Claims:We Claim:
1. A process of preparing a pharmaceutical formulation comprising dapsone and one or more polymers, the process comprising the steps of: (i) obtaining an aqueous polymer phase; (ii) obtaining a dapsone phase; (iii) homogenizing the aqueous polymer phase and dapsone phase, wherein the homogenizing step involves addition of the aqueous polymer phase and the dapsone phase at a controlled flow rate.

2. The process of claim 1, wherein the homogenizing step (iii) involves addition of the dapsone phase at a controlled flow rate of about 0.1 – 1.0 kg.

3. The process of claim 1, wherein the homogenizing step (iii) involves addition of the dapsone phase at a controlled flow rate of about 0.1 – 1.0 kg/Min and the polymer phase at a controlled flow rate of about 0.5 – 6.0 Kg/Min.

4. The process of claim 1, wherein the temperature of the polymer phase and dapsone phase is maintained at a temperature of below 20 °C.

5. The process of claim 1, wherein homogenizing process is carried out under recirculation mode.

6. The process of claim 1, wherein homogenization is carried out for about 30-400 mins at a speed of about 200 – 2000 RPM.

7. The process of claim 1, comprising the steps of: (i) obtaining an aqueous polymer phase; (ii) obtaining a dapsone phase; (iii) maintaining the temperature of the polymer phase and the dapsone phase below 20 °C; (iv) homogenizing the aqueous polymer phase and dapsone phase, wherein the homogenizing step involves addition of the aqueous polymer phase and the dapsone phase at a controlled flow rate; (v) carrying the homogenizing step (iv) under recirculation mode; (vi) optionally, carrying the homogenizing step (v) at controlled speed and for the desired duration.

8. The process of claim 1, comprising the steps of: (i) obtaining an aqueous polymer phase; (ii) obtaining a dapsone phase; (iii) maintaining the temperature of the polymer phase and the dapsone phase below 20 °C; (iv) homogenizing the aqueous polymer phase and dapsone phase, wherein the homogenizing step involves addition of the dapsone phases at a controlled flow rate of about 0.1 – 1.0 kg/Min and the polymer phase at a controlled flow rate of about 0.5 – 6.0 Kg/Min; (v) carrying the homogenizing step (iv) under recirculation mode; (vi) optionally, carrying the homogenizing step (v) for about 30-400 mins at a speed of about 200 – 2000 RPM.

9. The process of claim 1, wherein the pharmaceutical formulation comprises gel formulation comprising: dapsone in a microparticulate and dissolved state, carbomer, ethoxydiglycol, methylparaben, water and sodium hydroxide.

10. A method for treating acne comprising topically applying a gel composition comprising a dissolved and a microparticulate dapsone formulation manufactured according to the process of claim 1.
, Description:DAPSONE FORMULATION AND IMPROVED PROCESS FOR THE MANUFACTURE THEREOF

FIELD OF THE INVENTION

The present application discloses a pharmaceutical formulation comprising dapsone and one or more polymers and an improved process for the manufacture thereof. The process comprises the steps of: (i) obtaining an aqueous polymer phase; (ii) obtaining a dapsone phase; and (iii) homogenizing the aqueous polymer phase and the dapsone phase to prepare the pharmaceutical formulation of dapsone. More particularly, the invention provides a process wherein the dapsone phase has a flow rate of 0.1- 1 kg/min during the homogenization step.

BACKGROUND OF THE INVENTION

Acne is a group of common skin conditions characterized by the so-called "acneiform" or acne-like skin eruptions, which can be contaminated with bacteria, such as Propionibacterium acnes, and can also be marked by inflammation. Acne tends to occur in the areas of skin where the sebaceous glands are most active, such as the face. Acne is associated with psychological trauma, and, if left untreated, can lead to scar formation and disfigurement.

