FIELD OF THE INVENTION

The present invention relates to novel oral pharmaceutical compositions of retinoids. Methods of preparing such compositions are also provided.

BACKGROUND OF THE INVENTION

Retinoids are a class of compounds structurally related to vitamin A. The pharmacological action of retinoids may be explained by their effects on cell proliferation, cell differentiation, apoptosis, angiogenesis, keratinization, sebum secretion and immunomodulation.

Alitretinoin or 9-cis retinoic acid is a first generation retinoid. The chemical name of alitretinoin is (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-l-yl )nona- 2,4,6,8-tetraenoic a

OOH

Alitretinoin is an endogenous metabolite of vitamin A. Alitretinoin binds to RARs and the so-called retinoid X receptors (RXRs). Alitretinoin has demonstrated immunomodulatory and anti-inflammatory effects that are relevant to skin inflammation.

In Europe & Canada alitretinoin is commercially available as oral soft gelatin capsules 10 & 30 mg (TOCTINO ^® ) for use in adults who have severe chronic hand eczema. Alitretinoin is also available in US and Europe as 0.1% topical gel (PANRETIN ) for topical treatment of cutaneous lesions in patients with AIDS-related Kaposi's sarcoma.

EP 0552624 Al discloses a soft gelatin capsule formulation of 9-cis retinoic acid with a fill mass formulation consisting of oil and wax mixture.

WO 99/24024 discloses a soft gelatin capsule preparation of retinoids containing hydrogenated castor oil, synthetic triglycerides, medium chain triglycerides and DL-alpha- tocopherol.

US 20100136108 discloses improved soft gelatin capsule formulation of 9-cis retinoic acid as an active ingredient and a fill mass comprising natural vegetable oil, partially hydrogenated natural vegetable oil and medium chain triglycerides. Optionally, the formulation also comprises a natural wax. The composition exhibits improved dissolution rate and avoids pellicles formation after long-term storage at temperatures above 5°C.

In an attempt to develop novel oral 9-cis retinoic acid compositions, the present inventors have surprisingly found that use of mono and/or di glycerides resulted in compositions which are found to be chemically stable and having immediate release characteristics. To our knowledge, none of the prior arts disclose the use of mono and/or di glycerides in a retinoid formulation for oral administration.

SUMMARY OF THE INVENTION

The present specification relates to novel oral pharmaceutical compositions of retinoids.

In one aspect, the present specification relates to an oral pharmaceutical composition comprising:

(i) 9-cis retinoic acid,

(ii) one or more mono and/or di glycerides, and

(iii) one or more vegetable oils. In another aspect, the present specification relates to an oral pharmaceutical composition comprising:

(i) 9-cis retinoic acid,

(ii) one or more mono and/or di glycerides,

(iii) one or more vegetable oils, and

(iv) one or more medium chain triglycerides.

In another aspect, the present specification relates to an oral pharmaceutical composition comprising:

(i) 9-cis retinoic acid,

(ii) one or more mono and/or di glycerides,

(iii) one or more vegetable oils,

(iv) one or more medium chain triglycerides,

(v) one or more wax, and

(vi) one or more antioxidant.

In another aspect, the present specification relates to an oral pharmaceutical composition comprising:

(i) 1% to 10% (w/w) 9-cis retinoic acid,

(ii) 1% to 15% (w/w) mono and/or di glycerides,

(iii) 60% to 90% (w/w) vegetable oils,

(iv) 5% to 10%) (w/w) medium chain triglycerides,

(v) 1% to 10 % (w/w) wax, and

(vi) an antioxidant.

In yet another aspect, the present specification relates to an oral pharmaceutical composition comprising:

(i) 9-cis retinoic acid,

(ii) glyceryl monooleate, and

(iii) soybean oil.

In yet another aspect, the present specification relates to an oral pharmaceutical composition comprising: (i) 9-cis retinoic acid,

(ii) glyceryl distearate, and

(iii) soybean oil.

In yet another aspect, the present specification relates to an oral pharmaceutical composition comprising:

(i) 9-cis retinoic acid,

(ii) glyceryl monooleate,

(iii) glyceryl distearate,

(iv) soybean oil, and

(v) medium chain triglycerides.

The pharmaceutical compositions of present specification may be used for the treatment of eczema, chronic hand eczema or other skin disorders or diseases.

