THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10) FORM 2
AN ORAL PHARMACEUTICAL COMPOSITION
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059, MAHARASHTRA, INDIA.
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

The present invention relates to an oral pharmaceutical composition comprising phenytoin sodium and pharmaceutically acceptable excipients.
BACKGROUND OF THE INVENTION
Phenytoin is the generic name for 5, 5-diphenyl-2, 4-imidazolidinedione. It is also known as diphenylhydantoin. It is used to treat convulsive disorders such as epilepsy. The compound generally is utilized as a sodium salt, which is readily soluble in water. Anhydrous form of phenytoin sodium is known to rapidly dissociate into phenytoin which is insoluble in aqueous solutions. Commercial production of anhydrous sodium phenytoin is known to result in complex mixture of polymorphic forms and the individual polymorphs are known to exhibit different dissolution rates.
United States Patent Number 6,274,168 ('168 patent) discloses an erodible matrix composition comprising phenytoin sodium. It has been found by the inventors of the '168 patent that the processing of polymorphic mixtures of phenytoin sodium with the components of the erodible matrix yields consistently unique 'phenytoin species' and does not get converted into any other polymorph. The '168 patent requires presence of an adequate amount of aqueous solvent when granulation process is used because water is believed to dissolve the phenytoin sodium, regardless of its polymorphic form, so that upon drying and resolidification, the resulting mixture would consistently contain unique 'phenytoin species'. It is said that it is important that about 31 mg to about 61 mg of water is used per 100 mg of phenytoin sodium in the granulation process. The '168 patent teaches use of alkaline pH modifier like magnesium oxide to prevent conversion of sodium phenytoin into free phenytoin.
Sodium phenytoin has a narrow therapeutic index of 10-20 ug/ml. It is available commercially in different dosage forms for example, prompt release tablets, suspension, injection and extended release capsules which releases the phenytoin sodium for a period of about 2 hours. Because of the narrow therapeutic index and existence of different polymorphic forms, the dissolution of sodium phenytoin from extended release dosage forms is critical. For example, the United States Pharmacopoeia (USP) requires that the extended release sodium phenytoin capsules release specified amount of sodium phenytoin at different time points namely 30 minutes, 60 minutes and 120 minutes.
Generally the Pharmacopoeia checks the probability of a sample passing the dissolution test by initially testing a small sample size with narrow dissolution acceptance limit, if not passed, then a bigger sample size with a more relaxed dissolution acceptance limit is allowed for analysis. The initial test with six samples with requirement of each sample passing the dissolution test is referred to as SI ( for immediate release dosage forms) or LI (for extended release dosage forms) or Al (for delayed release dosage forms) stage. When this condition is not met, USP allows testing twelve samples with specified dissolution limits, this test referred to as S2 or L2 or A2 stage. If the condition at stage '2' is not met, USP further allows to check for twenty four samples, this stage is referred to as stage 3, i.e S3 or L3 or A3. For example, in case of phenytoin sodium extended release capsules, the requirement is
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considered to be met at SI stage if the quantities of phenytoin sodium dissolved from the individual capsules conform to the acceptance limits specified. If the requirement is not met at SI stage, then USP allows to continue testing twelve capsules (referred in the USP as S2 stage) or further twenty four capsules (referred in USP as S3 stage) with dissolution limits specified for S2 and S3 stage, respectively.
Although a batch that passes in S2 stage or S3 stage is considered to be USP compliant, it is always desirable to meet the USP dissolution requirements at the SI stage itself since a batch passing a dissolution test at SI stage signifies that there is a high probability that all the samples would fall within the required dissolution limits of SI stage.
Our pending PCT publication number WO2004087648 (patent publication '648) discloses a stable pharmaceutical composition comprising phenytoin or its pharmaceutically acceptable salts, lactitol and other pharmaceutically acceptable excipients, characterized in that the composition when stored at 25° C and 60 % relative humidity for one-year exhibits no change in coloration. When the composition of the '648 publication was manufactured in large scale, we found mat the USP dissolution requirement was not met at SI stage but was met at S2 or S3 stage. Surprisingly, we found that the problem was related to the amount of sodium lauryl sulphate and to the polymorphic form of the phenytoin sodium. When the composition was manufactured in large scale, decreasing the amount of sodium lauryl sulphate to a range of 0.01 % to 0.35 % by weight of the composition resulted in meeting the USP dissolution requirement at SI stage itself. Further we also found that the polymorphic form of phenytoin sodium remains unchanged in the composition during the shelf life.
OBJECTS OF THE INVENTION
It is the object of the present invention to provide an oral pharmaceutical composition comprising phenytoin sodium that shows polymorphic stability over a period of shelf life.
