CLIAMS:1. A process for preparing a stable oral liquid pharmaceutical composition of methyldopa or salt thereof, which process comprises step of:
(a) preparing a blend of preservative/s and antioxidant/s with medium chain triglycerides;
(b) adding or mixing suspending agent, emulsifying agent or surfactant, and stiffening agent to the blend of step (a) to prepare a mixture.
(c) adding methyldopa or salt thereof to the mixture of step (b) to prepare a liquid pharmaceutical composition, and
(d) optionally, filling the composition in a soft gelatin capsule;
wherein the composition is devoid of sucrose

2. The process of claim 1, wherein the suspending vehicles/agent is soybean oil.

3. The process of claim 1, wherein the emulsifying agent/surfactant is soya lecithin.

4. The process of claim 1, wherein the stiffening agent is bees wax.

5. The process of claim 1, wherein the antioxidant comprises of butylated hydroxytoluene (BHT), butylated hydroxyanisol (BHA) and propyl gallate.

6. The process of claim 1, wherein the preservative comprises of methyl paraben and propyl paraben.

7. The process of claim 1, wherein the temperature was maintained between 300 to 650C.

8. The process of 1, wherein the composition comprises:
(a) about 563.49 mg by weight of methyldopa or salt thereof,
b) about 0.5-10 mg by weight of beeswax,
(c) about 0.05-15 mg by weight of emulsifying agents/surfactant,
(d) about 10-70 mg by weight medium chain triglyceride,
(e) about 250-550 mg by weight of soybean oil,
(f) more than about 0.05 mg by weight of antioxidants and
(g) preservatives.

9. The process of 1, wherein the composition retains at least 90% w/w of the total potency of methyldopa or salts thereof after storage at 40°C and 75% relative humidity for at least 3 months.
,TagSPECI:DESCRIPTION

The present invention relates to process for preparing a stable oral liquid pharmaceutical composition comprising methyldopa or salts thereof with enhanced oral bioavailability. In particular, the present invention relates to a pharmaceutical compositions prepared into a soft gelatin capsule containing methyldopa or salts thereof as the active ingredient with enhanced oral bioavailability. There is also provided a method of use of such composition in the treatment of hypertension.

Methyldopa is an antihypertensive agent which may act centrally by stimulating alpha-adrenergic receptors. It inhibits the decarboxylation of dopa to dopamine and consequently reduces the amount of noradrenaline formed from dopamine.

Methyldopa (L-3-(3,4-dihydroxyphenyl)-2-methylalanine) is having a molecular formula of C10H13NO4 and has a molecular weight of 211.215 g/mol with the following structural formula:

Methyldopa is a colorless or almost colorless crystal or a white to yellowish white, odorless fine powder and is slightly soluble in water. It melts at 290°C. It is a BCS Class III drug i.e. low permeability and high solubility characteristics. Methyldopa 1.13 gm is approximately equivalent to 1 gm of anhydrous methyldopa.

Methyldopa were marketed by Merck as 125, 250 & 500mg tablets and 250mg/5mL suspension under the brand name Aldomet® in United States. Aldomet® is indicated for the treatment of hypertension. It acts by reducing the standing blood pressure and also reduces the supine blood pressure.

U.S. Patent No. 4,404,193 discloses an oral pharmaceutical composition of methyldopa for treatment of hypertension. The invention concerns a liquid suspension containing methyldopa and sucrose useful for oral treatment of hypertension. This invention further discloses weight ratio of methyldopa: sucrose is about 1:10. The document discloses use of sucrose for increasing bioavailability methyldopa liquid composition.

The commonly used dosage form for methyldopa is tablet. However these tablet formulations shows variation in bioavailability due to low permeation rate of methyldopa in gastrointestinal tract. The bioavailability after oral administration is about 25% (range 8 to 62%). The effects of methyldopa may appear after about 2 hours and reach a maximum in 6 to 8 hours, although the maximum hypotensive effect may not occur until the second day of treatment; some effect is still usually apparent 24 hours after a dose.