DESCRIPTION OF THE INVENTION

The present specification relates to novel oral pharmaceutical compositions of retinoids.

In one aspect, the present specification relates to an oral pharmaceutical composition comprising:

(i) 9-cis retinoic acid,

(ii) one or more mono and/or di glycerides, and

(iii) one or more vegetable oils.

In another aspect, the present specification relates to an oral pharmaceutical composition comprising:

(i) 9-cis retinoic acid,

(ii) one or more mono and/or di glycerides,

(iii) one or more vegetable oils, and

(iv) one or more medium chain triglycerides. In another aspect, the present specification relates to an oral pharmaceutical composition comprising:

(i) 9-cis retinoic acid,

(ii) one or more mono and/or di glycerides,

(iii) one or more vegetable oils,

(iv) one or more medium chain triglycerides,

(v) one or more wax, and

(vi) one or more antioxidant.

In another aspect, the present specification relates to an oral pharmaceutical composition comprising:

(i) 1% to 10% (w/w) 9-cis retinoic acid,

(ii) 1% to 15% (w/w) mono and/or di glycerides,

(iii) 60% to 90% (w/w) vegetable oils,

(iv) 5% to 10% (w/w) medium chain triglycerides,

(v) 1% to 10 % (w/w) wax, and

(vi) an antioxidant.

In yet another aspect, the present specification relates to an oral pharmaceutical composition comprising:

(i) 9-cis retinoic acid,

(ii) glyceryl monooleate, and

(iii) soybean oil.

In yet another aspect, the present specification relates to an oral pharmaceutical composition comprising:

(i) 9-cis retinoic acid,

(ii) glyceryl distearate, and

(iii) soybean oil.

In yet another aspect, the present specification relates to an oral pharmaceutical composition comprising:

(i) 9-cis retinoic acid, (ii) glyceryl monooleate,

(iii) glyceryl distearate,

(iv) soybean oil, and

(v) medium chain triglycerides.

As used herein, the term "oral pharmaceutical composition" refers to an oral dosage form comprising tablets, pills, sachets, or capsules. The preferred oral dosage form is in the form of capsule. The capsule may be a hard gelatin capsule or a soft gelatin capsule.

The oral pharmaceutical composition of the present specification includes retinoids as an active ingredient. The retinoids are selected from the group of retinol, retinal, retinoic acid and derivatives thereof. Specific examples are all-trans retinol, all-trans retinoic acid, 13- cis retinoic acid and 9-cis retinoic acid.

The term 9-cis retinoic acid refers to 9-cis retinoic acid and esters, salts, or derivatives thereof. The amount of 9-cis retinoic acid employed in the composition is in the range of 1% to 10% (w/w), 2% to 9% (w/w) of the total composition, e.g. 8.6% (w/w).

As used herein, the term "mono glyceride" includes mono ester of glycerol with fatty acid. As used herein, the term "di glycerides" includes di esters of glycerol with fatty acids. The fatty acids are long chain fatty acids containing 12 to 20 carbon atoms. The fatty acids could be saturated or unsaturated. Examples of mono or di glycerides include but are not limited to glyceryl monolaurate, glyceryl dilaurate, glyceryl monostearate, glyceryl distearate, glyceryl monooleate, glyceryl dioleate, glyceryl monolinoleate. The amount of mono and/or di glycerides employed in the composition is in the range of 1% to 15% (w/w), 1% to 8% (w/w), 1% to 7% (w/w) of the total composition, e.g. 5.9 % (w/w).

As used herein, the term "vegetable oil" includes any pharmaceutically acceptable vegetable oil selected from the group comprising soybean oil, corn oil, sunflower oil, rape seed oil, linseed oil, sesame oil, olive oil, coconut oil, peanut oil, safflower oil, castor oil and cottonseed oil or mixtures of two or more of these oils. The amount of vegetable oil employed in the composition is in the range of 60% to 90% (w/w), 70% to 85% (w/w), 72%) to 78%) (w/w) of the total composition, e.g. 73%> (w/w). As used herein, the term "medium chain triglycerides" includes triglycerides of saturated fatty acids containing 8 to 10 carbon atoms, e.g. triglycerides of caprylic acid and/or capric acid. The amount of medium chain triglycerides employed in the composition is in the range of 5% to 10% (w/w), 6% to 8% (w/w) of the total composition, e.g. 7.8 % (w/w).