Acne is often treated with antibiotics and it is one condition where a highly specialized topical drug delivery is needed. Dapsone is a medicament possessing several beneficial medicinal activities. Dapsone is typically administered as one of the medicinal agents used in the treatment of leprosy. Dapsone and its derivatives are also effective for treatment of bacterial infections, protozoal infections such as malaria, pneumocystis carinii, and plasmonic infections such as toxoplasmosis. Dapsone is also useful as an anti-inflammatory agent. It has been used to treat skin diseases characterized by the abnormal infiltration of neutrophils, such as Dermatitis herpetiformis, linear IgA dermatosis, pustular psoriasis, pyoderma gangrenosum, Sweet's Syndrome and acne vulgaris.

Various dapsone formulations along with the processes for their preparation have been disclosed in existing patent documents. For example US Patent numbers 5,863,560, US 6,060,085 and US 6,620,435 disclose topical compositions of dapsone. These patents also disclose the method for preparing a dermatological composition wherein dapsone is both in dissolved and microparticulate form. These patents disclose the importance of the order of addition of each component and its impact on certain morphological properties like final polydispersity of the formulation.

US patent numbers 9,161,926 and US 9,517,219 disclose dapsone and dapsone/adapalene compositions for treating a variety of dermatological conditions. The compositions of this disclosure include dapsone and/or adapalene in a polymeric viscosity builder. Use of the polymeric viscosity builder provides compositions with increased concentrations of diethylene glycol monoethyl ether relative to compositions without the polymeric viscosity builder.

Most of the prior art process for manufacturing the dapsone formulations are suitable only for small scale batches. The present inventors have come up with an improved process for preparing dapsone formulations which are suitable for large scale batches to meet commercial need and at the same time it also ensures that required amount of dapsone is available in both dissolved and microparticulate form. Moreover the morphology of the said formulation is also similar to Dapsone gel marketed as Aczone 5% by Allergan so as to achieve the desired results.

The amount of dapsone available in both dissolved and microparticulate form and its morphology are the important characteristic of a pharmaceutical composition which enables right amount of drug to permeate the stratum corneum layer of the epidermis and become available systemically, and the remaining drug is deposited directly at the target area, where it can be slowly released for sustained and significant therapeutic benefit.

Therefore, attaining an optimum penetration across stratum corneum layer of the epidermis remains one of the most challenging tasks in formulation development.

It is an object of the present disclosure to provide an improved process for manufacturing dapsone formulations.

SUMMARY OF THE INVENTION

The present disclosure relates to dapsone formulations and its improved manufacturing process.

According to one embodiment, the present disclosure relates to a process of preparing a pharmaceutical formulation comprising dapsone and one or more polymers, the process comprising the steps of: (i) obtaining an aqueous polymer phase; (ii) obtaining a dapsone phase; (iii) homogenizing the aqueous polymer phase and the dapsone phase to obtain the formulation, wherein the homogenizing step involves addition of the aqueous polymer phase and the dapsone phase at a controlled flow rate.

According to another embodiment, the present disclosure relates to a process of preparing a pharmaceutical formulation comprising dapsone and one or more polymers, the process comprising the steps of: (i) obtaining an aqueous polymer phase; (ii) obtaining a dapsone phase; (iii) homogenizing the aqueous polymer phase and the dapsone phase to obtain the formulation, wherein the homogenizing step involves addition of the dapsone phase at a controlled flow rate of about 0.1 – 1.0 kg/Min and the polymer phase at a controlled flow rate of about 0.5 – 6.0 Kg/Min.

In yet another embodiment, this disclosure also provides a homogenization process wherein the temperature of the polymer phase and dapsone phase are maintained at a temperature of below 20 °C.

According to another embodiment, this disclosure also provides a homogenization process which is carried out under recirculation mode.

Aspects of the present disclosure also relates to homogenization step, which is being carried out for about 30-400 mins at a speed of about 200 – 2000 RPM.

This disclosure also provides a process for obtaining a final product obtained by neutralizing the homogenized mixture with a suitable base.

This invention provides a method of treatment of a human patient suffering from acne vulgaris comprising administration to the human patient dapsone formulation prepared according to the process of the present disclosure.

