WO2019116386A1

WO2019116386A1 - Oral pharmaceutical compositions of amorphous apremilast and process for preparing thereof

Info

Publication number: WO2019116386A1
Application number: PCT/IN2018/050828
Authority: WO
Inventors: Arun Kumar Pandey; Umadoss POTHUVAN; Chandan Sharma; Binayak SADANGI
Original assignee: Alkem Laboratories Ltd
Current assignee: Alkem Laboratories Ltd
Priority date: 2017-12-12
Filing date: 2018-12-11
Publication date: 2019-06-20
Anticipated expiration: 2020-06-12

Abstract

The present invention relates an oral pharmaceutical compositions of Amorphous Apremilast and processes for preparing thereof wherein the core composition comprises: an amorphous form of Apremilast; as an active ingredient, an Ammonio methacrylate copolymer dispersion as a binding agent; a mixture of Lactose monohydrate and corn starch as a diluent; at least one Disintegrant & at least one lubricant and the core is coated with Polyvinyl acetate based film-forming agent; Wherein the said pharmaceutical composition about 90 to 95% of Apremilast is released in about 1 hour in an aqueous buffer solution of about pH 6.8 with a paddle speed of 75 RPM.

Description

DESCRIPTION

TITLE: ORAL PHARMACEUTICAL COMPOSITIONS OF AMORPHOUS

APREMILAST AND PROCESSES FOR PREPARING THEREOF

FIELD OF THE INVENTION

The invention relates to an oral pharmaceutical compositions of Amorphous Apremilast and processes for preparing thereof

BACKGROUND OF THE INVENTION

Apremilast is a phosphodiesterase 4 (PDE4) inhibitor. Apremilast is known chemically as N-[2- [(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH- isoindol-4-yl]acetamide. Its empirical formula is C22H24N207S and the molecular weight is 460.5.

Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels. The specific mechanism(s) by which apremilast exerts its therapeutic action in psoriatic arthritis patients is not well defined.

Following oral administration in humans, apremilast is a major circulating component (45%) followed by inactive metabolite M12 (39%), a glucuronide conjugate of O-demethylated apremilast. It is extensively metabolized in humans with up to 23 metabolites identified in plasma, urine and feces. Apremilast is metabolized by both cytochrome (CYP) oxidative metabolism with subsequent glucuronidation and non-CYP mediated hydrolysis. In vitro, CYP metabolism of apremilast is primarily mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6.

The plasma clearance of apremilast is about 10 L/hr in healthy subjects, with a terminal elimination half-life of approximately 6-9 hours. Following oral administration of radio-labeled apremilast, about 58% and 39% of the radioactivity is recovered in urine and feces, respectively, with about 3% and 7% of the radioactive dose recovered as apremilast in urine and feces, respectively.

Apremilast is available in the United States of America as OTEZLA® (apremilast) oral tablets and indicated for the treatment of adult patients with active psoriatic arthritis. It is available in various strengths i.e. 10, 20, and 30 mg strengths for oral administration

US 6,020,358 discloses substituted phenethylsulfones, including apremilast, and methods of use thereof for reducing TNFa levels.

WO 2003/080048 and WO 2003/080049 disclose the use of the (-) and (+) enantiomers of apremilast, respectively, in the treatment or prevention of diseases or disorders by the inhibiting TNF-a production or PDE4.

U.S. Pat. No. 7,427,638 discloses stereomerically pure (+)-2-[l-(3-ethoxy-4-methoxyphenyl)-2- methylsulfonylethyl]-4-acetylaminoisoindoline-l,3-dione, substantially free of its (-) isomer, or a pharmaceutically acceptable metabolite, salt, solvate or hydrate, thereof and its pharmaceutical composition. The stereomerically pure (+)-2-[l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl- ethyl]-4-acetylaminoisoindoline-l,3-dione is the (+)-isomer of racemic 2-[l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide

WO 2009/120167 and U.S. Pat. No. 7,893,101 disclose various solid forms comprising apremilast include single-component and multiple-component forms, including crystal forms and amorphous forms and their mixture comprising one or more of the Forms A, B, C, D, E, F, G and an amorphous solid form and provides representative XRPD patterns, DSC plots, TGA plots and DVS plots for each of Forms A, B, C, D, E, F and G.

WO 2009/120167 also generally mentions an amorphous form of apremilast but does not teach that a single amorphous form was actually obtained or characterized. US20130164376A1 disclose formulations and dosage forms of apremilast, i.e., (+)-2-[l-(3- ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-l,3-dione. or a pharmaceutically acceptable salt thereof; a filler; a disintegrant; and a lubricant. Methods of using the formulations and dosage forms are also provided herein.

WO 2014/072259 discloses pharmaceutical composition of amorphous apremilast with at least one excipients prepared by melt extrusion technique.

