FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"COMPOSITION OF STABLE LYOPHILIZED INTRAVENOUS
ADMINISTRATION"

2. APPLICANT
(a) NAME: MAC CHEM PRODUCTS INDIA PVT. LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: 304, Town Centre, Andheri-kurla Road, Andheri (E),
Mumbai-400059, 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:
The present invention relates to a novel stable parenteral lyophilized formulation of Rifampicin for intravenous administration with pharmaceutically acceptable excipients. The said composition improves the dissolution and bioavailability of Rifampicin which provides a stable formulation with simple and rapid manufacturing process. The said formulation has high curative effect to tuberculosis and reduces the damage caused by the oral medicament to liver.
Background and prior art:
Rifampicin is a semi-synthetic antibiotic derivative of Rifamycin SV. It is used in the treatment of both tuberculosis and the meningococcal carrier state. It is particularly active against rapid growing extra cellular organism but it also has intracellular bactericidal activity against slow and intermittently growing Mycobacterium tuberculosis. It inhibits DNA dependent RNA polymerase activity in susceptible cells.
Rifampicin IV infusion is indicated in patients who are unable to tolerate oral therapy e.g. post operative or comatose patients or patients in whom gastrointestinal absorption is impaired. Rifampicin injection is only intended to be administered via intravenous infusion. It should not be administered by intramuscular or subcutaneous route.
The injection of Rifampicin has been developed by Chinese Patent No. CN1097986 which describes the process for the preparation of Rifampicin injection containing Rifampicin, isoniazid and ethambutol which overcome the difficulties that the said Rifampicin is not easy to dissolve in water and dissolved Rifampicin has poor stability. The injection has high curative effect to tuberculosis and to reduce the damage of oral medicament to liver, another Chinese Patent No. CN1309966 describes the Rifampicin microemulsion and suspension perfusate and injection consisting of Rifampicin 1-12 wt%, emulsifier 3-25 wt% and distilled water 70-98wt% as main components. Adding assistant medicine components can produce perfusate and injection with microemulsion and suspension of Rifampicin.


Further Chinese Patent No. CN1742729 discloses the preparation method of Rifampicin injection including the slow addition of 300g of Rifampicin into 1000ml of mixed solution under the condition of continuously stirring with mixing anhydrous sodium sulfite, metal ion complexing agent, disodium ethylenediamine tetraacetate and propylene alcohol.
Indian Patent No. 211361 discloses pharmaceutical composition of anti tubercular drugs and process of preparation for oral use comprising Rifampicin and isoniazid wherein the bioavailability of Rifampicin and other drug is enhanced.
US Patent No. 7001893 discloses inclusion complex of anti-tubercular Rifampicin with beta-cyclodextrin or 2-hydroxypropyl beta -cyclodextrin as an anti-tubercular drug.
International Patent Publication No. WO2005/107741 which discloses oral compositions comprising anti-tubercular drugs in combination with alpha tocopherol and EP1750765 describes an improved process for the preparation of four drug anti-tubercular fixed dose combination viz. Rifampicin, Isoniazid, Pyrazinamide and Ethambutol Hydrochloride.
A stabilized oral powder or granule mixture made from at least two different antimicrobial tuberculosis drugs (Rifampicin, Isoniazid, Ethambutol, Pyrazinamide) for a short course therapy is described in International Patent Publication No. WO2005/074937 A1 and stabilized short course chemotherapy (SCC) of anti-tubercular drugs composition is disclosed in Indian Patent Application No. 124/MUM/2004.
US Patent No. 5104875 discloses pharmaceutical preparations containing Rifampicin and thioacetazone and optionally isonicotinic acid, hydrazide or ethambutol and the use of the same for the treatment of mycobacterial infections.
US Patent Publication No.20060246106 discloses a medical device which is resistant to bacterial infection, especially Staphylococcus infection. The device is at least partially coated or impregnated with a composition comprising Rifampicin and Tobramycin. The medical device can be a vascular graft, vascular patch or a heart valve. The device can include 0.05 to 0.15 mg/cm2 of Rifampicin and 0.02 to 0.05 mg/cm2 of Tobramycin.


