DESC:FIELD OF INVENTION

The present invention relates to Amorphous Lenacapavir Sodium solid dispersion and its process for preparation thereof. The amorphous Lenacapavir Sodium solid dispersions of the present application can be reproduced easily and is amenable for processing into a dosage form.

BACKGROUND OF THE INVENTION

Lenacapavir Sodium is chemically known as Sodium (4-chloro-7-(2-((S)-1-(2((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4] cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl) ethyl)-6(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl) (methylsulfonyl)amide, which has been approved as a Tablet having dosage strength 300 mg as well as Injection having dosage strength 463.5 mg/1.5 mL (309 mg/mL) in single-dose vials under the trade name SUNLENCA®. SUNLENCA is a human immunodeficiency virus type 1 (HIV-1) capsid inhibitor, in combination with other antiretroviral(s), is indicated for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations. Lenacapavir Sodium is structurally represented as follows:

Lenacapavir as well as its pharmaceutically acceptable salts were disclosed in US 9,951,043 B2 (US ‘043) and US 10,071,985 B2 (US ‘985) of Gilead Sciences. Further, discloses the pharmaceutically acceptable salts includes an appropriate base, such as an alkali metal (such as Li+, Na+, and K+), an alkaline earth metal (for example, magnesium), ammonium and NX4+ (wherein X is C1-C4 alkyl); organic carboxylic acids such as acetic acid, benzoic acid, camphorsulfonic acid, citric acid, glucoheptonic acid, gluconic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, mandelic acid, and etc. Further, discloses the synthesis of Lenacapavir Free base of Formula I(a), which is obtained as Amorphous solid and is as shown below:

US 11,267,799 B2 of Gilead Sciences Inc, discloses the Crystalline polymorphic Form I, Form II, Form III and Amorphous Form of Lenacapavir Sodium.

US 10,849,892 B2 of Gilead Sciences Inc, discloses the Lenacapavir N,N,N-Trimethylethanolammonium (Choline) Salt and its Crystalline polymorphic Form I, Form II, Form III, Form IV, Form V, Form VI & Form VII.

In the pharmaceutical industry there is a constant need to work on identifying different pharmaceutical compositions that positively affect the drug's dissolution profile, bioavailability, bioequivalence, stability, etc., which all play important roles in determining a drug's market acceptance and success. Amorphous solid dispersions of drugs are generally known to improve the stability and solubility of drug products.

In the case of Lenacapavir Sodium too, there is a need for the development of pharmaceutical compositions with improved solubility, stability, excellent storage and handling stabilities, bioavailability, etc.

The present inventors have developed the Amorphous Lenacapavir Sodium Solid dispersion (or) pre-mix with a pharmaceutically acceptable carrier, which is reproducible easily, more stable and is amenable for processing into a dosage form.

The present invention provides a process for the preparation of Amorphous Lenacapavir Sodium Solid dispersion, which is industrially applicable and suitable for formulations.

OBJECTIVES

An objective of the present invention is to provide Amorphous Lenacapavir Sodium solid dispersion which is industrially applicable and suitable for formulations.

Another objective of the present invention is to provide a process for the preparation of Amorphous Lenacapavir Sodium solid dispersion, which is economically suitable and industrially viable process.

SUMMARY OF THE INVENTION

The present invention provides Amorphous Lenacapavir Sodium solid dispersion with a pharmaceutically acceptable polymer HPMCAS.

The present invention also provides a process for the preparation of Amorphous Lenacapavir Sodium Solid dispersion comprises:
(a) dissolving Lenacapavir Sodium in a solvent;
(b) adding pharmaceutically acceptable carrier HPMCAS;
(c) isolating the obtained Amorphous Lenacapavir Sodium solid dispersion.

SUMMARY OF THE DRAWINGS

Figure 1 – PXRD of Amorphous Lenacapavir Sodium solid dispersion with HPMCAS of the present invention

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides Lenacapavir Sodium solid dispersion.

The solid dispersion of Lenacapavir Sodium of the present invention comprises Lenacapavir Sodium and one or more pharmaceutically acceptable polymers, wherein said polymer is comprises about 10-50% wt/wt to the pharmaceutical active ingredient.

The solid dispersion of Lenacapavir Sodium of the present invention may be Amorphous.

Solid dispersion as used herein refers to the dispersion of active ingredients in an inert excipient or polymer or carrier, where the active ingredients could exist in finely crystalline, solubilized or amorphous state.

Lenacapavir Sodium used as input material in the preparation of Solid dispersion is in any physical form, such as any solid form, any crystalline form or amorphous form.

In general, the term “solid dispersion” refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components. The term “solid dispersion” as used herein, refers to stable solid dispersions comprising amorphous drug substance and one or more polymers or carriers. Further the term “solid dispersion” as used herein also refers to stable solid dispersions comprising amorphous drug substance and one or more polymers or carriers with or without adsorbent/absorbent. By “amorphous drug substance,” it is meant that the amorphous solid contains drug substance in a substantially amorphous solid state form i.e. at least about 80% of the drug substance in the dispersion is in an amorphous form. More preferably at least about 90% and most preferably at least about 95% of the drug substance in the dispersion is in amorphous form.