US9351957 discloses the pharmaceutical composition comprising an amorphous solid dispersion of apremilast and one or more of pharmaceutically acceptable carriers, excipients or diluents used for the treatment of active psoriatic arthritis.

There is no disclosure found about the immediate-release pharmaceutical composition for oral administration of an amorphous form of apremilast and its characterization as well as physiochemical properties and its stability.

The different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e.g., tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity).

An amorphous form generally provides better solubility and bioavailability than the crystalline form and may be useful for formulations which can have better stability, solubility and compressibility etc. which are important for formulation and product manufacturing.

Therefore, it is desirable to have a stable amorphous form of drug with high purity to meet the needs of regulatory agencies and highly reproducible processes for its preparation. In view of the above, it is therefore, desirable to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of oral solid dosage form of amorphous form of apremilast. The amorphous form provided herein is stable under ordinary stability conditions with respect to purity and storage.

Despite the above mentioned prior arts on solid pharmaceutical formulations of Apremilast there still exists a need for an oral pharmaceutical composition of amorphous Apremilast , without using of solid dispersion or extrusion or hot melt extrusion technology and without using, of crystalline form of Apremilast or pharmaceutically acceptable salts thereof, It has now been found, surprisingly, that oral pharmaceutical compositions of Amorphous form of Apremilast which provides better solubility than the crystalline form of Apremilast and useful for formulations with the process of preparation with simple granulation process and the formulations have better stability, solubility, compressibility and dissolution rates (important in determining bioavailability).

OBJECT OF THE INVENTION

It is an object of the present invention to provide an oral pharmaceutical compositions of Amorphous Apremilast and processes for preparing thereof.

It is another object of the present invention to provide a pharmaceutical composition for oral administration comprising:

A) A core composition, wherein the core composition comprises:

a) an amorphous form of Apremilast, as an active ingredient,

b) an Ammonio methacrylate copolymer dispersion as a binding agent,

c) a mixture of Lactose monohydrate and corn starch as a diluent and

d) at least one lubricant

B) Coating composition, wherein the core is coated with Polyvinyl acetate based film-forming agent. Wherein the said pharmaceutical composition about 90 to 95% of Apremilast is released in about 1 hour in an aqueous buffer solution of about pH 6.8 with a paddle speed of 75 RPM.

It is also an object of the present invention to provide a process to prepare a stable solid pharmaceutical composition of a pharmaceutical composition for oral administration comprising:

A) A core composition, wherein the core composition comprises:

a) an amorphous form of Apremilast, as an active ingredient,

b) an Ammonio methacrylate copolymer dispersion as a binding agent,

c) a mixture of Lactose monohydrate and corn starch as a diluent and

d) at least one lubricant

B) Coating composition, wherein the core is coated with Polyvinyl acetate based film-forming agent.

Wherein the said pharmaceutical composition about 90 to 95% of Apremilast is released in about 1 hour in an aqueous buffer solution of about pH 6.8 with a paddle speed of 75 RPM.

It is yet another object of the present invention to provide an oral solid stable pharmaceutical composition of Amorphous Apremilast and processes for preparing thereof, which uses a new and different beneficial formulation but is still bioequivalent to the commercially available compositions in the United States of America i.e. OTEZLA® oral tablets.

SUMMARY OF THE INVENTION

The present invention relates to an oral pharmaceutical compositions of Amorphous Apremilast and processes for preparing thereof.

More particularly it relates to:

A. A pharmaceutical composition for oral administration comprising:

A) a core composition, wherein the core composition comprises:

a) an amorphous form of Apremilast, as an active ingredient,

b) an Ammonio methacrylate copolymer dispersion as a binding agent,

c) a mixture of Lactose monohydrate and corn starch as a diluent and

d) at least one lubricant B) Coating composition, wherein the core is coated with Polyvinyl acetate based film-forming agent.

B. The pharmaceutical composition as in A above, wherein the Disintegrant is Croscarmellose sodium.

C. The pharmaceutical composition as in A above, wherein the lubricant is Sodium Strearyl Furmarate.

D. The pharmaceutical composition as in A above, wherein the coating composition is Opadry II in which Polyvinyl acetate is a film-forming agent.

E. The pharmaceutical composition as in A above, wherein the an aqueous buffer solution is 0.30% sodium lauryl sulphate in 25 mM Sodium Phosphate Buffer.

F. The pharmaceutical composition as in A above, wherein the paddle speed is the speed of Dissolution Apparatus II USP (Paddle).

G. The pharmaceutical composition as in A above, wherein the said pharmaceutical composition is as physically stable as the commercially available compositions in the United States of America i.e. OTEZLA® oral tablets.

H. The pharmaceutical composition as in A above, wherein the said pharmaceutical composition is bioequivalent to the commercially available compositions in the United States of America i.e. OTEZLA® oral tablets.