All combinations of the various elements described herein are within the scope of the invention.

DESCRIPTION OF THE INVENTION

The present disclosure relates to dapsone formulations and its improved manufacturing process.

According to one embodiment, the present disclosure relates to a process of preparing a pharmaceutical formulation comprising dapsone and one or more polymers, the process comprising the steps of: (i) obtaining an aqueous polymer phase; (ii) obtaining a dapsone phase; (iii) homogenizing the aqueous polymer phase and the dapsone phase to obtain the formulation, wherein the homogenizing step involves addition of the aqueous polymer phase and the dapsone phase at a controlled flow rate.

In some embodiments, the present disclosure relates to a process of preparing a pharmaceutical formulation comprising dapsone and one or more polymers, the process comprising the steps of: (i) obtaining an aqueous polymer phase; (ii) obtaining a dapsone phase; (iii) homogenizing the aqueous polymer phase and the dapsone phase to obtain the formulation, wherein the homogenizing step involves addition of the dapsone phase at a controlled flow rate.

In some embodiments, the present disclosure relates to a process of preparing a pharmaceutical formulation comprising dapsone and one or more polymers, the process comprising the steps of: (i) obtaining an aqueous polymer phase; (ii) obtaining a dapsone phase; (iii) homogenizing the aqueous polymer phase and the dapsone phase to obtain the formulation, wherein the homogenizing step involves addition of the dapsone phase at a controlled flow rate of about 0.1 – 1.0 kg/Min.

In some embodiments, the present disclosure relates to a process of preparing a pharmaceutical formulation comprising dapsone and one or more polymers, the process comprising the steps of: (i) obtaining an aqueous polymer phase; (ii) obtaining a dapsone phase; (iii) homogenizing the aqueous polymer phase and the dapsone phase to obtain the formulation, wherein the homogenizing step involves addition of the dapsone phases at a controlled flow rate of about 0.1 – 1.0 kg/Min and the polymer phase at a controlled flow rate of about 0.5 – 6.0 Kg/Min.

The term, “controlled flow rate” refers to flow rate which can be modified by the operator by modulating either the equipment parameters or the formulation parameters or combination thereof. Additionally various means of controlling the flow rate of the drug phase and/or polymer phase known to the skilled artisan are encompassed within the present disclosure, which includes but not limited to displacement pump, gear pump, lobe pump, sliding vane pump, screw pump, centrifugal pump, peristaltic pump, reciprocating pump and or equivalent thereof. More particularly, this controlled flow of the drug phase results in formation of the crystalline microparticles of dapsone. The complexity of process at a larger scale arises when the drug phase and the polymer phase are added in uncontrolled or random or single step lump sum addition to the homogenizer, more particularly where drug phase is added directly at one go. The resulting formulation fails to meet the one or more of the critical parameters like the amount of dapsone available in both dissolved and microparticulate form; its morphology; and the content uniformity.

In some embodiments, during the homogenization step the temperature of the polymer phase and drug phase are maintained at below 20 °C.

In some embodiments, the temperatures are maintained at about 5 – 20 °C.

In some embodiments, the temperatures are maintained at about 9 – 14 °C.

In some embodiments, the homogenization step is carried out under recirculation mode.

Aspects of the recirculation mode includes but are not limited to a continuous passage of drug phase from the homogenizer to the polymer phase vessel so as to minimize the lump formation, agglomeration, and thereby achieve the desired content uniformity and morphology. In some embodiments, the homogenization step is a continuous process which is carried out till the complete addition of the drug phase to the polymer phase and for an additional period thereafter, so as to achieve the desired morphological properties and its equilibrium. In some embodiments, the homogenization step is carried out under recirculation mode using a closed loop system or any other system known to the skilled artisan.

In some embodiments, the homogenization step is carried out at a predetermined speed.

In some embodiments, the homogenization step is carried out at the speed of 100-10000 RPM. In another embodiment, the homogenization step is carried out at the speed of 200-2000 RPM.