The phrase “pharmaceutically acceptable” is employed herein to refer to those substances which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. In some embodiments, the carrier is a solid at room temperature.

Pharmaceutically acceptable polymers is selected from a polymeric carrier, and at least one selected from the group consisting of gelatines, ovalbumin, soybean proteins, gum arabic, non-sucrose fatty acid esters, starches, modified starches, Cellulose, Methylcellulose (MC), Ethylcellulose (EC), Hydroxyethylcellulose (HEC), Hydroxypropylcellulose (HPC), Hydroxypropylmethylcellulose (HPMC), Hydroxypropyl Methylcellulose Acetate Succinate / Hypromellose acetate succinate (HPMCAS), polycarbophil, polyethylene glycol (PEG), polyethylene glycol-polylactic acid (PEG-PLA), polyethylene glycol-polyhydroxybutyric acid (PEG-PHB), polyethylene oxides, polyoxyalkylene derivatives, polymethacrylates, Kollidon® VA 64 (a vinylpyrrolidone-vinyl acetate copolymer), cyclodextrins such as a-cyclodextrins, ß-cyclodextrins, ?-cyclodextrins, hydroxyl-propyl-cyclodextrins, hydroxypropyl-ß-cyclodextrin (HPßCD), Povidone, Copovidone, Crospovidone, sodium carboxymethyl cellulose, sodium alginate, chitosan, cross-linked high amylase starch, cross-linked polyacrylic acid (carbopol), or a mixture thereof.

The amorphous solid dispersion of Lenacapavir Sodium of the present invention is stable during storage.

In a preferred embodiment, the polymeric carrier suitable for the preparation of a solid dispersion of Lenacapavir Sodium is HPMCAS.

The solid dispersion of Lenacapavir Sodium with HPMCAS is in the amorphous form.

The amorphous solid dispersion of Lenacapavir Sodium with HPMCAS of the present invention has a characteristic XRD pattern substantially as depicted in Figure 1.

The present invention also provides a process for the preparation of amorphous solid dispersion of Lenacapavir Sodium with HPMCAS.

The present invention provides a process for the preparation of amorphous solid dispersion of Lenacapavir Sodium, which comprises dissolving Lenacapavir Sodium in a solvent selected from the group comprising of alcohols, ketone, halogenated solvents, ethers, esters, hydrocarbons, nitriles and Polar aprotic solvents at 10 to 80°C and stirred the reaction mixture for 5 minutes to 30 minutes at 10 to 80°C. To the obtained reaction mixture, added pharmaceutically acceptable carrier selected from selected from a polymeric carrier, and at least one selected from the group consisting of gelatines, ovalbumin, soybean proteins, gum arabic, non-sucrose fatty acid esters, starches, modified starches, Cellulose, Methylcellulose (MC), Ethylcellulose (EC), Hydroxyethylcellulose (HEC), Hydroxypropylcellulose (HPC), Hydroxypropylmethylcellulose (HPMC), Hydroxypropyl Methylcellulose Acetate Succinate / Hypromellose acetate succinate (HPMCAS), polycarbophil, polyethylene glycol (PEG), polyethylene glycol-polylactic acid (PEG-PLA), polyethylene glycol-polyhydroxybutyric acid (PEG-PHB), polyethylene oxides, polyoxyalkylene derivatives, polymethacrylates, Kollidon® VA 64 (a vinylpyrrolidone-vinyl acetate copolymer), cyclodextrins such as a-cyclodextrins, ß-cyclodextrins, ?-cyclodextrins, hydroxyl-propyl-cyclodextrins, hydroxypropyl-ß-cyclodextrin (HPßCD), Povidone, Copovidone, Crospovidone, sodium carboxymethyl cellulose, sodium alginate, chitosan, cross-linked high amylase starch, cross-linked polyacrylic acid (carbopol), or a mixture thereof; and stirred the reaction mixture at 10 to 80°C. Isolating the obtained Amorphous Lenacapavir Sodium solid dispersion.

The present invention provides preferably a process for the preparation of amorphous solid dispersion of Lenacapavir Sodium with HPMCAS, which comprises dissolving Lenacapavir Sodium in methanol at 10 to 80°C and stirred the reaction mixture for 5 minutes to 30 minutes at 10 to 80°C. To the obtained reaction mixture, added HPMCAS and stirred the reaction mixture at 10 to 80°C. Isolating the obtained Amorphous Lenacapavir Sodium solid dispersion.