Thus, there still exists an enduring need to develop a pharmaceutical composition of methyldopa or pharmaceutically acceptable salt thereof with improved oral bioavailability.

Therefore, it is an object of the present invention to provide stable oral liquid pharmaceutical compositions of methyldopa or salts thereof with enhanced oral bioavailability. In particular, the present invention provides a stable oral pharmaceutical liquid composition of methyldopa or salts thereof with an enhanced oral bioavailability, wherein the composition is devoid of sucrose.

Inventors of the present invention have surprisingly found that oral liquid pharmaceutical composition of methyldopa devoid of sucrose exhibits an enhanced oral bioavailability as compared to currently marketed methyldopa tablets formulation. Such composition, moreover, may remain stable during the period intended for use.

It has been also found that the patient compliance was improved with minimal inter patient variability and toxicity

In one general aspect, there is provided a stable oral liquid pharmaceutical composition comprising methyldopa or salts thereof and one or more pharmaceutically acceptable excipients wherein the composition is devoid of sucrose.

In another general aspect, there is provided a stable oral liquid pharmaceutical composition comprising methyldopa or salt thereof and one or more pharmaceutically acceptable excipients filled in capsule.

In another general aspect, there is provided a stable oral liquid pharmaceutical composition comprising methyldopa or salt thereof and one or more pharmaceutically acceptable excipients filled in capsule, wherein the composition is devoid of sucrose.

In another general aspect, there is provided a stable oral liquid pharmaceutical composition comprising methyldopa or salt therof embedded into an oily components; emulsifying agent/surfactant; stiffening agent; suspending vehicles/agents, antioxidants, preservatives and one or more pharmaceutically acceptable excipients.

In another general aspect, a stable oral pharmaceutical composition comprises of: (a) a therapeutically effective amount of methyldopa or salts thereof;
(b) suspending vehicle
(c) emulsifying agent/surfactant
(d) stiffening agent and
(e) pharmaceutically acceptable excipients, wherein the composition is devoid of sucrose.

In another general aspect, an oral liquid pharmaceutical composition comprises of: (a) a therapeutically effective amount of methyldopa or salts thereof,
(b) suspending vehicle,
(c) emulsifying agent/surfactant
(d) stiffening agent and,
(e) pharmaceutically acceptable excipients,
wherein the said composition is filled into capsule.

In another general aspect of the invention comprises a suspension of the following components:
(a) a therapeutically effective amount of methyldopa or salts thereof;
(b) a suspending vehicle,
(c) at least one emulsifying agent/surfactant,
(d) at least one stiffening agent, and
(e) pharmaceutically acceptable excipients,
wherein the composition is devoid of sucrose and filled into capsule.

In another general aspect, there is provided soft gelatin capsules of a pharmaceutical composition comprising:
(a) about 563.49 mg by weight of methyldopa or salt thereof,
b) about 0.5-10 mg by weight of beeswax,
(c) about 0.05-15 mg by weight of emulsifying agents/surfactant,
(d) about 10-70 mg by weight medium chain triglyceride,
(e) about 250-550 mg by weight of soybean oil,
(f) more than about 0.05 mg by weight of antioxidants and
(g) preservatives.

In another general aspect, the present invention provides a process for preparing a stable oral liquid pharmaceutical compositions of methyldopa or salt thereof, which process comprises step of preparing blend of preservative/s and antioxidant/s with medium chain triglycerides; blending soya lecithin and beeswax along with some amount of soybean oil, wherein the beeswax melts into the above blend to form an oily liquid matrix; mixing for at elevated temperature to said matrix to form a suspension; adding remaining amount of soybean oil to the suspension; addition of the methyldopa or salt thereof into the liquid suspension at a constant temperature and disposing the resultant pharmaceutical complex into a capsule.