In some preferred embodiments, the homogenization step is carried out for about 30-400 mins at a speed of about 200 – 2000 RPM.

In some embodiments, the homogenization is optionally carried out in a modified homogenizer designed to meet the process requirements.

In some embodiments, the homogenization is carried out in a modified homogenizer having one or more inlets for the drug phase and/or polymer phase, one or more of recirculation loop and/or outlet for finished product. Further the said inlet and outlet are positioned on the surface of the homogenizer at various locations to meet the manufacturing location process flow requirements. Additionally the homogenizer chamber can optionally be jacketed to control the temperature of the product. Further, the said inlets and outlets are positioned on the surface of the homogenizer to create an angle of about 0° to about 180°, with the said plane surface of the homogenizer.

In some embodiments, the disclosure relates to a process of preparing a pharmaceutical formulation comprising dapsone and one or more polymers, the process comprising the steps of: (i) obtaining an aqueous polymer phase; (ii) obtaining a dapsone phase; (iii) homogenizing the aqueous polymer phase and the dapsone phase to obtain the formulation, wherein the homogenizing step involves addition of the dapsone phase at a controlled flow rate; (v) carrying the homogenizing step (iv) under recirculation mode; (vi) optionally, carrying the homogenizing step (v) at controlled speed and for the desired duration.

In embodiments, the final product is obtained by neutralizing the homogenized mixture with a suitable base.

This invention provides a method of treatment of a human patient suffering from acne vulgaris comprising administration to the human patient dapsone formulation prepared according to the process of the present disclosure.

The term "formulation" is intended to encompass a combination of active ingredient called the “drug” (wherein the drug is either dissolved and/or solubilized and/or microparticulate form); and the "excipient" which is not a pharmacologically active. The excipient or "pharmaceutically acceptable excipient" means a one or more of “polymer phase” along with any other additional component. The excipients that are useful in preparing pharmaceutical compositions are generally safe, non- toxic, and are acceptable for veterinary use as well as human pharmaceutical or cosmetic use.

The formulations according to the invention can be present as a gel, as a cream, as a lotion or as foam, with gels being preferred according to the invention.

The term “dapsone” as used herein is defined to mean at least one form of dapsone chosen from dapsone base, active metabolites thereof, complexes thereof, pharmaceutically acceptable salts thereof or polymorph thereof. Any of these said forms can be crystalline or amorphous. The concentration of dapsone employed in the present disclosure is in the range of 3 – 10 % w/w, based on the total weight of the formulation.

The topical gel formulation of the present invention can include one or more other ingredients, such as solubilizers, polymers, carbomers, solvents, base, preservatives, antioxidants, pH adjusting agents etc.

Suitable solubilizes includes a pharmaceutically acceptable vehicle wherein dapsone is completely solubilized. The solubilizing agents of the present disclosure, include, but are not limited to, ethoxydiglycol and 1-methyl-2-pyrollidone and the like.

Suitable polymers includes polymer thickeners that may be used include those known to one skilled in the art, such as hydrophilic and hydroalcoholic gelling agents frequently used in the cosmetic and pharmaceutical industries. Preferably, the hydrophilic or hydroalcoholic gelling agent comprises "CARBOPOL®" (B. F. Goodrich, Cleveland, Ohio), "HYPAN®" (Kingston Technologies, Dayton, N.J.), "NATROSOL®" (Aqualon, Wilmington, Del.), "KLUCEL®" (Aqualon, Wilmington, Del.), or "STABILEZE®" (ISP Technologies, Wayne, N.J.). Preferably, the gelling agent comprises between about 0.2% to about 4% by weight of the composition. More particularly, the preferred compositional weight percent range for "CARBOPOL®" is between about 0.5% to about 2%, while the preferred weight percent range for "NATROSOL®" and "KLUCEL®" is between about 0.5% to about 4%. The preferred compositional weight percent range for both "HYPAN®" and "STABILEZE®" is between about 0.5% to about 4%.