In another embodiment throughout the invention, alcohols are selected from the group comprising of methanol, ethanol, butanol, t-BuOH, isopropanol and the like; ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; the halogenated solvents are selected from the group comprising of dichloromethane, ethylene dichloride, chloroform and the like; ethers are selected from the group comprising of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, isopropyl ether, methyl isobutylether, methyl t-butyl ether, dioxane and the like; esters are selected from the group comprising of ethyl acetate, isopropyl acetate and the like; hydrocarbons are selected from the group comprising of toluene, xylene and the like; nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, acrylonitrile and the like; Polar aprotic solvents are selected from the group comprising of N,N-dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide and the like.

In another embodiment throughout the invention, the mixture of solvents means two or more solvents.

In another embodiment, obtained Amorphous Lenacapavir Sodium Solid dispersion can be optionally isolated and optionally purified by conventional methods.

In another embodiment throughout the invention, isolation of Amorphous Lenacapavir Sodium Solid dispersion can be performed by conventional methods such as cooling, removal of solvents, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, filtration, centrifugation and the like.

The solid dispersions of the present invention are preferably prepared using conventional spray drying techniques, it will be understood that suitable solid dispersions may be formed utilizing other conventional techniques known to those skilled in the art, such as vacuum drying, ATFD, RCVD, fluid-bed drying, Lyophilization (or) freeze-drying, rotary evaporation, drum drying, or other solvent removal process.

The Abbreviations used throughout the invention are as follows:
CuI : Copper(I) iodide
Cs2CO3 : Cesium carbonate
Et3N / TEA : Triethyl amine
EA / EtOAc : Ethyl acetate
HATU : 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
MsCl : Methanesulfonyl chloride (Mesyl chloride)
NaOH : Sodium hydroxide
N,N-DIPEA : N,N-Diisopropylethylamine
N,N-DMF / DMF: N,N-Dimethyl formamide
Pd(PPh3)2Cl2 : Bis(triphenylphosphine)palladium(II) Dichloride
Pd(dppf)Cl2 : [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)

The invention of the present application will be explained in more detail with reference to the following examples, which should not be construed as limiting the scope of the invention in any manner.

Examples

Example 1: Preparation of Lenacapavir Sodium

To the Lenacapavir (5 gm), added Isopropyl acetate (25 ml) at 20 – 30°C. Stirred the reaction mixture for 5 minutes to 10 minutes at 20 – 30°C. To the obtained clear solution, was added NaOH solution (NaOH dissolved in MeOH) and stirred the reaction mixture for 30 minutes to 40 minutes at 20 – 30°C. The obtained reaction mixture was distilled under vacuum at below 45°C. To the obtained solid, was added isopropyl acetate (25 ml) and stirred the reaction mixture for 15 to 20 minutes at 20 – 30°C. To the obtained clear solution, was added n-Heptane (7.5 ml) drop wise and stirred the reaction mixture for 2 hours to 3 hours at 20 – 30°C. To the obtained solid, was added isopropyl acetate (50 ml) and stirred the reaction mixture for 16 hours at 20 – 30°C. Filtered the obtained solid and washed with n-Heptane (25 ml), followed by drying the solid for 30 minutes to 40 minutes and further dried under vacuum for 16 hours at 50°C to yield Lenacapavir Sodium.

Yield: 4 gm (78.27%)

Example 2: Preparation of Amorphous Lenacapavir Sodium solid dispersion with HPMCAS

To the Lenacapavir Sodium (10 gm), added Methanol (200 ml) and stirred the reaction mixture for 10 minutes to 20 minutes at 25 – 35°C. To the obtained clear solution, was added HPMCAS (10 gm) and stirred the reaction mixture for 20 minutes to 30 minutes at 25 – 35°C. The obtained clear solution was distilled under vacuum at 40°C, further isolated the obtained product with Heptane (50 ml) and dried for 12 hours to 14 hours in hot air oven at 50 – 60°C to yield Amorphous Lenacapavir Sodium solid dispersion.

Yield : 19 gm

,CLAIMS:
1. Amorphous Lenacapavir Sodium solid dispersion with a pharmaceutically acceptable polymer HPMCAS.

2. The solid dispersion as claimed in Claim 1, wherein said HPMCAS comprises about 10-50% wt/wt to the pharmaceutical active ingredient, Lenacapavir Sodium.

3. The solid dispersion as claimed in Claim 1, PXRD pattern of Amorphous Lenacapavir Sodium solid dispersion with HPMCAS is depicted in Figure 1.

4. A process for the preparation of Amorphous Lenacapavir Sodium solid dispersion comprises:
(a) dissolving Lenacapavir Sodium in a solvent selected from the group comprising of alcohols;
(b) adding pharmaceutically acceptable carrier HPMCAS;
(c) isolating the obtained Amorphous Lenacapavir Sodium solid dispersion.

(d) The process as claimed in Claim 4, wherein alcohols used in Step (a) selected from the group comprising of methanol, ethanol, butanol, t-BuOH, isopropanol or mixture thereof.