As used herein, the term "wax" includes any pharmaceutically-acceptable natural wax. Examples include but are not limited to natural wax, yellow bees wax, white bees wax, carnauba wax. The amount of wax employed in the composition is in the range of 1% to 10% (w/w), 2% to 8% (w/w), 2% to 4% (w/w), e.g. 3.7% (w/w).

The composition of the present specification may include an antioxidant. The antioxidant may be selected from one or more of DL-alpha-tocopherol, butylhydroxy toluene (BHT), butylhydroxy anisole (BHA), ascorbyl palmitate, ascorbic acid and propyl gallate. The amount of antioxidant employed in the composition is in the range of 0.01 to about 0.5% (w/w) of the total composition, e.g. 0.09% (w/w).

The pharmaceutical composition of present specification may be prepared by any conventional process for oral solid dosage forms. For example, the soft gelatin capsules may be prepared by using the following process steps: The vegetable oil, mono or di glyceride, medium chain triglyceride and wax are taken in to a suitable vessel, heated to a temperature of 65°C -70°C. The resultant mixture is cooled to 40°C with constant stirring. An antioxidant may be added to the resulting mixture followed by stirring. Subsequently, the retinoid is added to the above blend and stirred until a homogeneous suspension is obtained which is then stored in a stainless steel vessel under inert gas, tightly sealed and protected from light until encapsulation. The encapsulation of the homogenous suspension into soft gelatin capsules is then carried out on a rotary-die machine.

The pharmaceutical compositions of present specification were subjected to accelerated and long term stability studies.

The pharmaceutical compositions of present specification may be used for the treatment of eczema, chronic hand eczema or other skin disorders or diseases. The pharmaceutical compositions of present specification may be subjected to pharmaceutical bioequivalence testing in comparison with the reference product (TOCTINO ^® ) in an open-label, randomized, two-treatment, two-period, two-sequence, single-dose, crossover study in healthy adult human male subjects under fasting and fed conditions.

The specifications will now be described in greater detail by reference to the following non-limiting examples.

Table 1 : Formulation compositions

The above test formulations of Table 1 were prepared by the following method: Soybean oil, glyceryl distearate/ glyceryl monooleate/ glyceryl monolinoleate, medium chain triglyceride and wax were weighed in a suitable stainless steel vessel, heated to a temperature of 65°C -70°C and stirred constantly to get a homogeneous mixture. The resultant mixture was cooled to 40°C under constant stirring. DL-alpha Tocopherol was added to the resulting mixture. Subsequently, 9-cis retinoic acid was added to the above blend and stirred until a homogeneous suspension was obtained. The homogenous suspension was stored in a stainless steel vessel under inert gas, tightly sealed and protected from light until encapsulation. The encapsulation of the homogenous suspension into soft gelatin capsules was then carried out on a rotary-die machine.

Stability study The stability of the oral retinoid compositions of present specification was evaluated through accelerated stability studies. The composition prepared according to the formula and process of Example 4, was subjected to stability study at various temperature and humidity conditions. The composition was found to be chemically stable under accelerated conditions. Table 2 presents the stability study data.

Table 2: Stability data for Example 4 formulation composition

Bioequivalence Study

The pharmaceutical bioequivalence of the oral compositions of present specification was studied through comparative pharmacokinetic study against the reference product (TOCTINO ^® capsules). The pharmaceutical composition of the present invention (Test; 30 mg of 9-cis retinoic acid composition) was compared with the marketed formulation of 9- cis retinoic acid (Reference; 30 mg TOCTINO ^® capsules) in an open-label, randomized, two-treatment, two-period, two-sequence, single-dose, crossover study in healthy adult human male subjects under fasting and fed conditions.

Values for various pharmacokinetic parameters, including observed Cmax, AUCo-t, and AUCo-inf for fasting and fed conditions were calculated and the composition was found to be bioequivalent against the reference product. The results are provided in Table 3 and Table 4 below.

Table 3 : Results of bioequivalence study in fasted conditions Parameter Ratio[%Ref] CI 90 Lower CI_90 Upper CV %

Cmax 102.14 81.81 127.51 45

AUC _t 106.49 89.97 126.04 33

AUC _inf 111.73 94.06 132.73 33

Table 4: Results of bioequivalence study in fed conditions