In another general aspect, before disposing the resultant pharmaceutical complex (suspension) into a capsule, the resultant liquid suspension passes through mill for getting uniform liquid suspension. The temperature was maintained between 300 to 65cC through out the process.

In another general aspect, there is provided a stable oral liquid pharmaceutical composition of methyldopa or salt thereof which retains at least 90% by weight of the total content of methyldopa or salt thereof after storing at 40°C and 75% relative humidity over a period of at least 3 months.

In another general aspect, there is provided a method of treating hypertension in patients in need thereof by administering the stable oral liquid pharmaceutical composition comprising methyldopa or salt thereof as substantially described throughout the specification.

In accordance with the present invention, it has now unexpectedly been found that stable oral liquid pharmaceutical methyldopa or salts thereof composition, filled in soft gelatin capsule and composition is devoid of sucrose exhibits an improved bioavailability and remains stable during the period intended for use.

Thus, with an objective to provide improved formulation of methyldopa, Inventors of the present invention have formulated oral liquid pharmaceutical composition of methyldopa devoid of sucrose exhibits an enhanced oral bioavailability as compared to currently marketed methyldopa tablets formulation and remains stable during the period intended for use.

In an embodiment, the stable oral liquid pharmaceutical composition comprising methyldopa or salts thereof and one or more pharmaceutically acceptable excipients wherein the composition is devoid of sucrose.

In another embodiment, the stable oral liquid pharmaceutical composition comprising methyldopa or salt thereof and one or more pharmaceutically acceptable excipients filled in capsule.

In another embodiment, the stable oral liquid pharmaceutical composition comprising methyldopa or salt thereof and one or more pharmaceutically acceptable excipients filled in capsule, wherein the composition is devoid of sucrose.

The term 'pharmaceutically acceptable excipient(s)' used in pharmaceutical compositions of invention comprise but not limited to oily components; emulsifying agent/surfactant; stiffening agent; suspending vehicles/agents, antioxidants and preservatives.

As the oily component in the present invention used can be selected from plant oil, a mineral oil and animal oil. It can be consist of one or a mixture of two or more esterified compounds of fatty acid and primary alcohol (fatty acid ester), medium chain fatty acid triglycerides and fatty acid monoglycerides. Preferably one or more medium-chain triglycerides (MCT) can be used.

An MCT comprises a triglyceride backbone having attached thereto three fatty acid chains that are generally from about C6 to C12 in length, although shorter or longer chains may be included within the term in differing contexts, as understood by those having skill in the art. The three medium chain fatty acids that are attached to the triglyceride backbone of the MCT may be, but need not be, identical. The medium chain fatty acids can be either saturated or unsaturated, but are preferably saturated. Examples of medium chain fatty acids that comprise the medium chain triglycerides of the invention include C6 (caproic fatty acid), C8 (caprylic fatty acid), C10 (capric fatty acid), and C12 (lauric fatty acid), as well as mixtures thereof. Further, the MCTs of the present invention may include minor amounts of short or long chain fatty acids. Needless to say, it is possible to use one or more triglycerides in combination

Suspending vehicles/agents are used in suspensions in order to prevent the separation of the vehicle from the solid by the settling of the solid and to maintain the dynamic homogeneity prior to, and during the encapsulation process. These types of vehicles are well known in the art. The nature and concentration of the suspending agent will vary, depending on several factors, for example, the concentration of suspending agent must meet both the requirement for a physically stable suspension and the requirement for the mixture to have the proper flow characteristics, also, the suspending vehicle may act to coat the suspended solids imparting a certain lubricity to them that aids in encapsulation. Suspending vehicles/agents useful in the present invention include but are not limited to soybean oil, peanut oil, sesame oil, cottonseed oil, corn oil, sunflower, olive oil, safflower oil and coconut oil. According to the invention, soybean oil is preferably used.

