DESC:FIELD OF INVENTION
The invention related to pharmaceutical stable composition comprising 3-8% w/v of magnesium hydroxide, 15-40% v/v of liquid paraffin and 0.01-1.0% w/v of sodium picosulfate with pharmaceutically acceptable carrier, stabilizer, surfactant and preservative.
The invention also related the pharmaceutical stable composition comprising a liquid oral composition of magnesium hydroxide, liquid paraffin, sodium picosulfate and process for preparation thereof.
BACKGROUND OF THE INVENTION
The human gastrointestinal (GI) microbiota, the "GI microbiome", is complex and is composed of around 3.3 million non-redundant microbial genes. Most of these are bacterial species, and the entire cohort harbors between 1,000 and 1,150 prevalent bacterial species. The gastrointestinal microbiome is considered now to be a "virtual organ", where only a small percentage of the entire cohort can be cultured and studied with respect to the metabolic pathways and activities of the bacteria. Genomic studies are easier but they do not give us the answer as to the functional capacity of various bacteria.
Being a "virtual organ," this bacterial cohort is susceptible, like any other organ of the body, to suffer from various "organ disorders". The most common one is infection, and so the intestinal microbiome can become infected e.g., with parasites, bacteria or viruses. Clinically, such infection can either be acute or chronic, and some examples of such acute infections are Salmonella or Shigella, and of chronic ones are Clostridium difficile, Giardia lamblia, Blastocysts hominis etc. Probably the most common infections of the gut microbiome are yet to be described and constitute what we have come to know as 'Irritable Bowel Syndrome' or IBS. It is now known that symptomatically infection of the gut flora does not always end up in diarrhea, but rather may be present in many forms that may be asymptomatic, or can cause diarrhea, cramping, abdominal pain, gas; and, in particular, an infection of the gut flora can also cause constipation.
For centuries constipation has been viewed as a benign condition somehow related to our diet. In recent decades the role of fiber has taken center stage and in the medical and lay public's mindset constipation is caused by 'inadequate dietary fiber, too little exercise and lack of water intake'. Few have addressed the super-infection of the intestinal microbiome as contributory.
Constipation is a very common condition especially in the developing countries. Notwithstanding the causality and the many secondary rather than primary causes such as hypothyroidism, hypercalcaemia and various medications, e.g., narcotic derivatives, there is a clinical need for effective laxatives that do not have any long term adverse effects. In the past therapies for constipation have included the increasing of fiber intake, many and varied laxatives such as Senna, Coloxyl, exotic teas and osmotic laxatives such as sorbitol, mannitol, lactulose and polyethylene glycol and others. Various other laxatives have been used including bisacodyl and castor oil, linactolide, prucalopride and colchicine. Methylnaltrexone has also been used to antagonise opiate induced constipation. Prokinetic agents including cisapride, metoclopramide, mosapride and domperidone have also been used to increase motility in some patients, Antibiotics such as erythromycin and vancomycin have also been used.
For such condition there is a need to develop a pharmaceutical stable, patient compliance dosage form which is capable to deliver the onset of action required to overcome the patient sufferings.
Magnesium hydroxide suspension is widely known as an antacid or laxative in the form of milk of magnesia in the pharmaceutical industry. Dry powder magnesium hydroxide is also used in a wide range of industries and applications as well as in combinations with other elements to create a versatile substance.
A pharmaceutical suspension is a coarse dispersion in which insoluble particles, generally greater than 1 µm in diameter, are dispersed in a liquid medium. An aqueous suspension is a useful formulation system for administrating an insoluble or poorly soluble drug. The large surface area of the dispersed drug ensures a high availability for dissolution and hence absorption. Such coarse suspensions are thermodynamically unstable due to the large surface energy and the tendency of settling for the dispersed particles
Therapeutically magnesium hydroxide is used as an alkaline mouth wash, antacid and mild laxative. It is commercially available in tablet form and as a magma, i.e., a milk of magnesia. The most popular dosage form is the milk of magnesia. However, there are some reported disadvantages associated with this dosage form. The viscosity coupled with the earthy, chalky taste of the magma magnesia makes it very unpalatable and objectionable to ingest. One of the main disadvantages to the use of milk of magnesia is the quantity that must be taken to get a laxative effect, i.e., the bulk dosage necessary. For example, the recommended laxative adult dose is from two to four table spoonful.