The US Patent No. 4613496 describes solid pharmaceutical preparations containing Rifampicin, crystalline cellulose, sodium lauryl sulfate and a lubricant which have improved elution properties.
The International Patent Publication No. WO/2005/046567 describes the six compound pharmaceutical formulations and its process of making, comprising of antituberculosis agents like Rifampicin, Isoniazid, Pyrazinamide, and Ethambutal with addition of antioxidants such as d-alpha tocopherol or tocopheryl acetate and pharmaceutically accepted salts thereof and ascorbic acid in required therapeutic quantities for use in treatment of tuberculosis in mammals. This six drug formulation shows synergistic . mycobactericidal activity coming along with reduction in oxidative stress, leading to reduction in lung cell damages.
However, there is no formulation or delivery system for Rifampicin in particular, in lyophilized injection form, except Rafadin l.V. of Hoechst Marion Roussel by considering high dose of Rifampicin for therapeutic efficacy.
Rifampicin is having very poor solubility in water. To make lyophilized injection, one of the important criteria of product is that it should get reconstituted within minute in aqueous media, therefore can be suitably diluted further for infusion.
600 mg of Rifampicin will not easily get dissolved in water also it requires super solubilizer as well as stabilizer to overcome the risk of reprecipitation, recrystallization and degradation of active ingredients. None of the report has suggested a pharmaceutical technological solution to the above problem of parenteral delivery. The invention after careful experimentation and studies for sufficient period of time, have found a novel way to solve the bioavailability problem of drug.
The instant invention provides a lyophilized stable injectable form of Rifampicin by using suitable excipients like chelating agent, antioxidant, super solubilizers and compatible vehicle in combination which improves the dissolution of insoluble Rifampicin in


formulation. Hence, provides a super stable formulation suitable for administration by IV infusion.
Object of the Invention:
The main object of the present invention is to provide commercially viable and stable
parenteral formulation, useful for intravenous administration of anti-bacterial drug such
as Rifampicin along with pharmaceutically acceptable excipients in particular as
lyophilized (freeze dried) injection.
Another objective of the present invention is to obtain an efficient formulation suitable
for intravenous delivery having good lyophilization mass and product characteristics
which is safe and has 100% bioavailability.
Yet another object of the present invention is that the said stable Lyophillized
formulation gives fast reconstitution of high dose Rifampicin suitable for IV infusion
administration.
Summary of the invention:
In accordance with the above objectives, the instant invention provides a commercially viable and stable lyophilized parenteral formulation and a method for preparing a pharmaceutical composition for intravenous administration. The invention provides lyophilized parenteral formulation comprising Rifampicin along with pharmaceutical acceptable excipients such as solubilizer, antioxidant, complexing agent and a vehicle, which increases the dissolution and bioavailability of the said drug.
Detailed Description of the Invention:
The instant invention provides a commercially viable and stable lyophilized parenteral formulation and a method for preparing a pharmaceutical composition for intravenous administration. The invention provides lyophilized parenteral formulation comprising Rifampicin along with pharmaceutical acceptable excipients such as solubilizer, antioxidant, complexing agent and a vehicle, which increases the dissolution and bioavailability of the said drug.

The invented and developed injection is found comparatively superior with respect to dissolution easy for reconstitution and physicochemical stable than marketted injection. This is due to presence of novel composition consisting of best complexing agent, excellent solubilizer and suitable vehicle medium contribution.
This novel, stable formulation made with simple and rapid manufacturing process.
The present invention describes pharmaceutical compositions, which comprises therapeutically effective amount of Rifampicin along with appropriate solubilizer such as kollidon 12PF in variable ratios to achieve the maximum dissolution of the drug. The composition requires some additional solvent in combination with water, which can easily solubilize complete excipients alongwith active moiety in one solvent phase media.
The solvent phase media included solvent such as Butanol in 10-40% ratio for preparation of solution for lyophilization. During the process of lyophilization, the mass did not get collapsed and after lyophilization easy reconstitution with complete solubilization of the active moiety without recrystallization of particles has been observed.
The present invention comprises of a complexing agent such as disodium EDTA, Sodium Formaldehyde Sulfoxylate, Solubilizing agent such as Kollidon 12PF in the range of molar ratio 1:2 to 1:4 with respect to Rifampicin and one solvent phase media such as Butanol to provide stable formulation.
The lyophilized pharmaceutical composition of the present invention may be prepared according to the following steps:
1. Charging stainless steel manufacturing tank with filtered aqueous-butanol vehicle;
2. Adding and dissolving EDTA in manufacturing tank with continuous stirring;
3. Adding and dissolving Sodium Formaldehyde Sulfoxylate,

