WO2015150959A1 - Oral liquid pharmaceutical compositions comprising methyldopa or salts thereof - Google Patents

Oral liquid pharmaceutical compositions comprising methyldopa or salts thereof Download PDF

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Publication number
WO2015150959A1
WO2015150959A1 PCT/IB2015/052016 IB2015052016W WO2015150959A1 WO 2015150959 A1 WO2015150959 A1 WO 2015150959A1 IB 2015052016 W IB2015052016 W IB 2015052016W WO 2015150959 A1 WO2015150959 A1 WO 2015150959A1
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Prior art keywords
methyldopa
pharmaceutical composition
weight
composition
agent
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PCT/IB2015/052016
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French (fr)
Inventor
Pankaj Trimbak ADSARE
Vijay SUGGALA
Kapileswar Swain
Yatendra Kumar
Original Assignee
Wockhardt Limited
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Application filed by Wockhardt Limited filed Critical Wockhardt Limited
Priority claimed from IN1179MU2014 external-priority patent/IN2014MU01179A/en
Priority claimed from IN1178MU2014 external-priority patent/IN2014MU01178A/en
Publication of WO2015150959A1 publication Critical patent/WO2015150959A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

Definitions

  • the present invention relates to oral liquid pharmaceutical compositions comprising methyldopa or salts thereof having excellent storage stability and enhanced oral bioavailability.
  • the present invention relates to a pharmaceutical composition prepared into a soft gelatin capsule containing methyldopa or salts thereof as the active ingredient with one or more pharmaceutically acceptable excipients.
  • a process for preparation of methyldopa composition and method of use of such composition in the treatment of hypertension is also provided.
  • 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 C10H1 3 NO4 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 is 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 of methyldopa liquid composition.
  • the commonly used dosage form for methyldopa is tablet.
  • 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.
  • the present invention provides stable oral liquid pharmaceutical compositions of methyldopa or salts thereof with enhanced oral bioavailability.
  • 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 and said composition is filled into soft gelatin capsule.
  • oral liquid pharmaceutical composition of methyldopa devoid of sucrose wherein the composition is filled into soft gelatin capsule exhibits an enhanced oral bioavailability as compared to currently marketed methyldopa tablets or suspension formulation.
  • Such composition moreover, may remain stable during the period intended for use.
  • 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.
  • a stable oral liquid pharmaceutical composition comprising methyldopa or salt thereof and one or more pharmaceutically acceptable excipients filled into soft gelatin capsule.
  • a stable oral liquid pharmaceutical composition comprising methyldopa or salt thereof and one or more pharmaceutically acceptable excipients filled into soft gelatin capsule, wherein the composition is devoid of sucrose.
  • a stable oral liquid pharmaceutical composition comprising methyldopa or salt therof embedded into oily components such as emulsifying agent, stiffening agent, and suspending agent; and one or more pharmaceutically acceptable excipients.
  • a stable oral pharmaceutical composition comprises: (a) a therapeutically effective amount of methyldopa or salts thereof;
  • composition is devoid of sucrose.
  • an oral liquid pharmaceutical composition comprises: (a) a therapeutically effective amount of methyldopa or salts thereof,
  • composition is filled into soft gelatin capsule.
  • an oral liquid pharmaceutical composition comprises:
  • composition is devoid of sucrose and filled into soft gelatin capsule.
  • soft gelatin capsules of a pharmaceutical composition comprising:
  • composition is devoid of sucrose.
  • the present invention provides a process for preparing a stable oral liquid pharmaceutical composition 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 soft gelatin capsule.
  • the resultant liquid suspension before disposing the resultant pharmaceutical complex (suspension) into a capsule, the resultant liquid suspension passes through mill for getting uniform liquid suspension.
  • 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 6 months.
  • 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.
  • Inventors of the present invention have formulated oral liquid pharmaceutical composition of methyldopa which is devoid of sucrose and exhibits an enhanced oral bioavailability as compared to currently marketed methyldopa tablet or suspension formulation and remains stable during the period intended for use.
  • 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.
  • the stable oral liquid pharmaceutical composition comprising methyldopa or salt thereof and one or more pharmaceutically acceptable excipients is filled into soft gelatin capsule.
