LYOPHILIZED FORMULATIONS FOR PARENTERAL USE

Camus Pharma Pvt. Ltd.
An Indian Entity
Camus House, 29-B, Suraj Nagar (East),
Civil Lines, Jaipur-302006 (India).

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

LYOPHILIZED FORMULATIONS FOR PARENTERAL USE

FIELD OF THE INVENTION:
The present invention relates to the field of parenteral solutions of drugs which are insoluble or only sparingly soluble in water or which are unstable in water, combined with selected synthetic or semi-synthetic derivative of rifamycin.

The solutions provide a means for alleviating problems associated with drug precipitation at the injection site or other organs of the body following parenteral administration.

The present invention more specifically relates to the field of lyophilized formulations comprising at least a derivative of rifamycin such as Rifabutin for parenteral use.

BACKGROUND OF THE INVENTION:
The existing art provides oral forms of Rifabutin in the form of Capsules in the market.

The present invention provides lyophilized formulations comprising a derivative of rifamycin such as Rifabutin which can gain easy access to the systemic circulation with complete drug absorption and therefore reaching the target site of drug rapidly, resulting in faster action and lesser side effects.

The present invention also provides a method for the preparation of the lyophilized formulations for parenteral use comprising a derivative of rifamycin such as Rifabutin.

OBJECT OF THE INVENTION:

The object of the invention is to provide lyophilized formulations comprising at least a derivative of rifamycin such as Rifabutin for parenteral use, wherein the lyophilized formulations provide the following advantages:
a) Ease of processing a liquid, which simplifies aseptic handling
b) Enhanced stability of a dry powder
c) Removal of water without excessive heating of the product
d) Enhanced product stability in a dry state
e) Rapid and easy dissolution of reconstituted product
The object of the invention is to provide formulations for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection

The object of the invention is to provide formulations having bactericidal activity against most gram-positive and gram-negative organisms (including Pseudomonas aeruginosa) and specifically Mycobacterium tuberculosis.

DESCRIPTION OF THE INVENTION:

The present invention in a preferred embodiment provides lyophilized formulations comprising at least a derivative of rifamycin, and methods of preparation thereof.

In an embodiment of the invention, the at least a derivative of rifamycin may be a synthetic derivative of rifamycin or a semi-synthetic derivative of rifamycin.

In an embodiment of the invention, the at least a derivative of rifamycin is rifabutin.

In an embodiment of the invention, the Lyophilized formulations are administered in a parenteral form.

In an embodiment of the invention, the Lyophilized formulations are administered in an injection form.

In an embodiment of the invention, lyophilized formulations of the present invention may further comprise suitable additives.

In an embodiment of the invention, the method for preparing the lyophilized formulations comprising at least a derivative of rifamycin comprises freeze drying a solution comprising derivative of rifamycin, a solubilizer and a stabilizer.

In an embodiment of the invention, the freeze drying method step involves sequential steps of cooling and heating.

In an embodiment of the invention, the freeze drying method step is carried out in vacuum conditions.

In an embodiment of the invention, the method for preparing the lyophilized formulations comprising at least a derivative of rifamycin further comprises of additional drying cycles..

In an embodiment of the invention, a suitable excipient is added to the Lyophilized formulations of the present invention to prepare consumable formulations for effective therapeutic delivery.

In an embodiment of the invention, the Lyophilized formulations as an active ingredient may be used alone or in combination with other active ingredient or therapeutic agents

In an embodiment of the invention, the desirable dose of the formulations may vary depending on the condition and the weight of the subject, severity, drug form, route and period of administration.

In an embodiment of the invention, lyophilized formulations of the present invention may further comprise auxiliary, stabilizing, thickening, flavoring, fragrance and coloring agents.

In an embodiment of the invention, the "lyophilized formulation(s)" as mentioned herein is prepared by first making a bulk solution, then condensing this solution in a condenser at approximately a constant temperature. Then this condensed mixture is dried gradually and sealed in vials.

In another embodiment of the invention, the "lyophilized formulation(s)" as mentioned herein is prepared by first filling the bulk solution in the vials followed by condensing this solution in a condenser at approximately a constant temperature and then drying this condensed mixture.

In an embodiment of the invention, the various advantages of lyophilizing the formulation or drug formulation for parenteral administration are as follows: Ease of processing a liquid, which simplifies aseptic handling, Enhanced stability of a dry powder or in a dry state, Removal of water without excessive heating of the product, Rapid and easy dissolution of reconstituted product.