Emulsifying agents are known to those skilled in the art who will appreciate that the nature and concentration of emulsifying agent used is dependent on many factors including, active ingredient, viscosity of the vehicle, desired release of the active ingredient etc. Examples of suitable emulsifying or wetting agents for use in the present invention include but are not limited to lecithin, polysorbate 20, 40, 60 and 80. According to the invention, soy lecithin is preferably used which may also used as an surfactant, antioxidant, stabilizer, lubricant and wetting agent.

Antioxidants lessen the formation of oxidative degradation products, such as peroxides, from the unsaturated lipids, or other components. A non-limiting example of such a preferred antioxidant is α-tocopherol, or its derivatives (such as tocopherol succinate), which are members of the Vitamin E family. Many other antioxidants, which are known in the art as safe for human consumption may be used, such as butylated hydroxytoluene (BHT), butylated hydroxyanisol (BHA), propyl gallate. The content of the antioxidant in the final composition is commonly in the range of about 0.05-2% of the total weight of the composition, more preferably about 0.05-1.5% of the total weight of the composition, and still more preferably about 0.05-0.5% of the total solid weight of the mixture

The composition of present invention further comprises a stiffening agent, e.g., beeswax, paraffin, stearic acid, stearyl alcohol, cetyl alcohol, lanolin or lanolin alcohol.

In an embodiment, the stable oral soft gelatin capsules comprising:
(a) about 563.49 mg by weight of methyldopa or salt thereof,
b) about 0.5-10 mg by weight of beeswax,
(c) about 0.05-15 mg by weight of emulsifying agents/surfactant,
(d) about 10-70 mg by weight medium chain triglyceride,
(e) about 250-550 mg by weight of soybean oil,
(f) more than about 0.05 mg by weight of antioxidants and
(g) preservatives.

The weight ratio between the suspending vehicles and the stiffening agent is between 490:1 and 250:1, and it is preferably close to 380:1. These two components can be mixed together with 5 to 20% weight of soybean oil at room temperature or under hot conditions during the preparation of the composition in order to form a suspension or paste or an ointment. The temperature is adjusted as a function of the nature of the components used.

The above components are mixed with the active principle of the medicinal product according to the techniques usually used for pharmaceutical preparations, by adding thereto, where appropriate, various common excipients and additives for pharmaceutical formulation.

The term “methyldopa” as used throughout the specification refers to not only methyldopa per se, but also its other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.

The term "capsule" refers to any flexible, rigid or semi-rigid container containing active ingredients. Other synonyms to a capsule are: "pod", "pad", "cartridge" or "sachet". The capsule can be single use. The container can also be filled with active ingredients by the user to form the capsule just before use.

In general, gelatin capsule formulations for soft gelatin capsule comprise raw gelatin, plasticizer, solvent and optional further auxiliary materials, such as dyes, colorant pigments, flavouring agents, sugar, oligosaccharides or polysaccharides. Typically the plasticizer includes glycerin and or sorbitol. A preferred plasticizer in this case is glycerin. One preferred gelatin formulation for the soft gelatin capsule used in accordance with preferred embodiments includes gelatin in the range of about 40-45 % and a plasticizer in the range of about 5-25%. Capsule formulation can also include other suitable additives, which impart specific characteristics such as the look and feel of the capsule. The term gelatin as used herein includes not only unmodified gelatin as in the European Pharmacopeia but also modified gelatin, such as for example succinated gelatin.

As used herein, the term "liquid" refers to material in a form of matter, which moves freely and assumes the shape of the container within which it resides. The term "liquid" refers to any non-solid and non-gas and is understood to include non-aqueous liquids such as organic liquids and oils. Liquids commonly used in the filling of capsules are those known not to react with components of a specific capsule shell and include, but are not limited to castor oil, cottonseed oil, corn oil, olive oil, peanut oil, sesame oil, soybean oil, sunflower oil, caprylic acid, capric acid, glycerin and others. Furthermore, the liquid may be comprised of more than one liquid with excipients in order to facilitate the desired solubility characteristics.

