colloidal silica, powdered cellulose, talc and tribasic calcium phosphate.

7. A novel taste masked oral discrete dosage form of claim 2, wherein the lubricant or flow aid is one or more selected from the group comprising calcium silicate, colloidal silicon dioxide, stearic acid, its salts and derivatives.

8. A novel taste masked oral discrete dosage form of claim 2, wherein the wetting agent comprises polysorbates, sodium lauryl sulphate and poloxamers.

9. A novel taste masked oral discrete dosage form of claim 1, wherein one or more coating layer(s) comprises one or more excipients selected from the group comprising coating agents, plasticizers, antitacking agents, surfactants, coloring agents and opacifiers.

10. A novel taste masked oral discrete dosage form of claim 9, wherein the coating agent is selected from the group comprising polysaccharides, alkyl celluloses, hydroxyalkylcelluloses, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinylpyrrolidone and vinyl acetate and polymers based on methacrylic acid, alginate based coating agents and mixtures thereof.

11. A novel taste masked oral discrete dosage form of claim 9, wherein the plasticizer is selected from the group comprising dibutyl phthalate, triethyl citrate, polyethylene glycol and mixtures thereof.

12. A novel taste masked oral discrete dosage form of claim 9, wherein the antitacking agent is one or more selected from the group comprising colloidal silicon dioxide, talc, stearic acid, its salts and its derivatives.

13. A novel taste masked oral discrete dosage form of claim 9, wherein the surfactant is one or more selected from the group comprising polysorbates and sodium lauryl sulphate.

14. A novel taste masked solid oral discrete dosage form of claim 1, are pellets.

15. A process of preparation of novel taste masked solid oral discrete dosage forms comprising griseofulvin, the said process comprising the steps of reducing the particle size of griseofulvin, blending with the other excipients, granulation, extrusion- spheronization, drying and screening to obtain discrete dosage forms, said discrete dosage forms being further coated with one or more film coating layers to achieve taste masking.

16. A process of preparation of novel taste masked solid oral discrete dosage forms comprising griseofulvin, the said process comprising the steps of reducing the particle size of griseofulvin; blending with the other excipients; preparation of binder solution; loading of carrier or substrate, blended drug and binder solution in fluidized bed processor; said discrete dosage forms being further coated with one or more film coating layers to achieve taste masking.

17. A pharmaceutical suspension composition in the form of a novel taste masked pellets comprising griseofulvin and one or more coating layers.

18. The pharmaceutical suspension composition of claim 17, wherein the suspension further comprises of one or more excipients selected from the group comprising wetting agents, sweeteners, thickening agents, dispersing agents, pH stabilizing agents, flavouring agents, taste enhancing agents, preservatives, coloring agents, lubricants and flow aids and antifoaming agents.