  • the stable oral liquid pharmaceutical composition comprising methyldopa or salt thereof and one or more pharmaceutically acceptable excipients is filled into soft gelatin capsule, wherein the composition is devoid of sucrose.
  • compositions of invention comprise but not limited to oily components; emulsifying agent/surfactant; stiffening agent; suspending vehicles/agents, antioxidants and preservatives.
  • An oily component(s) used in the present invention 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 C 6 to C 12 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 C 6 (caproic fatty acid), C$ (caprylic fatty acid), C 10 (capric fatty acid), and C 12 (lauric fatty acid), as well as mixtures thereof.
  • 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. MCT may be present in an amount from about 0.1 to about 10% or about 1 to about 5% or about 2.5% by weight of the total composition.
  • Suspending 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. Suspending agent may be present in an amount from about 35 to about 65% or about 45 to about 55% or about 47% by weight of the total composition.
  • 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.
  • 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 be used as a surfactant, antioxidant, stabilizer, lubricant and/or wetting agent.
  • Emulsifying agent may be present in an amount from about 0.01 to about 2% or about 0.05 to about 1% or about 0.25% by weight of the total composition.
  • 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 a-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.
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisol
  • the content of the antioxidant in the final composition is commonly in the range of about 0.05 to about 2% or about 0.05 to about 1.5% or about 0.05 to about 1% of the total weight of the composition.
  • composition of present invention further comprises a stiffening agent, e.g., beeswax, paraffin, stearic acid, stearyl alcohol, cetyl alcohol, lanolin or lanolin alcohol.
  • Stiffening agent may be present in an amount from about 0.01 to about 2% or about 0.05 to about 1 % or about 0.1 % by weight of the total composition.
  • the stable oral liquid pharmaceutical composition which comprises;
  • the weight ratio between the suspending agent 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.
  • methyldopa 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/or pharmaceutically acceptable prodrugs thereof.
  • 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.
  • 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.
  • 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.
  • gelatin as used herein includes not only unmodified gelatin as in the European Pharmacopeia but also modified gelatin, such as for example succinated gelatin.
  • 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.
  • the liquid may be comprised of more than one liquid with excipients in order to facilitate the desired solubility characteristics.
  • the oral liquid pharmaceutical compositions comprising essentially of a methyldopa or salt thereof embedded into an medium chain triglyceride; emulsifying agent; stiffening agent; suspending agent, antioxidants, preservatives and one or more pharmaceutically acceptable excipients.
  • the total amount of methyldopa or salts thereof in the pharmaceutical composition ranges from about 45.50 to about 65.50% or about 50.50 to about 60.50% by weight of the total composition.
  • the emulsifying agent and the stiffening agent are present in weight ratio of 1.5: 1 to 3.5: 1 or about 2: 1.
  • suspending agent and the stiffening agent are present in weight ratio of 650: 1 to 350: 1 or about 470: 1.
  • an oral liquid pharmaceutical composition comprises of:
  • the process for preparing a stable oral liquid pharmaceutical composition of methyldopa or salt thereof comprises step of:
  • step (c) homogenization of resultant suspension of step (b) and
  • the process for preparing a stable oral liquid pharmaceutical composition of methyldopa or salt thereof comprises step of:
  • step (b) adding or mixing suspending agent, emulsifying agent, and stiffening agent to the blend of step (a) to prepare a mixture
  • step (c) adding methyldopa or salt thereof to the mixture of step (b) to prepare a liquid pharmaceutical composition
  • composition is devoid of sucrose.
  • the process for preparing a stable oral liquid pharmaceutical compositions of methyldopa or salt thereof 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.
  • the resultant liquid suspension 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 30 to 65°C through out the process.
  • 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
  • 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.
  • 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 6 months.
  • the preservative/s and antioxidant/s were 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.
  • 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.
  • 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.
  • Dissolution of methyldopa soft gelatin capsules was carried out in 0.5% Tween 80 in 0.1N HCl, at 100 rpm.
  • the said composition exhibits remarkably good and consistent dissolution profile over a period of 6 months under accelerated conditions as depicted in Table 5.