I. A process to prepare a pharmaceutical composition for oral administration comprising:

A) A core composition, wherein the core composition comprises:

a) an amorphous form of Apremilast, as an active ingredient,

b) an Ammonio methacrylate copolymer dispersion as a binding agent,

c) a mixture of Lactose monohydrate and corn starch as a diluent and

d) at least one lubricant

B) Coating composition, wherein the core is coated with polyvinyl acetate based a film-forming agent. Wherein the said pharmaceutical composition about 90 to 95% of Apremilast is released in about 1 hour in an aqueous buffer solution of about pH 6.8 with a paddle speed of 75 RPM.

Wherein the process comprises:

A. Mixing Apremilast, mixture of Lactose monohydrate & corn starch and Croscarmellose Sodium,

B. Granulating (A) with a water and Ammonio Methacrylate copolymer dispersion in Fluid bed processer and drying the granulate,

C. Milling the dried granules (B) to a uniform size,

D. Blending (C) with a mixture of Lactose Monohydrate and corn starch,

E. Lubricating (D) with Sodium Strearyl Furmarate,

F. Compressing (E) in to tablets,

G. Coating the (F) with Polyvinyl acetate based film-forming agent.

DETAILED DESCRIPTION OF THE INVENTION

Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for their availability to the applicant prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed

The term "stable" as used herein refers to chemical stability of amorphous form of Apremilast in solid dosage forms wherein there is no change in assay values and dissolution and/or the total impurity remains less than 1%, when the dosage form is kept at 40°C/75% RH for 6 months.

The term“composition” as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant that the diluent, excipient or carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof

As used herein, the term“polymorph” refers to polymorph form of Apremilast which, when present as a solid, exists as different crystalline forms. Desirably, polymorph includes solid forms of a compound such as crystals, microcrystals, foams, and powders, among others. Polymorphs typically differ in their physical properties due to the order of the molecules in the lattice of the polymorph. In addition, the physical properties of the polymorph can differ due to the presence of solvates or other molecules incorporated into the lattice of the polymorph. Typically, polymorphs are readily distinguished using techniques such as melting point, rate of dissolution, Infrared (IR) and Raman spectroscopy, and X-ray diffraction such as crystal and powder techniques.

The term“amorphous” as used herein refers to a compound having no definite crystal structure or form. In the present application, the term amorphous refers to amorphous Apremilast that can be present in the amorphous form as a solid or in a solution.

According to this invention, and the teachings contained in this patent application, the dosage form can be formulated as oral formulation by any suitable granulation process, dry or wet in the form of tablet, coated tablet or multiparticulate formulation known to those skilled in the art.

According to this invention, and the teachings contained in this patent application, the dosage form can be formulated as oral tablets formulation and dissolution of formulated oral tablets is evaluated by Drug Dissolution Apparatus II USP (Paddle), known to those skilled in the art.

The pharmaceutical composition of the present invention may further comprise conventional pharmaceutically acceptable excipients. Conventional pharmaceutical excipients include those which function in a dosage form, for example, as fillers or diluents, binders, disintegrants, lubricants, glidants, and film forming material.

Fillers or diluents for use in the formulations of the present invention include fillers or diluents typically used in the formulation of pharmaceuticals. Examples of fillers or diluents for use in accordance with the present invention include but are not limited to Starlac(mixture of Lactose monohydrate and corn starch), sugars such as lactose, dextrose, glucose, sucrose, cellulose, starches and carbohydrate derivatives, polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cycludextrins, calcium carbonates, magnesium carbonates, microcrystalline cellulose, combinations thereof, and the like. Several types of lactose are suitable for use in the formulations described herein, for example, lactose selected from the group consisting of anhydrous lactose, lactose monohydrate, lactose fast flow directly compressible anhydrous lactose, and modified lactose monohydrate.

Binders for use in the formulations of the present invention include binders commonly used in the formulation of pharmaceuticals. Examples of binders for use in accordance with the present invention include but are not limited to an Ammonio methacrylate copolymer dispersion (Eudragit Type A and Type B) or Acrylic derivatives.

Disintegrants include, but are not limited to, carboxymethcellulose(e.g.,croscarmellose sodium, such as AC -DI-SOL®). In one embodiment, the disintegrant is carboxymethyl cellulose. In another embodiment, the disintegrant is croscarmellose sodium. In still another embodiment, the disintegrant is AC-DI-SOL®.

Lubricants for use in the formulations of the present invention include lubricants commonly used in the formulation of pharmaceuticals. Examples of lubricants for use in accordance with the present invention include but are not limited to magnesium carbonate, magnesium laurylsulphate, calcium silicate, talc, fumed silicon dioxide, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulphate, magnesium lauryl sulphate, sodium benzoate, colloidal silicon dioxide, magnesium oxide, microcrystalline cellulose, starches, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium acetate, sodium chloride, combinations thereof.