It is another object of the present invention to provide an oral pharmaceutical composition that contains permissible amounts of free phenytoin.
SUMMARY OF THE INVENTION
The present invention provides an oral pharmaceutical composition comprising phenytoin sodium and sodium lauryl sulphate in the amount in the range of 0.01 % to 0.35 % by weight of the composition, said composition when subjected to United States Pharmacopoeia XXX (USP XXX) dissolution method for extended release phenytoin sodium capsules, providing for each of the six capsules tested, the dissolution values within limits specified in the USP.
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DETAILED DESCRIPTION OF THE PRESENT INVENTION
According to the present invention, when sodium lauryl sulphate is present in the amount in the range of 0.01 % to 0.35 % by weight of the pharmaceutical composition of phenytoin sodium, it was found that the United States Pharmacopoeia XXX (USP XXX) dissolution requirements for extended release phenytoin sodium capsules were met at SI stage itself.
The USP XXX describes the dissolution test for extended release phenytoin sodium capsules. The dissolution acceptance limits and the method, differs according to the phenytoin sodium strengths. For example, for 100 mg strength of sodium phenytoin capsules, it is required to perform the dissolution test using 900 ml water as the dissolution medium using basket apparatus 1 rotating at 50 rpm. The SI stage is considered to be met, which is as per the present invention, if each of the six capsules releases 20 % to 40 % by weight of labeled amount of phenytoin sodium in 30 minutes, 40 % to 80 % by weight of labeled amount of phenytoin sodium in 60 minutes and not less than 75 % by weight of labeled amount of phenytoin sodium in 120 minutes.
For 200 mg and 300 mg strengths of phenytoin sodium, the USP requires to carry out the dissolution in 900 ml of water as the dissolution medium in basket apparatus rotating at 75 rpm speed. The SI stage is considered to be met if each of the 6 capsules releases 10 % to 35 % by weight of labeled amount of phenytoin sodium in 30 minutes, 30 % to 75 % by weight of labeled amount of phenytoin sodium in 60 minutes and not less than 65 % by weight of labeled amount of phenytoin sodium in 120 minutes.
According to the USP XXX method, the phenytoin sodium is analyzed by high performance liquid chromatography. In the present invention, the USP specified method or any other suitable method of analysis of phenytoin sodium can be employed to determine the phenytoin sodium content.
According to the present invention, the oral pharmaceutical composition comprises phenytoin sodium in amounts ranging from about 50 mg to about 500 mg per unit dosage form. Preferably, the amount of phenytoin sodium ranges from about 75 mg to about 400 mg and most preferably, from about 100 mg to about 300 mg per unit dosage form.
According to one preferred embodiment of the present invention, the phenytoin sodium used is in the anhydrous form. In one preferred embodiment of the present invention, the phenytoin sodium is obtained from Katwijk Chemie, Netherlands. The polymorphic nature of the sodium phenytoin is determined by X-ray crystallography and Raman Spectra. The sodium phenytoin from Katwijk, Chemie is in anhydrous form having an X-ray diffraction pattern with specific peaks at 2-theta (20) = 5.5867° and 6.5548° (± 0.2°). It exhibits a Raman spectrum with characteristic Raman scattering lines at 1599 cm-1, 1190 cm-1, 1158 cm-1, 1034 cm-1, 1004 cm-1, 972 cm-1, 677cm-1 and 288cm-1.
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According to the present invention, the oral pharmaceutical composition comprises sodium lauryl sulphate in amounts ranging from 0.01 % to 0.35 % by weight of the composition, preferably 0.1 % to 0.32 % and most preferably about 0.25 % by weight of the composition.
According to one preferred embodiment of the present invention, the pharmaceutical composition comprises phenytoin sodium, sodium lauryl sulphate in amounts ranging from 0.15 % to 0.35 % by weight of the composition. It was found that the composition of the present invention when manufactured at a scale of sixteen lakhs unit dosage forms, the batch passed the United States Pharmacopoeial limits of dissolution.
It is known that free phenytoin is practically insoluble in water and the composition on storage may convert the sodium phenytoin to free phenytoin. The free phenytoin content of the composition of the present invention was determined at initial time point and after storage for 3 months at 40°C and 75 % relative humidity in HDPE bottles having ribbed child resistant cap and silica gel bags as the desiccant. The free phenytoin content was determined by potentiometric titration wherein the composition was first dissolved in dimethylformamide and then titrated against 0.1 M sodium methoxide, potentiometrically.
When the composition of the present invention is stored at accelerated storage conditions for e.g 40 °C, 75 % relative humidity for about three months in closed containers which corresponds to the shelf life of the product, the free phenytoin content does not exceed about 7.5 %, preferably about 5 %, most preferably 3 % by weight of the composition. The permissible amount of free phenytoin in the composition of the present invention is less than 7.5 % by weight of the composition during the shelf life of the product. According to one preferred embodiment, the free phenytoin content of the pharmaceutical composition of the present invention contains less than 5 % by weight of the composition.