In an embodiment, the oral liquid pharmaceutical compositions comprising essentially of a methyldopa or salt thereof embedded into an medium chain triglyceride; emulsifying agents/surfactant; stiffening agent; suspending vehicles/agents, antioxidants, preservatives and one or more pharmaceutically acceptable excipients.

In another embodiment, the total amount of methyldopa or salts thereof in the pharmaceutical composition ranges from about 45.50% w/w to about 65.50% w/w of the composition.

The weight ratio between the soya lecithin and the bees wax is between 1.5:1 and 3.5:1, and it is preferably close to 2:1.

In another embodiment, an oral liquid pharmaceutical compositions comprises of:
(a) a therapeutically effective amount of methyldopa or salts thereof;
(b) a medium chain triglyceride
(c) a suspending vehicle;
(d) at least one emulsifying agent/surfactant
(e) at least one stiffening agent and
(f) pharmaceutically acceptable excipients,
whereby the said composition is filled into soft gelatin capsule.

In another embodiment, the process for preparing a stable oral liquid pharmaceutical composition of methyldopa or salt thereof, which process comprises step of:
(a) Base preparation
(b) Addition of medicament to step (a)
(c) homogenization of resultant suspension of step (b) and optionally
(d) filled into capsule.

In another embodiment, the process for preparing a stable oral liquid pharmaceutical composition of methyldopa or salt thereof, which process comprises step of:
(a) preparing blend of preservative/s and antioxidant/s with medium chain triglycerides;
(b) adding/mixing soya lecithin, beeswax and soybean oil to step (a).
(c) addition of the methyldopa or salt thereof to step (b) and optionally
(d) filled into soft gelatin capsule.

In another embodiment, the process for preparing a stable oral liquid pharmaceutical compositions of methyldopa or salt thereof, which process comprises step of preparing blend of preservative/s and antioxidant/s with medium chain triglycerides; blending soya lecithin and beeswax along with some amount of soybean oil, wherein the beeswax melts into the above blend to form an oily liquid matrix; mixing for at elevated temperature to said matrix to form a suspension; adding remaining amount of soybean oil to the suspension; addition of the methyldopa or salt thereof into the liquid suspension at a constant temperature and disposing the resultant pharmaceutical complex into a capsule.

In another general aspect, before disposing the resultant pharmaceutical complex (suspension) into a capsule, the resultant liquid suspension passes through mill for getting uniform liquid suspension.

In a further general aspect, mill used for homogenization purpose may be selected but not limited from colloid mill, roller mill or koruma mill.

The capsule is a soft gelatin capsule consisting of a capsule shell comprising gelatin, one or more plasticizing agents and optionally further auxiliary materials, and a capsule formulation (or capsule filling), characterized in that the capsule formulation (or capsule filling) comprises the liquid suspension formulation.

The soft gelatin capsule according to the invention may be prepared by conventional methods of producing soft gelatin capsules known from the literature, such as for example the "rotary die procedure", described for example in Swarbrick, Boylann, Encyclopedia of pharmaceutical technology, Marcel Dekker, 1990, Vol. 2, pp 269 ff or in Lachmann et al., "The Theory and Practice of Industrial Pharmacy", 2nd Edition, pages 404-419, 1976, or other procedures, such as those described for example in Emerson R. F. et al., "Soft gelatin capsule update", Drug Dev. Ind. Pharm., Vol. 12, No. 8-9, pp. 1133-44, 1986

In another embodiment, there is provided a method of treating hypertension in patients in need thereof by administering the stable oral liquid pharmaceutical composition comprising methyldopa or salt thereof as substantially described throughout the specification.