A further disadvantage is that commercially available milk of magnesia which is an aqueous suspension containing from about 7% to about 9% of magnesium hydroxide has a tendency to coagulate and clump upon standing. This characteristic is particularly evident when the product is allowed to freeze and eventually thaw. Freezing results in a denser precipitate or flocculation. Upon thawing a clear water stratum separates on top of the bottle. The magnesium hydroxide cannot be readily redispersed upon shaking thus making the product unfit for further use. Furthermore, freezing of commercial milk of magnesia has resulted in the breaking of the glass containers. It is because of this very poor stability with freezing temperatures that the US Pharmacopeia cautions “avoid freezing” and the commercial labeling requires “Do Not Freeze warnings”.
Picosulphate is a known active ingredient for use as a laxative. Picosulfate, typically used in the form of its bis-sodium salt, sodium picosulfate. Kenneth G. et al. in US5631022A disclosed a pharmaceutical laxative composition of picosulphate intended for constipation associated with irritable bowel syndrome, and bowel cleansing.
Sodium picosulfate is a prodrug that itself has no physiological effect and hydrolyzed by colonic bacteria to bis-(p-hydroxyphenyl)-pyridyl-2-methane (commonly known as "desacetyl bisacodyl") which is the active species). Contact of the desacetyl bisacodyl with the mucosa stimulates sensory nerve endings to produce increased propulsive peristaltic contractions of the colon which accelerate movement of contents through the colon. Administration of picosulphate has also been shown to promote fluid and ion accumulation in the colon, which increases its laxative effect. Since desacetyl bisacodyl acts upon contact with lumenal mucosa of the large intestine, its laxative effect is dependent upon generation of sufficient levels of the drug in the lumen of the colon.
Commercially available picosulphate laxatives are designed to deliver the picosulphate to the small intestine. Although these dose forms provide effective laxative activity, doses which produce maximal laxation also evoke undesirable side effects such as secondary episodes of diarrhea or repeat bowel movements.
An advantage of providing picosulphate to patients using the compositions of this invention is that laxation benefits are generally achieved without the secondary diarrhea commonly associated with conventional picosulphate compositions. Another advantage is that such laxation benefits are often achieved more quickly than with conventional picosulphate compositions. Another advantage is that a lesser dosage amount of picosulphate is needed to achieve laxation than is needed with conventional picosulphate compositions. Another advantage is that due to the lesser dosage amount and the more prompt onset of laxation activity, the side effects of cramping and pain are lessened.
Pharmaceutical products containing picosulfate in the form of sodium picosulfate along with other actives as per the present invention to treat constipation or for the clearance of the bowel prior to X-ray examination, endoscopy or surgery. Picosulfate, a stimulant laxative, can be used in combination with an osmotic laxative. Particularly useful are products that contain sodium picosulfate in combination with magnesium oxide and other pharmaceutical actives which together in solution form, an osmotic laxative with a powerful cathartic effect.
Paraffin hydrocarbon, also called alkane, any of the saturated hydrocarbons having the general formula CnH2n+2.Liquid paraffin is a type of medicine called as laxative, which works by softening and lubricating the stools. This helps the stools to move more easily through the bowel. Paraffin relieves constipation, making stools easier to pass. This means it can also be used to reduce pain associated with passing stools in people with conditions affecting the haemorrhoids.
Roger Macarthur A. et al in US2168228A disclosed method of making milk of magnesia comprises hydrating magnesium oxide in water by hydration reaction between said oxide and Water to form a suspension of the magnesium hydroxide in Water, said hydration reaction being carried out in the presence of an amount of dissolved electrolytic hydrating agent effective to impart substantially greater non-settling property of the suspension.
William Gorman G et al. claimed in US3692898 that milk of magnesia containing aqueous pharmaceutical suspension of magnesium hydroxide having improved particle stability, viscosity, homogeneity, suspension stability and palatability.
A combination of Liquid Paraffin, Milk of Magnesia and Sodium Picosulphate is approved by Central Drugs Standard Control Organization on Jan 2009, appears to provide better results for the treatment of patient population suffering from constipation. The combination is widely accepted in developing as well as developed countries for treatment of constipation.
Though there are various oral composition exiting in the market containing liquid paraffin, milk of magnesia and sodium picosulphate either alone or in combination. However, it has been found that such compositions are often facing the issue like settling, caking, discoloration, sedimentation and separation of layers.
These limitations motivated inventors of the present invention to develop such a dosage form which is having improved, viscosity, homogeneity, stability and palatability along with the combination of Liquid Paraffin, Milk of Magnesia and Sodium Picosulphate and other pharmaceutical acceptable excipients.