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Abstract

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

Description

ORAL LIQUID PHARMACEUTICAL COMPOSITIONS COMPRISING
METHYLDOPA OR SALTS THEREOF
FIELD OF THE INVENTION:
The present invention relates to oral liquid pharmaceutical compositions comprising methyldopa or salts thereof having excellent storage stability and enhanced oral bioavailability. In particular, the present invention relates to a pharmaceutical composition prepared into a soft gelatin capsule containing methyldopa or salts thereof as the active ingredient with one or more pharmaceutically acceptable excipients. There is also provided a process for preparation of methyldopa composition and method of use of such composition in the treatment of hypertension.
BACKGROUND OF THE INVENTION:
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:
Figure imgf000002_0001
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 is 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 of 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 excellent stability and 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 and said composition is filled into soft gelatin capsule. SUMMARY OF THE INVENTION:
Inventors of the present invention have surprisingly found that oral liquid pharmaceutical composition of methyldopa devoid of sucrose, wherein the composition is filled into soft gelatin capsule exhibits an enhanced oral bioavailability as compared to currently marketed methyldopa tablets or suspension 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. Soft gelatin capsules containing methyldopa composition advantageously have good palatability and increased patient compliance.
DETAILED DESCRIPTION OF THE INVENTION:
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 into soft gelatin 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 into soft gelatin 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 oily components such as emulsifying agent, stiffening agent, and suspending agent; and one or more pharmaceutically acceptable excipients. In another general aspect, a stable oral pharmaceutical composition comprises: (a) a therapeutically effective amount of methyldopa or salts thereof;
(b) a suspending agent,
(c) an emulsifying agent,
(d) a stiffening agent and
(e) pharmaceutically acceptable excipients, wherein the composition is devoid of sucrose.
In another general aspect, an oral liquid pharmaceutical composition comprises: (a) a therapeutically effective amount of methyldopa or salts thereof,
(b) a suspending vehicle,
(c) an emulsifying agent,
(d) a stiffening agent and,
(e) pharmaceutically acceptable excipients,
wherein the said composition is filled into soft gelatin capsule.
In another general aspect of the invention an oral liquid pharmaceutical composition comprises:
(a) a therapeutically effective amount of methyldopa or salts thereof;
(b) a suspending agent,
(c) an emulsifying agent,
(d) a stiffening agent, and
(e) pharmaceutically acceptable excipients,
wherein the composition is devoid of sucrose and filled into soft gelatin capsule.
In another general aspect, there are provided soft gelatin capsules of a pharmaceutical composition comprising:
(a) about 455 to about 655 mg by weight of methyldopa or salt thereof,
(b) about 0.5 to about 10 mg by weight of stiffening agent,
(c) about 0.05 to about 15 mg by weight of emulsifying agent,
(d) about 10 to about 70 mg by weight of medium chain triglyceride,
(e) about 250 to about 550 mg by weight of suspending agent, (f) about 0.05 to about 5 mg by weight of antioxidants and
(g) about 0.05 to about 5 mg by weight of preservatives,
wherein the composition is devoid of sucrose.
In another general aspect, the present invention provides a process for preparing a stable oral liquid pharmaceutical composition 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 soft gelatin 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 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 6 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 composition of methyldopa or salts thereof, filled into soft gelatin capsule wherein the 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 which is devoid of sucrose and exhibits an enhanced oral bioavailability as compared to currently marketed methyldopa tablet or suspension formulation and remains stable during the period intended for use.
In an embodiment there is provided 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 is filled into soft gelatin capsule.
In another embodiment, the stable oral liquid pharmaceutical composition comprising methyldopa or salt thereof and one or more pharmaceutically acceptable excipients is filled into soft gelatin 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.
An oily component(s) used in the present invention 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), C$ (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. MCT may be present in an amount from about 0.1 to about 10% or about 1 to about 5% or about 2.5% by weight of the total composition.