In another embodiment, the stable oral liquid pharmaceutical composition of methyldopa or salt thereof which retains at least 90% by weight of the total content of methyldopa or salt thereof after storing at 40°C and 75% relative humidity over a period of at least 3 months.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1: Methyldopa liquid suspension
Table-1
Sr. No. Name of Ingredients Unit Qty.
1 Methyldopa 563.49
2 Soyabean oil 407.01
3 Soya Lecithin 2.50
4 Hariol 538 25.00
5 Bees Wax 1.05
6 Butylated Hydroxyanisol 0.15
7 Butylated Hydroxytoluene 0.15
8 Propyl gallate 0.15
9 Methylparaben 0.40
10 Propylparaben 0.10
Total 1000.00

Process:
The preservative/s and antioxidant/s was added into medium chain triglycerides with continuous stirring at 50-55°C temperature; blending soya lecithin and beeswax along with some amount of soybean oil, wherein the beeswax melts into the above blend to form an oily liquid matrix; remaining amount of soybean oil to the suspension was added; this mixture was stirred for about 10 to 20 minutes or until uniform. While stirring the above mixture, methyldopa or salt thereof was added at a constant temperature 35-40°C and further continuosly stirred for 20 minutes. The suspension was then passed through a mill to deaggreate the particles and deaerated by methods known to those skilled in the art. Prior to capsule filling, the mixture/suspension was passed through #60 mesh and stirred for 20 min under mechanical stirrer. Finally the resultant liquid pharmaceutical suspension was filled into soft gelatin capsule.

The following example illustrate preferred embodiments of several soft-gelatin-shell methyldopa or salt thereof formulations. Capsules may be made from the following formulations by methods that include those well known in the pharmaceutical art. Capsules made by other methods or by using different formulations are also contemplated for use with the pharmaceutical formulations and methods described herein. These examples illustrate particular embodiments of the invention and are not intended to limit the scope of the invention in any way

Example 2: Capsule shell
Table- 2
Sr. No. Name of Ingredients % W/W
1 Gelatin 42.00
2 Glycerin 10.00
3 Sorbitol 70% 10.00
4 Methyl paraben 0.30
5 Propyl paraben 0.10
6 Ponceau 4R Lake 0.10
7 Purified water 37.50

The Methyldopa liquid suspension was subjected for stability studies at temperature of about 40°C and relative humidity of about 75% for 6 months. The said composition exhibits remarkably good storage stability as depicted in Table 3.
Table- 3
Month %Assay Water by KF Wt./ml pH
Initial 105 7.21 1.2195 7
1 101 7.37 1.2195 6.9
3 97.9 6.1 1.2195 6.9
6 99.2 6.79 1.245 6.7

The Methyldopa liquid suspension filled into soft gelatin capsule and subjected for stability studies at 40°C/75% storage condition. The stability data for 2 months reveals that the composition was stable through out period as depicted in Table 4.

Table - 4
Strength Month/Sample pack Assay(%) Water by KF- Method(%w/w) Density(Wt./ml)
125mg Initial 95.6 6.82 1.158
1/ PVC_Clear 100.3 6.50 1.1717
1/ Triplex_Clear 99.4 6.40 1.1732
2/ PVC_Clear 98.7 7.37 1.1712
2/ Triplex_Clear 97.3 5.04 1.1491
250mg Initial 97.6 6.82 1.158
1/ PVC_Clear 99.6 6.81 1.1819
1/ Triplex_Clear 97.5 6.60 1.1775
2/ PVC_Clear 97.8 7.18 1.1745
2/ Triplex_Clear 97.8 6.51 1.1684
500mg Initial 97.8 6.82 1.158
1/ PVC_Clear 98.3 6.68 1.1669
1/ Triplex_Clear 98.6 6.78 1.1643
2/ PVC_Clear 93.5 4.66 1.1716
2/ Triplex_Clear 96.2 6.42 1.1684

The above stability data reveals that the methyldopa liquid suspension filed in capsule is well protected against moisture uptake as characterized by Karl-Fischer method and has good physical stability of methyldopa soft gelatin capsule as there is no substantial change in density of said composition.