In an embodiment of the invention, the drug formulations or the "lyophilized formulation(s)" of the present invention has various applications such as but not limited to, a second-line treatment for Tuberculosis, treatment of mycobacterium avium complex disease (a bacterial infection most commonly encountered in late-stage AIDS patients), tolerated by patients with HIV-related tuberculosis (TB), Tuberculosis infections of the lung, in trials for treating Crohn's Disease as part of the anti-MAP therapy, treatment of (Chlamydia) Chlamydophila pneumoniae (Cpn) Infection.

Rifabutin has seen to be active against non-tuberculous (atypical) mycobacteria including M. avium-intracellulare (MAC), in vitro as well as in experimental infections caused by these pathogens in mice with induced immuno-deficiency.

In an embodiment of the invention, a solvent may be used for preparing the Lyophilized formulations of the present invention, and the solvent used may be any suitable solvent such as but not limited to one or more of methanol, ethanol, n-propanol, isopropanol, hexane, heptane, petroleum ether, cyclohexane, diethyl ether, dusopropyl ether, ethyl acetate, methyl acetate, ethyl formate, methyl formate, isobutyl acetate, n-butyl acetate, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, acetone, ethyl methyl ketone, diisobutyl ketone, methyl isobutyl ketone, 1,4- dioxane, toluene, ammonia solution, glacial acetic acid, ammonium hydroxide, sodium hydroxide, calcium hydroxide, calcium carbonate, potassium hydroxide, potassium carbonate, water and other solvents known by those of skilled in the art.

In an embodiment of the invention, the formulations of the present invention may optionally comprise auxiliary ingredients, as known in the art, such as but not limited to buffers, bulking agents, diluents, co-solvents, solvents, preservatives, chelating agents, antioxidants, tonicity adjusters, whose presence may help to provide a rapidly solublize freeze-dried product or extend the storage time of the formulation.

In an embodiment of the invention, the formulations of the present invention may optionally comprise Antimicrobial preservatives.
The term, "lyophilized formulations" deems to include the solid freeze-dried formulations of matter prepared by the process of this invention and comprising as essential ingredients: synthetic or semi-synthetic derivative of rifamycin such as Rifabutin, Sodium Formaldehyde Sulfoxylate, and a solvent.

As used herein, the term “solvent” means that part of a solution that is the dissolving medium for the other components.

The expression "parenteral" as used herein refers to routes of administration other than through the gastrointestinal tract or lungs, and to formulations for use in administering drugs by such routes. Thus, "parenteral" as used herein includes, for example, intramuscular, subcutaneous intra-articular (i.e. into the joint, which in turn includes intra-synovial, i.e. into the synovial fluid) and, especially, intravenous routes and formulations. The words "parenteral" and "injectable" are used interchangeably herein.

For the purpose of this invention, the term formulation deems to include a composition, and the terms formulation and composition may be alternately used.

In an exemplary embodiment of the invention, each vial comprises of 40 to 80 milligrams of Rifabutin and quantum sufficiat (q.s) of excipients and additives.

In an exemplary embodiment of the invention, the process for preparation of lyophilized formulation vials for the purpose of the present invention comprises the steps of:

a) transferring Water For Injection in a vessel;
b) flushing nitrogen through the vessel for 15 minutes;
c) mixing Rifabutin, exipients and diluents in the vessel with continuous nitrogen flushing until the solution is clear;
d) transferring the solution to filtration (optionally through sterile 0.2 micron membrane filter;
e) optionally bubbling sterile nitrogen through the bulk;
f) filling of the filtered solution into sterile vials (optionally USP type I glass);
g) loading semi-stoppered vials on the self of a Lyophilizer;
h) closing the door of a Lyophilizer after filling operation is over;
i) starting Lyophilization cycle after which vials are plugged using hydraulic system under vacuum;
j) breaking the vacuum using filtered Nitrogen;
k) unloading of the vials from Lyophilizer; and
l) sealing of the vials.