Coats include, but are not limited to, Opadry (e.g., Opadry). In one embodiment, the coat is Opadry. In another embodiment, the coat is Opadry II.

The pharmaceutical compositions of the present invention may be prepared by the conventional processes such as wet granulation, dry granulation or direct compression as known to those skilled in the art.

The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.

Example 1

The composition of the present invention was prepared as given in table 1.

Table: 1

Manufacturing Procedure:

Apremilast, StarLac {Lactose Monohydrate: Maize Starch} and Croscarmellose Sodium were shifted through required sieve and loaded in FBP, followed by granulation with binder solution using Ammonio Methacrylate Copolymer dispersion and water. After granulation, granules were dried in FBD. This was followed by milling through required sieve. Loaded above granules in a blender followed by sifted extra-granular material StarLac* {Lactose Monohydrate: Maize Starch} and blended for sufficient time. Lubrication was done with Sodium Stearyl Fumarate. After lubrication, lubricated blend was compressed using suitable punch. This was followed by coating using opadry II dispersion.

Example 2

The composition of the present invention was prepared as given in table 2.

Table: 2

The composition of this example was prepared by the same process as given in example 1 above. Dissolution Profile study : The comparative dissolution study between the Apremilast Tablets 30 mg of Otezla^® Oral tablets as reference product and Example 1 and Example 2 of the present invention as Test product and showed about 90 to 95% of Apremilast is released in about 1 hour in an aqueous buffer solution of about pH 6.8 with a paddle speed of 75 RPM wherein the an aqueous buffer solution is 0.30% sodium lauryl sulphate in 25 mM Sodium Phosphate Buffer in Dissolution Apparatus II ETSP (Paddle). The results are as shown in tables 3 and 4.

Amorphous Apremilast Tablets 30 mg of Example 1

Table: 3

Amorphous Apremilast Tablets 30 mg of Example 2

Table: 4

Bioequivalence Study: The comparative study between the Apremilast Tablets 30 mg of Otezla^® Oral tablets as reference product and Example 1 of the present invention as Test product showed that the two formulations were bioequivalent. (Within 90% confidence interval for the ratios). The results are as shown in tables 5 and 6.

Fasting Bioequivalence result:

Table: 5

Fed Bioequivalence result:

Table: 6

C_max = Maximum plasma concentration AUC₍o-_t) = Area under the plasma concentration time curve from time 0 to t

AUC₍o-inf₎ = Area under the plasma concentration time curve from time 0 to inf

All pharmacokinetic parameters of Amorphous Apremilast were within the acceptable limit in pilot level bio equivalency study of fed and fasted stage.

Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any“preferred” embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are preferred by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.

Claims

Claims:

1. A pharmaceutical composition for oral administration comprising:

A) a core composition, wherein the core composition comprises:

a) an amorphous form of Apremilast, as an active ingredient,

b) an Ammonio methacrylate copolymer dispersion as a binding agent,

c) a mixture of Lactose monohydrate and corn starch as a diluent,

d) at least one lubricant

2. The pharmaceutical composition as in claim 1, wherein the Disintegrant is Croscarmellose sodium.

3. The pharmaceutical composition as in claim 1, wherein the lubricant is Sodium Strearyl Furmarate.

4. The pharmaceutical composition as in claim 1 , wherein the coating composition is Opadry II in which polyvinyl acetate is a film-forming agent.

5. The pharmaceutical composition as in claim 1, wherein an aqueous buffer solution is 0.30% sodium lauryl sulphate in 25 mM Sodium Phosphate Buffer.

6. The pharmaceutical composition as in claim 1, wherein the paddle speed is the speed of Dissolution Apparatus II USP (Paddle).

7. The pharmaceutical composition as in claim 1 , wherein the said pharmaceutical composition is as physically stable as the commercially available compositions in the United States of America i.e. OTEZLA® oral tablets.

8. The pharmaceutical composition as in claim 1 , wherein the said pharmaceutical composition is bioequivalent to the commercially available compositions in the United States of America i.e. OTEZLA® oral tablets.

9. A process to prepare a pharmaceutical composition for oral administration comprising:

A) A core composition, wherein the core composition comprises:

a) an amorphous form of Apremilast, as an active ingredient,

b) an Ammonio methacrylate copolymer dispersion as a binding agent,

c) a mixture of Lactose monohydrate and corn starch as a diluent,

d) at least one lubricant

B) Coating composition, wherein the core is coated with polyvinyl acetate based a film-forming agent.

Wherein the process comprises:

C. Milling the dried granules (B) to a uniform size,

D. Blending (C) with a mixture of Lactose Monohydrate and corn starch,

E. Lubricating (D) with Sodium Strearyl Furmarate,

F. Compressing (E) in to tablets,

G. Coating the (F) with polyvinyl acetate based film-forming agent.