"CARBOPOL®" is one of numerous cross-linked acrylic acid polymers that are given the general adopted name carbomer. These polymers dissolve in water and form a clear or slightly hazy gel upon neutralization with a caustic material such as sodium hydroxide, potassium hydroxide, triethanolamine, or other amine bases. "KLUCEL®" is a cellulose polymer that is dispersed in water and forms a uniform gel upon complete hydration. Other preferred gelling polymers include hydroxyethylcellulose, cellulose gum, MVE/MA decadiene crosspolymer, PVM/MA copolymer, or a combination thereof.

Suitable “Solvents” may be selected from purified water or non-aqueous solvents. The non-aqueous solvent may be selected from dimethyl sulfoxide, propylene glycol, polyethylene glycol 400, diethylene glycol monoethyl ether, ethanol, isopropyl alcohol, N-methyl pyrrolidone, acetone, cyclomethicone, dimethicone or combination thereof. Dimethyl sulfoxide imparts clarity, non-greasy, non-sticky and smooth appearance to the gel composition. Additionally, water provides a non-warming characteristic to the gel composition by releasing the heat of hydration.

Base helps in neutralization of the polymers dissolve in water, specially the carbomers they form a clear or slightly hazy gel upon addition of these caustic material. Suitable base include, but are not limited to, sodium hydroxide, potassium hydroxide, triethanolamine, or other amine bases. Addition of any of these amine base completes the formation of the gel.

Preservatives may also be used in this invention and preferably comprise about 0.05% to 0.5% by weight of the total composition. The use of preservatives assures that if the product is microbially contaminated, the formulation will prevent or diminish microorganism growth. Suitable preservatives include, but are not limited to, methylparaben, propylparaben, butylparaben, chloroxylenol, sodium benzoate, DMDM Hydantoin, 3-Iodo-2-Propylbutyl carbamate, potassium sorbate, chlorhexidine digluconate, or a combination thereof.

Suitable antioxidants and/or chelating agents include, but are not limited to, Butylated hydroxyanisole (BHA), sodium metabisulfite, citric acid and EDTA which can also be added to formulations to help slow down or completely stop any impurity formation. Moreover, BHA in addition to its antioxidant property also provides protection to ethoxydiglycol and/or dapsone from discoloration due to oxidation.

It is known that low pH of the composition can have an irritating effect on the skin. The present invention provides a topical composition comprising fluconazole, one or more flavonoids wherein pH of the composition is in the range of 3.0-7.0. The pH of the composition remains constant throughout the shelf-life of the product. A suitable pH of the topical composition is generally in the range of from about 3.0 to about 7.0, and in particular between about 4.0 to about 6.0. The pH can be adjusted by the use of suitable pH-modifying agents. The pH-modifying agents may be selected, for example, from one or more of the group consisting of lactic acid, malic acid, citric acid and other such aliphatic polyhydroxy carboxylic acids, basic amines, such as triethanolamine, diethanolamine, diethyl amine, sodium hydroxide and tris buffer.

The polymer is generally dispersed in the water component of the formulation, while the remaining ingredients will be dissolved or dispersed in whichever of the two components are best for dissolving or dispersing the ingredient. For example, it is suggested to dissolve methylparaben, propylparaben, and BHA in ethoxydiglycol. After the ethoxydiglycol component and water component are combined, neutralizer is added to formulate the gel.

In embodiments, the invention comprises a dermatological formulation having about 0.5% to 4.0% carbomer and about 0.5% to 10% of dapsone that exists in both a dissolved state and a microparticulate state. The dissolved dapsone has the capacity to cross the stratum corneum, whereas the microparticulate dapsone does not. Addition of an amine base, potassium hydroxide solution, or sodium hydroxide solution completes the formation of the gel. A preferred ratio of microparticulate to dissolved dapsone is 5 or less.

