DESC: FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:

“STABLE SMALL VOLUME PARENTERAL DOSAGE FORM OF SODIUM AMINOSALICYLATE”

2. APPLICANT:

(a) NAME: RUSAN PHARMA LIMITED

(b)NATIONALITY: Indian Company incorporated under the
Companies Act, 1956

(c) ADDRESS: 58-D, Government Industrial Estate, Charkop,
Kandivali (West), Mumbai – 400 067, Maharashtra, India

3.PREAMBLE TO THE DESCRIPTION:

The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD:
This invention relates to stable, small volume parenteral dosage form with higher systemic bio-availability and lower toxicity of sodium aminosalicylate. The lyophilized formulation contains combination of sodium aminosalicylate, polyvinyl pyrrolidone and stabilizers. The formulation is stable at temperature less than 30 degree celsius for at least 3 years. The small volume parenteral formulation has a short reconstitution time of less than 1 minute, and is suitable for parenteral administration through various routes such as intravenous, intramuscular, intraperitoneal, or subcutaneous.

BACKGROUND AND PRIOR ART:
4-aminosalicylic acid, commonly known as PAS, is an antibiotic used to treat tuberculosis. Aminosalicylate sodium is a sodium salt of aminosalicylic acid, that is commonly used with other anti-tubercular medicines, to help the body to overcome tuberculosis (TB).

Sodium amino salicylate (Sodium PAS) is available in oral and parenteral formulation. In oral form, it is available in enteric coated tablets and granules form. The maximum dose is 12 g per day via oral route. Sodium PAS is also available in parenteral form, it is available in sterile powder form for injection. One such marketed form is having a brand name of Pas-Fatol N, wherein the active is given in an amount of 13.49 gm, which is equivalent to approximately 12 gm of salicylic acid.

The two reported major considerations in the clinical pharmacology of Pas-Fatol N acid are the prompt production of a toxic inactive metabolite under acid conditions and the short serum half-life of one hour for the free drug.

Sodium amino salicylate sterile powder for injection available in the market needs to be reconstituted using 500 ml sterile water for injection or sterile 0.9% saline solution.

In the literature, the clinical use of intravenous sodium para-amino salicylate (Sodium PAS) and polyvinyl pyrrolidone (PVP) is reported in journal Dis Chest 1954: 26, 47-51 that a combination of sodium para-amino salicylate and polyvinyl pyrrolidone results in blood PAS levels which are approximately twice as high and last twice as long in therapeutic range. However, this article failed to teach stable preparations of sodium PAS with PVP.

The WO application 2007/086039 discloses method of preparing porous microparticles comprises the steps of combining one or more organic compounds with a volatile solvent system, and spray drying the system thus formed to provide porous microparticles of the organic compound or composite porous microparticles of combinations of organic compounds. Organic compounds used in the method may be one or more of a bioactive that includes PAS and a pharmaceutically acceptable excipient which includes PVP together with a pharmaceutically acceptable adjuvant or combinations thereof. This applications highlights the use of sodium PAS for respiratory administration.

Journal of the American Pharmaceutical Association, 1954, 43, 398-401 titled “Study of possible complex formation between macromolecules and certain pharmaceuticals”. ” discloses the preparation of complexes in solution between polyvinylpyrrolidone and p-aminobenzoic acid, benzoic acid, salicylic acid, p-hydroxybenzoic acid, m-hydroxy-benzoic acid, and phenobarbital.

Journal of Pharmaceutical Sciences, May 1968, 57, 832-835, titled “Dissolution of salicylic acid and polyvinylpyrrolidone from compressed mixtures”. Here it was reported that PVP enhances the intrinsic dissolution of salicylic acid.

Till today, the manufacturers are supplying the sodium amino salicylate for Injection in large volume parenteral (LVP) bottles mainly 500 ml capacity as mentioned above. The large volume parenteral injection consists of 10-12 gms of active without PVP. The LVP injection has to get reconstituted with isotonic saline or water for injection (used as reconstitution fluid) before administration. The volume of reconstitution fluid is nearly very large and about 500 ml. The major limitation of LVP is that a patient needs to get hospitalized for administration of infusion for minimum of 3-4 hours and therefore cannot be used in out-patients. Moreover, this large dose of sodium amino salicylate in an amount of 10-12 gms in single administration has more systemic toxic effects in comparison to low dose. LVP can only be administered through intravenous route.