Suspending 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. Suspending agent may be present in an amount from about 35 to about 65% or about 45 to about 55% or about 47% by weight of the total composition.
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 be used as a surfactant, antioxidant, stabilizer, lubricant and/or wetting agent. Emulsifying agent may be present in an amount from about 0.01 to about 2% or about 0.05 to about 1% or about 0.25% by weight of the total composition.
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 a-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 to about 2% or about 0.05 to about 1.5% or about 0.05 to about 1% of the total weight of the composition.
The composition of present invention further comprises a stiffening agent, e.g., beeswax, paraffin, stearic acid, stearyl alcohol, cetyl alcohol, lanolin or lanolin alcohol. Stiffening agent may be present in an amount from about 0.01 to about 2% or about 0.05 to about 1 % or about 0.1 % by weight of the total composition.
In an another embodiment, there is provided the stable oral liquid pharmaceutical composition which comprises;
(a) about 455 to about 655 mg by weight of methyldopa or salt thereof,
(b) about 0.5 to about 10 mg by weight of stiffening agent,
(c) about 0.05 to about 15 mg by weight of emulsifying agent,
(d) about 10 to about 70 mg by weight of medium chain triglyceride,
(e) about 250 to about 550 mg by weight of suspending agent,
(f) about 0.05 to about 5 mg by weight of antioxidants and
(g) about 0.05 to about 5 mg by weight of preservatives. The weight ratio between the suspending agent 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/or 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 there is provided, the oral liquid pharmaceutical compositions comprising essentially of a methyldopa or salt thereof embedded into an medium chain triglyceride; emulsifying agent; stiffening agent; suspending agent, antioxidants, preservatives and one or more pharmaceutically acceptable excipients.
In another preferred embodiment, the total amount of methyldopa or salts thereof in the pharmaceutical composition ranges from about 45.50 to about 65.50% or about 50.50 to about 60.50% by weight of the total composition. The emulsifying agent and the stiffening agent are present in weight ratio of 1.5: 1 to 3.5: 1 or about 2: 1. And suspending agent and the stiffening agent are present in weight ratio of 650: 1 to 350: 1 or about 470: 1.
In another embodiment, an oral liquid pharmaceutical composition 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
(d) filling 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) preparing a blend of preservative/s and antioxidant/s with medium chain triglycerides,
(b) adding or mixing suspending agent, emulsifying agent, 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) filling the composition in a soft gelatin capsule;
wherein the composition is devoid of sucrose.
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. The temperature was maintained between 30 to 65°C through out the process.
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 6 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 examples 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
Figure imgf000014_0001
Process:
The preservative/s and antioxidant/s were 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
Figure imgf000015_0001
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
Figure imgf000015_0002
The Methyldopa liquid suspension filled into soft gelatin capsule and subjected for stability studies at 40°C/75% storage condition. The stability data for 6 months reveals that the composition was stable through out period as depicted in Table 4.
Table - 4
Figure imgf000016_0001
1M 40°C/75%RH
98.3 6.68 1.1669 PVC_Clear
1M 40°C/75%RH
98.6 6.78 1.1643 Triplex_Clear
2M 40°C/75%RH
93.5 4.66 1.1716 PVC_Clear
2M 40°C/75%RH
96.2 6.42 1.1684 Triplex_Clear
3M 40°C/75%RH
97 5.83 1.1813 PVC_Clear
3M 40°C/75%RH
98.1 5.85 1.1762 Triplex_Clear
6M 40°C/75%RH
99 6.48 1.1839 PVC_Clear
6M 40°C/75%RH
98.8 6.09 1.1871 Triplex_Clear
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 as there is no substantial change in density of said composition.
Dissolution of methyldopa soft gelatin capsules was carried out in 0.5% Tween 80 in 0.1N HCl, at 100 rpm. The said composition exhibits remarkably good and consistent dissolution profile over a period of 6 months under accelerated conditions as depicted in Table 5.
Table - 5
Figure imgf000017_0001
3M 40°C/75%RH
82 102 PVC_Clear
3M 40°C/75%RH
87 103 Triplex_Clear
6M 40°C/75%RH
82 98 PVC_Clear
6M 40°C/75%RH
81 97 Triplex_Clear
Initial 74 98
1M 40°C/75%RH
81 96 PVC_Clear
1M 40°C/75%RH
88 99 Triplex_Clear
2M 40°C/75%RH
79 94 PVC_Clear
2M 40°C/75%RH
83 95
250mg Triplex_Clear
3M 40°C/75%RH
66 96 PVC_Clear
3M 40°C/75%RH
71 91 Triplex_Clear
6M 40°C/75%RH
69 98 PVC_Clear
6M 40°C/75%RH
80 97 Triplex_Clear
Initial 87 100
1M 40°C/75%RH
78 95 PVC_Clear
1M 40°C/75%RH
82 97 Triplex_Clear
2M 40°C/75%RH
72 93 PVC_Clear
2M 40°C/75%RH
84 94
500mg Triplex_Clear
3M 40°C/75%RH
84 97 PVC_Clear
3M 40°C/75%RH
80 96 Triplex_Clear
6M 40°C/75%RH
82 99 PVC_Clear
6M 40°C/75%RH
78 97 Triplex_Clear