In another embodiment, the invention comprises about 1-2 % polymer, about 70-90% water, about 5- 15% ethoxydiglycol, about 0.2% methylparaben, about 0.3% to 8.0% dapsone including both microparticulate dapsone and dissolved dapsone, and about 1.5-3 % caustic base material. More particularly, the polymer may include "CARBOPOL 980" and the caustic material may include sodium hydroxide solution.

The relative percentages for each of the reagents used in the present invention may vary depending upon the desired strength of the target formulation, gel viscosity, and the desired ratio of microparticulate to dissolved dapsone. Unless otherwise designated, all reagents listed above are commonly known by one of ordinary skill in the art and are commercially available from pharmaceutical or cosmetic excipient suppliers.

The dissolved dapsone and the microparticulate dapsone is one of the critical process parameter which is to be routinely examined by measuring the fraction of soluble and insoluble component in the formulation through analytical techniques. Additionally, the final shape of the dapsone microparticulate, its morphology and particle size distribution to be examined microscopically. For example, the dapsone microparticulate has a particle size distribution characterized as a D10 of NMT 8.0 microns, a D50 of NMT 20.0 microns, and a D90 of NMT 80.0 microns.

Another embodiment of the invention includes forms of packaging for topical formulation that are maintained during transportation, storage and use for commercially relevant times (e.g, 6 months, 12 months, 24 months or intermediate or longer periods). The topical formulation may be packed in tubes of glass, polymer or metal materials. Metal tubes may be made of aluminum or plastics, as they provide ideal barriers for products needing maximum protection and shelf life. A metal tube is advantageous as it is non-porous, light in weight, sanitary, durable, versatile, non-refillable, decorative, easy to handle, has a long shelf life and is adaptable to modern mass production methods and to automatic packaging.

Laminated tubes also may be used for packaging. The features and advantages of laminated tubes include ability to retain smoothness, flexibility and softness, increase in product shelf-life, excellent barrier properties, excellent sealability, resistant to print bleeding, tamper evident closures with nozzle seals available and hot foil stamping. In embodiments, the inventions provide the topical compositions for treatment of the fungal infections in packages suitable for commercial scale that provide stability during storage or transportation. HDPE tubes can also be used for packaging of the topical compositions of the present invention. Pre-printed monolayer plastic tubes made of 100% HDPE by extrusion processes, with snap-on tamper evident caps or flip top tamper evident caps made up of polypropylene by injection molding processes are useful.

The following examples further describe certain specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are provided for purposes of illustration only and are not intended to limit the scope of the invention in any manner.

Examples
Example 1:

Ingredients % (w/w)
Dapsone 5-8
Carbomer homopolymer type C 0.5-1.5
Diethylene glycol monoethyl ether 20-30
Methyl Paraben 0.2
Sodium hydroxide 0.2
Purified water q.s.

I. DISPENSING:

Required quantities of drug and other raw materials were dispensed.

II. MIXING:

1. Polymer Phase – I: Purified water was heated at temperature of 70- 75°C. To this Methyl Paraben, carbomer homopolymer type C were added. Stirred to obtain lump free dispersion and cooled to room temperature.
2. Dapsone Phase – II: Diethylene Glycol monoethyl ether was charged in a separate SS container. To this Dapsone was added and mixed to obtain a clear a solution.
3. NaoH Solution: NaoH was dissolved in water to to obtain a solution which was cooled to room temperature.
4. The temperature of the Phase I & II was maintained at NMT 20°C.
5. The dapsone phase (Phase – II) was added to the polymer phase (Phase – I) at a controlled flow rate. Dapsone phases was pumped at a controlled flow rate of about 0.1 – 1.0 kg/Min and the polymer phase was pumped at a controlled flow rate of about 0.5 – 6.0 Kg/Min.
6. The mixture was homogenized under recirculation mode for 200 min at 200-2000 rpm.
7. The pH of the homogenized mixture of step (6) was neutralized to pH 5.5-6.0 by using sodium hydroxide solution to obtain a gel.
8. Check the final weight of Gel.