The stability is major issue with sodium PAS formulation. It is well reported in literature that sodium amino salicylate is highly oxidizable and results in formation of related substances like m-amino phenol which is highly toxic to the human body. The British Pharmacopoeia described the limit for m- amino phenol in Sodium amino salicylate i.e. NMT 0.25%.

In the light of the above, it is evident that the prior art fails to suggest stable small volume parenteral of sodium PAS that can be administered to the patients who is in need thereof without hospitalization.

Therefore, there is a need in the art to provide stable small volume parenteral dosage form of sodium amino salicylate so as to eliminate the problems involved in the administration of large volume parenteral as detailed above.

Accordingly, in an attempt to achieve the above object, it was found that the small volume parenteral dosage form innovated by the instant inventors can be used for out-patients with less systemic toxic effects. None of the prior-arts report about the stable small volume parenteral formulation of Sodium amino salicylate with higher bioavailability. With the technology described in this patent application, the current dose of sodium amino salicylate that is normally administered without PVP can be reduced to half of that of plain sodium amino salicylate dose.

SUMMARY OF THE INVENTION:
Accordingly, in one aspect, the invention provides a stable small volume lyophilized combination product of Sodium Para aminosalicylate with higher bioavailability equivalent to the large volume Sodium PAS without PVP, i.e, marketed formulation in half or lesser dose.

The lyophilized product of the invention can be prepared by dissolving Sodium PAS, PVP and stabilizers in aqueous system and then lyophilized using freeze drying technology.

This formulation can be administered to the patients in small volume with lesser toxicity.
DETAILED DESCRIPTION:
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.

Accordingly, the present invention describes the importance of usage of combination of Sodium Aminosalicylate and polyvinyl pyrrolidone in lyophilized form. It was observed that the combination provides higher bioavailability, stability and less toxicity. The formulation can be provided to out patients in bolus injectable form, without hospitalization and can be safely used in small health clinics. Moreover the handling during transportation is easy and can be easily reconstituted in comparison to large volume parenterals.

In a preferred embodiment, the invention provides a stable lyophilized combination product of Sodium Para amino salicylate with polyvinyl pyrrolidone comprising Sodium Para amino salicylate in an amount of 60-98%w/w; PVP in an amount of 5-30%w/w; complexing agent in an amount of 0.01-2%w/w and stabilizing agent in an amount of 0.01-2%w/w.

The complexing agent selected is disodium EDTA in an amount of 0.01%-2% w/w to the total composition.

The stabilizing agent selected is sodium sulfite or metabisulfite in an amount of 0.01%-2% w/w to the total composition.

The lyophilized product for parenteral administration can be prepared by a process comprises dissolving Sodium PAS, Polyvinyl pyrrolidone (PVP), complexing agent and stabilizers in aqueous system followed by lyophilization using freeze drying technology.

The lyophilized composition is reconstituted with WFI to obtain small volume of 5 ml to 100 ml. This small volume parenteral formulation has a short reconstitution time of less than 1 minute, and is suitable for parenteral administration through various routes such as intravenous, intramuscular, intraperitoneal, or subcutaneous.
The solution of sodium PAS, combination of sodium PAS and PVP was kept at room temperature for 10 days and the sampling was done after intervals of every 24 hrs. The samples were analyzed for m-amino phenol level; it was found that the combination solution shows less increment of m-amino phenol in comparison to plain solution of sodium PAS.

Further, the stability of the combination (sodium PAS and PVP) in powder (without lyophilization) and lyophilized form was compared with plain powder form and lyophilized form of sodium PAS. It was found that the lyophilized combination product (sodium PAS and PVP) possess a highest stability.

Based on the above pilot studies, the stability of the formulation was further subjected to accelerated degradation studies and found that the formulation of the instant invention was found to be stable upto 3 years at 30 degree celsius and 65% RH, with m-aminophenol content of NMT 0.25%.

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.