The composition of the present invention was checked for polymorphic stability at initial time point and upon storage at after storage for about three months at 40°C and 75 % relative humidity in HDPE bottles having ribbed child resistant cap and silica gel bags as the desiccant. It was found that the XRD pattern and the Raman spectrum of sodium phenytoin remained unchanged during the storage.
The oral pharmaceutical composition of the present invention comprises a mixture of suitable fillers. The examples of the fillers that may be used include, but are not limited to, lactose, lactitol, mannitol, starch, microcrystalline cellulose, sorbitol, glucose and the like and mixtures thereof. In one preferred embodiment, lactitol is used as filler. The amount of lactitol that may be used according to one embodiment of the present invention, ranges from about 10 % to about 90 % by weight of the composition, preferably, 20 % to 70 % by weight of the composition and most preferably from about 40 % to about 55 % by weight of the composition.
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The oral pharmaceutical composition of the present invention may contain additional excipients like lubricants, glidants selected from the group comprising talcum, magnesium stearate, sodium stearyl fumarate and the like and mixtures thereof.
The oral pharmaceutical composition may be in unit dosage forms such as powder filled in capsules, granules filled in capsules, compressed tablets and the like.
In one embodiment of the present invention, the oral pharmaceutical composition is prepared by dry mixing the excipients such as phenytoin sodium, fillers such as lactitol, surfactants such as sodium lauryl sulphate, glidants such as magnesium stearate and the like. The dry mix blend may be filled into hard gelatine capsules. According to another embodiment of the present invention, the dry mix is subjected to slugging and compaction. The slugs are milled. The milled slugs may be filled into hard gelatin capsule.
According to another embodiment the process of the present invention comprises the following steps (i) lubricating phenytoin sodium with lubricants (ii) lubricating lactitol with lubricants (iii) slugging the blend of (i) and (ii), (iv) adding sodium lauryl sulphate; to the slugs of step (iii)
The examples that follow do not limit the scope of the invention and are presented as illustrations.
EXAMPLE 1
Table 1

Ingredients amt. in mg % w/w
Phenytoin sodium 100.0 40
Magnesium stearate 10.0 4
Lactitol monohydrate 133.0 53.2
talcum 6.0 2.4
Sodium lauryl sulphate 0.50 0.2
Phenytoin sodium, magnesium stearate are sifted separately through 40 mesh. Phenytoin sodium is blended with magnesium stearate. Lactitol, magnesium stearate are sifted through 20 mesh. Talc is sifted through 60 mesh sieve Lactitol and magnesium stearate are added to the phenytoin sodium blend. The blend is slugged. The slugs a•; milled. Sodium lauryl sulphate is sieved through 60 mesh sieve. Sifted sodium lauryl sulphate is mixed with tit phenytoin sodium blend in geometric proportion. The blend is filled into '0'size hard gelatin capsules.
EXAMPLE 2
The composition of Example 1 was tested for the in vitro dissolution using the United States pharmacopoeia! method using 900 ml water as dissolution medium at 50 rpm. The release was measured at 30 minutes, 60 minut ; and 120 minutes. The phenytoin content was determined by high performance liquid chromatography.
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Table 2: in vitro Dissolution Results

Time Points (minutes) phenytoin sodium released from the composition Amount in % w/w
Minimum Maximum Average of 6
30 (20-40 % of the label claim) 30 34 32
60 (40-80 % of the label claim) 49 55 53
120 (not less than 75 % of the label claim) 75 86 79
It is seen from the data that phenytoin sodium composition comprising about 0.2 % by weight of sodium lauryl sulphate, passes the USP XXX dissolution test at SI stage.
EXAMPLE 3
The free phenytoin content of the pharmaceutical composition prepared according to example I was determined
initially and after storing the composition for three months at 40 ° C and 75 % relative humidity.
Table 3: Free phenytoin content
Time point Free phenytoin.content
Initial 3.4
3 months 2.6
EXAMPLE 4
The X-ray diffraction and Raman spectrum of the composition of Example 1 was recorded at zero initial time. The composition of Example 1 was stored at room temperature for three months at 40 °C and 75 % relative humidity an J Raman Spectra was recorded. It is seen from the XRD and Raman spectra that the polymorphic form of phenytu... sodium does not change over a period of shelf life.