Adding and dissolving kollidon 12 PF in manufacturing tank with continuous stirring;
5. Finally, adding Rifampicin in manufacturing tank and stirring the solution continuously;
6. Adjusting the pH of the solution upto 8.5 with 1M sodium hydroxide solution;
7. Making up the volume of the aqueous solution with cooled aqueous-butanol and stirring the solution for 30 minutes; and
8. Adjusting the pH of the solution to 8.5±0.2. and
9. lyophilizing the mass.
The present investigation is more specifically explained by following examples. However, it will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
The following example is for the purpose of illustration of the invention only and is not intended in any way to limit the scope of the invention.

Formula Rifampicin Sodium
Formaldeyde
Sulfoxylate EDTA Kollidon 12PF Aqueous
Butanol
Q.S Sodium Hydroxide (To adjust pH 8.5)
1 600mg 0.1% 0.2% 400mg 10ml q.s
2 600mg 0.1% 0.2% 450mg 10ml q.s
3 600mg 0.1% 0.2% 500mg 10ml q.s
4 600mg 0.1% 0.2% 350mg 10ml q.s
5 600mg 0.1% 0.2% 300mg 10ml q.s
Best Formulation

Formula Rifampicin Sodium
Formaldeyde
Sulfoxylate EDTA Kollidon 12PF Aqueous
Butanol
Q.S Sodium Hydroxide to adjust pH8.5
1 600mg 0.1% 0.2% 350mg 10ml q.s
2 600mg 0.1% 0.2% 360mg 10ml q.s
3 600mg 0.1% 0.2% 370mg 10ml q.s
4 600mg 0.1% 0.2% 300mg 10ml q.s
5 600mg 0.1% 0.2% 310mg 10ml q.s
Stability:
The parenteral formulation of the present invention was found to be stable upto 3 years at room temperature. No significant change in any of the test specification obtained till expiry

The best formulation can be obtained in combination where Rifampicin and kollidon 12PF are in the ration of 1:3 and 1:4. The said parenteral formulation was found to be stable upto 36 months at room temperature without any significant change in any of the test parameters. The present invention is formulated with simple manufacturing process without any technical hurdles.

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We Claim,
1. A stable parenteral lyophilized formulation useful for intravenous administration
comprising,
i. Rifampicin in an amount of 600mg
ii. Chelating agent in an amount of 0.1%-0. 2% iii. Solubilizing agent in an amount of 1:2 to 1:4 iv. Vehicle co-solvent in an amount of 10-40 % (v/v).
2. A stable parenteral lyophilized formulation as claimed in claim 1, comprises of a Chelating agent such as Disodium EDTA and antioxidant Sodium Formaldeyde Sulfoxylate present in the range of 0.1%-0. 2% and 0.1% respectively.
3. A stable parenteral lyophilized formulation as claimed in claim 1, comprises of the solubilizing agent such as Kollidon 12PF in the ratio of 1:2 to 1:4.
4. A stable parenteral lyophilized formulation as claimed in claim I, comprises of the vehicle such as aqueous Butanol in range of 10-40% (v/v).
5. A stable parenteral lyophilized formulation as claimed in claim 1, wherein the said formulation is stable at room temperature, have increased dissolution and bioavailability.
6. A process for preparation of Rifampicin injection formulation comprising the steps of:
a. Charging stainless steel manufacturing tank with filtered aqueous Butanol,
b. Adding and dissolving EDTA in manufacturing tank with continuous
stirring,
c. Then adding and dissolving Sodium Formaldehyde Sulfoxylate,


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d. Adding and dissolving Kollidon 12 PF in manufacturing tank with continuous stirring,
e. Finally, adding Rifampicin in manufacturing tank and stirring the solution continuously,
f. Adjusting the pH of the solution upto 8.5 with 1M sodium hydroxide solution,
g. Making up the volume of the aqueous solution of butanol and stirring the solution for 30 minutes, and
h. Lyophilizing the mass product.
Dated this 9tn day of September 2008

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