Exemplary Specifications of the Injectable Rifabutin

Storage Condition To be stored below 25 deg C
Description Reddish Violet Cake
Completeness and clarity of the solution a. The solid should dissolve completely, leaving no visible residue as undissolved matter
b. Solution should be clear reddish violate in colour
Identification by IR The absorption maxima in the spectrum obtained with the sample should correspond to those in the spectrum obtained with the standard preparation
Reconstitution time Content should dissolve within 3 minutes (1 vial reconstitute with 10 ml WFI)
Weight of the cake About 1.800 gm/vial (Limit 1.75 gm to 1.85 gm)
Particulate Matter Should pass the test as per USP
10 µm should not exceed 3000 per container
25 µm should not exceed 300 per container
Sterility Test Should pass the test for sterility as per USP
BET NMT 4.378 EU/mg
pH 6.0 to 8.0
Water Content NMT 5.0%
Chromatographic purity Any other impurity Not more than 1.0%
Total impurity Not more than 4.5%
Limit of N-Isobutyl piperidone Not more than 0.5%
Assay 90% to 110%

In the description, any or all numbers disclosed are deemed to be approximate values, regardless whether the word "about" or "approximate" is used in connection therewith. They may vary by 1 percent, 2 percent, 5 percent, or, sometimes, 10 to 20 percent. Whenever a numerical range with a lower limit, RL and an upper limit, Ru, is disclosed, any number falling within the range shall be specifically disclosed. In particular, the following numbers within the range are specifically disclosed: R=RL+k*(Ru-R ), wherein k is a variable ranging from 1 percent to 100 percent with a 1 percent increment, i.e., k is 1 percent, 2 percent, 3 percent, 4 percent, 5 percent,..., 50 percent, 51 percent, 52 percent,..., 95 percent, 96 percent, 97 percent, 98 percent, 99 percent, or 100 percent. Moreover, any numerical range defined by two R numbers as defined in the above is also specifically disclosed.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, or components, but do not preclude or rule out the presence or addition of one or more other features, integers, steps, operations, elements, components, or groups thereof.

The process steps, method steps, protocols, or the like may be described in a sequential order, such processes, methods, and protocol may be configured to work in alternate orders. In other words, any sequence or order of steps that may be described does not necessarily indicate a requirement that the steps be performed in that order. The steps of processes described herein may be performed in any order practical. Further, some steps may be performed simultaneously, in parallel, or concurrently.

The aim of this specification is to describe the invention without limiting the invention to any one embodiment or specific collection of features. A person skilled in the relevant art may realize the variations from the specific embodiments that will nonetheless fall within the scope of the invention, and such variations are deemed to be within the scope of the current invention.

It may be appreciated that various other modifications and changes may be made to the embodiment described without departing from the spirit and scope of the invention.

Claims:

1. Lyophilized formulations comprising at least a derivative of rifamycin and at least an excipient.

2. Lyophilized formulations of claim 1, wherein the derivative of rifamycin is rifabutin.

3. Lyophilized formulations of claim 1, wherein the formulations comprise 40 to 80 milligrams of Rifabutin.

4. Lyophilized formulations of claim 1, wherein the formulation is administered in a parenteral form.

5. Lyophilized formulations of claim 4, wherein the formulation is administered in an injection form.

6. Method of preparation of lyophilized formulations of claim 1, the method comprising freeze drying a solution comprising derivative of rifamycin, a solubilizer and a stabilizer.

7. The method as claimed in claim 6, wherein the freeze drying method step involves sequential steps of cooling and heating.

8. The method as claimed in claim 6, wherein the method is carried out in vacuum conditions.

9. The method as claimed in claim 6, wherein the method further comprises of additional drying cycles.

10. The process for preparation of lyophilized formulation vials for the purpose of the present invention comprises the steps of:
a) transferring Water For Injection in a vessel;
b) flushing nitrogen through the vessel for 15 minutes;
c) mixing Rifabutin, exipients and diluents in the vessel with continuous nitrogen flushing until the solution is clear;
d) transferring the solution to filtration;
e) optionally bubbling sterile nitrogen through the bulk solution;
f) filling of the filtered solution into sterile vials;
g) loading semi-stoppered vials on the self of a Lyophilizer;
h) closing the door of a Lyophilizer after filling operation is over;
i) starting Lyophilization cycle after which vials are plugged using hydraulic system under vacuum;
j) breaking the vacuum using filtered Nitrogen;
k) unloading of the vials from Lyophilizer; and
l) sealing of the vials.

Dated this 9th day of January, 2014

ABHISHEK PANDURANGI,
APPLICANT'S AGENT
(INPA-1722)