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COMPARATIVE EXAMPLE
Table 4: composition
Ingredients amt. in mg % w/w
Phenytoin sodium 100.0 40
magnesium stearate 10.0 4
lactitol monohydrate 133.0 53.2
talcum 6.0 2.4
Sodium lauryl sulphate 1.0 0.4
Phenytoin sodium, magnesium stearate are sifted separately through 40 mesh. Phenytoin sodium is blended with magnesium stearate. Lactitol, magnesium stearate are sifted through 20 mesh. Talc is sifted through 60 mesh sieve. Lactitol and magnesium stearate are added to the phenytoin sodium blend. The blend is slugged. The slugs are milled. Sodium lauryl sulphate is sieved through 60 mesh sieve. Sifted sodium lauryl sulphate is mixed with the phenytoin sodium blend in geometric proportion. The blend is filled into '0'size hard gelatin capsules.
The composition prepared according to the comparative example was tested for the in vitro dissolution using the United States pharmacopoeial method using 900 ml water as the dissolution medium at 50 rpm. The release was measured at 30 minutes, 60 minutes and 120 minutes. The phenytoin content was determined by high performance liquid chromatography.
Table 5: in vitro dissolution data

Time Points (minutes) Dissolution of phenytoin sodium in percentage
Minimum Maximum Average of 6
30 (20-40 % of label claim) 31 48 39
60 (40-80% of label claim) 50 72 61
120 (no unit is less than 75 % of label claim) 72 96 83
It is seen that the composition of comparative Example does not pass the USP XXX dissolution test at SI stage.
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We Claim
1. An oral pharmaceutical composition comprising phenytoin sodium and sodium lauryl sulphate in the amount in the range of 0.01 % to 0.35 % by weight of the composition, said composition when subjected to United States Pharmacopoeia XXX (USP XXX) dissolution method for extended release phenytoin sodium capsules providing tor each of the six capsules tested, the dissolution values within limits specified in the USP.
2. An oral pharmaceutical composition of claim 1 wherein the amount of phenytoin sodium per unit dosage form is 100 mg. speed of basket used in the USP XXX dissolution method is 50 rpm and the dissolution values are 20 % to 40 % by weight of labeled amount of phenytoin sodium released in 30 minutes, 40 % to 80 % by weight of labeled amount of phenytoin sodium released in 60 minutes and not less than 75 % of labeled amount of phenytoin sodium released in 120 minutes.
3. An oral pharmaceutical composition of claim 1 wherein the amount of phenytoin sodium is 200 mg or 300 mg per unit dosage form, speed of basket apparatus used in the USP XXX dissolution method is 75 rpm and the dissolution values are 10 % to 35 % by weight of labeled amount of phenytoin sodium released in 30 minutes, 30 % to 75 % by weight of labeled amount of phenytoin sodium released in 60 minutes and not less than 65 % by weight of labeled amount of phenytoin sodium is released in 120 minutes.
4. An oral pharmaceutical composition as claimed in claim 1 wherein the sodium lauryl sulphate is about 0.25 % by weight of the composition.
5. An oral pharmaceutical composition as claimed in claim I sodium phenytoin is in anhydrous form having an X-ray diffraction pattern with specific peaks at 2-theta (20) = 5.5867° and 6.5548° and/or Raman Spectra with characteristic lines at 1599 cm-1, 1190 cm-1, 1158 cm-1, 1034 cm-1, 1004 cm-1, 972 cm-1, 677 cm-1 -and 288 cm-1.
6. An oral pharmaceutical composition as claimed in claim 1 wherein the composition comprises lactitol.
7. An oral pharmaceutical composition as claimed in claim 6 wherein the amount of lactitol is in the range of about 40 % to about 55 % by weight of the composition.
8. An oral pharmaceutical composition as claimed in claim 1 wherein the composition does not change polymorphic form of sodium phenytoin when stored at 40 ° C and 75 % relative humidity for about three months.
9. An oral pharmaceutical composition as claimed in claim 1 wherein the upon storage at 40 ° C and 75 % relative humidity for about three months, the free phenytoin content is not more than 7.5 % by weight of the composition.
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10. A process for the preparation of an oral pharmaceutical composition comprising phenytoin sodium, wherein th process comprises steps of
(i) lubricating phenytoin sodium with lubricants
(ii) lubricating lactitol with lubricants
(iii) slugging the blend of (i) and (ii),
(iv) adding sodium lauryl sulphate; to the slugs of step (iii)


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ABSTRACT
An oral pharmaceutical composition comprising phenytoin sodium and sodium lauryl sulphate in the amount in the range of 0.01 % to 0.35 % by weight of the composition, said composition when subjected to United States Pharmacopoeia XXX (USP XXX) dissolution method for extended release phenytoin sodium capsules providing for each of the six capsules tested, the dissolution values within limits specified in the USP.
To,
The Controller of the Patent
Patent Office
Mumbai-400037