Examples
Example 1
Disodium EDTA, 100 mg was dissolved in 70 ml WFI (water for injection). Polyvinyl pyrrolidone, 350 mg and Sodium sulphite, 10 mg were added to the above solution. Adjusted the pH to 8.5- 10.5 using 0.1N sodium hydroxide and Para-aminosalicylic acid, 2.5 grams (as sodium aminosalicylate) was added and maintained the pH between 8 to 10. The volume was made up to 100 ml and freeze dried.

Example 2
Disodium EDTA, 100 mg was dissolved in 70 ml WFI (water for injection). Polyvinyl pyrrolidone, 350 mg and Sodium metabisulphite, 10 mg were added to it. Adjusted the pH to 6.5 using 0.1N sodium hydroxide and Para-aminosalicylic acid, 25% w/v (as sodium aminosalicylate) was added and maintained the pH between 8 to 10. The volume was made up to 100 ml and freeze dried.
Example 3
Reconstitution:
Reconstitution of the lyophilized product can be achieved within one minute using 10ml of WFI, that can be administered to patient immediately upon reconstitution.
Clarity of the solution:
The solution is clear and color is less intense than BY3 (as per standard procedure mentioned in British Pharmacopoeia).

Turbidity/particulate matter:
There is no turbidity after reconstitution and particulate matter is within the range of pharmacopoeial limits of small volume pareneteral.

Stability results
The combination product described in invention was found to be stable for 3 years in real time studies at 30 degree celsius and 65% RH.

Toxicity results
Single dose toxicity studies of combination product Para-aminosalicylic acid, 25% w/v (as sodium aminosalicylate) and PVP (3.5% w/v) was performed in 30 wistar rats (15 male and 15 female) against plain Para-aminosalicylic acid, 25% w/v (as sodium aminsoalicylate) and Plain PVP (3.5% w/v). The results are summarized below.

Clinical Parameters Sodium Aminosalicylate in combination with PVP (G1) Plain Sodium Aminosalicylate (G2) Plain PVP (G3)
Mortality (%) 0 0 0
Body weight (After 14 days) No significant change No significant change No significant change
Average food consumption (g/rat/day) Increased, RSD below 2 Increased, RSD below 2 Increased, RSD below 2
Hematology after 14 days Normal Normal Normal
Clinical chemistry Normal Normal Normal

Organs and Lesions Group G1 G2 G3
Sex M F M F M F
No. of Animals 5 5 5 5 5 5
No abnormality detected 5 5 5 5 5 5
Clear fluid ooze out from nostrils 0 0 0 0 0 0
Tail: blackish brown discoloration and necrosis 0 0 0 0 0 0
No abnormality detected 5 5 5 5 5 5
Whitish depression in a lobe 0 0 0 0 0 0
Cyanotic blackish discoloration 0 0 0 0 0 0
Reddish discoloration and enlargement of size 0 0 0 0 0 0
Froth in trachea 0 0 0 0 0 0 ,CLAIMS:We claim,

1. Stable, small volume pharmaceutical composition for parenteral administration comprising Sodium Para amino salicylate in an amount of 60-98%w/w; PVP in an amount of 5-30%w/w; disodium EDTA as complexing agent in an amount of 0.01-2%w/w and sodium sulfite or metabisulphite as stabilizing agent in an amount of 0.01-2%w/w.

2. The stable, small volume pharmaceutical composition according to claim 1, wherein the composition is in lyophilized form.

3. The stable, small volume pharmaceutical composition according to claim 1, wherein the composition is reconstituted with WFI (water for injection) to obtain small volume of 5-100 ml.

4. A process for preparation of stable, lyophilized product for parenteral administration comprising dissolving Sodium PAS, Polyvinyl pyrrolidone (PVP), complexing agent and stabilizers in aqueous system followed by lyophilization using freeze drying technology.

5. The process according to claim 4, wherein the lyophilized product is reconstituted with WFI (water for injection) to obtain small volume of 5-100 ml.
6. The process according to claim 4, wherein the complexing agent is selected from disodium EDTA.

7. The process according to claim 4, wherein the stabilizing agent is selected from sodium sulfite or metabisulphite.

Dated this 11th day of November, 2014

Dr. P. Aruna Sree
(Regn.No.: IN/PA 998)
Agent for Applicant
Gopakumar Nair Associates