Claims

CLAIMS:
1. A stable oral liquid pharmaceutical composition comprising methyldopa or salts thereof and one or more pharmaceutically acceptable excipients filled into a soft gelatin capsule wherein the composition is devoid of sucrose.
2. The pharmaceutical composition of claim 1, wherein the methyldopa is present in an amount from about 45.50 to about 65.50% or about 50.50 to about 60.50% by weight of the total composition.
3. The pharmaceutical composition of claim 1, wherein the one or more pharmaceutically acceptable excipients comprise medium chain triglyceride, suspending agent, emulsifying agent, stiffening agent, antioxidants and preservatives.
4. The pharmaceutical composition of claim 3, wherein the suspending agent is soybean oil.
5. The pharmaceutical composition of claim 3, wherein the stiffening agent is bees wax.
6. The pharmaceutical composition of claim 3, wherein the suspending agent and the stiffening agent are present in weight ratio of 650: 1 to 350: 1.
7. The pharmaceutical composition of claim 3, wherein the emulsifying agent is soya lecithin.
8. The pharmaceutical composition of claim 3, wherein the emulsifying agent and the stiffening agent are present in weight ratio of 1.5: 1 to 3.5: 1.
9. The pharmaceutical composition of claim 3, wherein the antioxidants comprise butylated hydro xytoluene, butylated hydroxyanisol and propyl gallate.
10. The pharmaceutical composition of claim 3, wherein the preservatives comprise methyl paraben and propyl paraben.
11. The pharmaceutical composition of claim 3, wherein the composition comprises:
(a) about 455 to about 655 mg by weight of methyldopa or salt thereof,
(b) about 0.5 to about 10 mg by weight of stiffening agent,
(c) about 0.05 to about 15 mg by weight of emulsifying agent,
(d) about 10 to about 70 mg by weight of medium chain triglyceride,
(e) about 250 to about 550 mg by weight of suspending agent,
(f) about 0.05 to about 5 mg by weight of antioxidants and
(g) about 0.05 to about 5 mg by weight of preservatives.
12. A process for preparing the pharmaceutical composition of claim 3, which 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, 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) filling the composition into the soft gelatin capsule;
wherein the composition is devoid of sucrose.
13. The process of claim 12, wherein a temperature is maintained between about 30 to about 65°C throughout the process.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4404193A (en) 1981-10-09 1983-09-13 Merck & Co., Inc. Methyldopa composition
EP0156977A2 (en) * 1984-03-22 1985-10-09 MIRA LANZA S.p.a. Process for the preparation of a bleaching activator in granular form

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4404193A (en) 1981-10-09 1983-09-13 Merck & Co., Inc. Methyldopa composition
EP0156977A2 (en) * 1984-03-22 1985-10-09 MIRA LANZA S.p.a. Process for the preparation of a bleaching activator in granular form

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
EMERSON R. F. ET AL.: "Soft gelatin capsule update", DRUG DEV. IND. PHARM., vol. 12, no. 8-9, 1986, pages 1133 - 44
LACHMANN ET AL.: "The Theory and Practice of Industrial Pharmacy", 1976, pages: 404 - 419
SWARBRICK; BOYLANN: "Encyclopedia of pharmaceutical technology", vol. 2, 1990, MARCEL DEKKER, pages: 269 FF

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