OBJECT OF THE INVENTION
Object of present invention relates to bring the market, a more user-friendly and far more effective stable oral pharmaceutical composition for constipation, which also brings the advantage over exist product to be devoid of sugar (carbohydrate) besides stability and temperature in hot and higher humid zone.
SUMMARY OF INVENTION
Provided herein are simple and easily scalable stable oral pharmaceutical compositions of liquid paraffin, magnesium hydroxide and sodium picosulphate with improved viscosity, homogeneity, stability or palatability, and the process of preparing such composition. The present invention provides a pharmaceutical stable oral composition containing liquid paraffin, magnesium hydroxide and sodium picosulphate with pharmaceutical acceptable excipients which provides high stability of actives within the compositions.
In one aspects of the present invention, it relates to stable oral pharmaceutical composition comprising 3-8% w/v of magnesium hydroxide, 15-40% v/v of liquid paraffin and 0.01-1.0% w/v of sodium picosulfate, wherein the composition contains 01-05% w/v of colloidal anhydrous silica as stabilizing agent and 1-4% w/v of non-ionic surfactant.
In another aspects of the present invention, it relates to stable oral pharmaceutical composition according to claim 1 wherein non-ionic surfactant comprising sorbitan monooleate (span 80) or polysorbate 80 (tween 80) or mixture thereof.
In yet another aspects of the present invention, it relates to a process of preparing stable oral pharmaceutical composition of magnesium hydroxide, liquid paraffin and sodium picosulfate wherein the process comprising the steps of:
i) preparation of milk of magnesia by mixing purified water, sorbitol solution and magnesium hydroxide at the temperature ranges between 60-70°C.
ii) process the liquid in colloidal mill for time duration ranging between 15 to 45 min.
iii) cooling the processed liquid of step (ii) up to temperature ranging between 20-40°C.
iv) adding preservative and taste masking agent in solution.
v) combining sodium picosulfate in to the liquid.
vi) optionally adding coloring agent to the above solution.
vii) mixing colloidal anhydrous silica (aerosil) for the time duration ranging between 15-45 min.
viii) adding 30-50% of non-ionic surfactant in to above step during stirring.
ix) mixing liquid paraffin and 35-35% of non-ionic surfactant followed by stirring
x) adding the mixture of step (ix) in to the material prepared in step (viii).
xi) adding remaining surfactant in above step followed by stirring.
xii) optionally adding flavoring agent with continue stirring for 10-60 min.
In yet different aspects of the present invention, it relates to a process of preparing stable oral pharmaceutical composition of magnesium hydroxide, liquid paraffin and sodium picosulfate, wherein the process comprising the steps of:
i) preparation of milk of magnesia by mixing purified water, sorbitol solution and magnesium hydroxide at the temperature ranges between 60-70°C.
ii) process the liquid in colloidal mill for time duration ranging between 05 to 35 min.
iii) adding the preservative and chelating agent with sweetener on aqueous phase at the temperature ranging of 70-90°C.
iv) optionally adding coloring agent to the above solution.
v) adding thickening agent in to above solution by continue stirring for the time duration ranges 10-30min.
vi) mixing liquid paraffin and 35-35% of non-ionic surfactant followed by stirring
vii) adding the mixture of step (v) in to the material prepared in step (vi)
viii) mixing colloidal anhydrous silica (aerosil) for the time duration ranging between 15-45 min.
ix) combining sodium picosulfate at the temperature ranges 25-45°C.
x) optionally adding flavoring agent with continue stirring for 10-60 min.
In yet another aspects of the present invention, it relates to preparing pharmaceutical stable composition for oral administration comprising a step of admixing the stable o/w liquid with pharmaceutically acceptable excipients, optionally, comprising a step of adding desired flavoring agents to mask the taste and packed in appropriate PET bottles.
The stable oral pharmaceutical composition of magnesium hydroxide, liquid paraffin and sodium picosulfate according to present invention may be useful in for the treatment of various bowel movement disorder e.g. constipation.
Various other specific aspects of the invention are further detailed in the description part of the specification, wherever appropriate.
DETAILED DESCRIPTION
The present invention provided the stable oral pharmaceutical composition comprising of magnesium hydroxide, liquid paraffin and sodium picosulfate useful in the treatment of bowel movement disorder.
In one embodiment according to the present invention, it provides a stable oral pharmaceutical composition comprising 3-8% w/v of magnesium hydroxide, 15-40% v/v of liquid paraffin and 0.01-1.0% w/v of sodium picosulfate, wherein the composition contains 01-05% w/v of colloidal anhydrous silica as stabilizing agent and 1-4% w/v of non-ionic surfactant.
Magnesium hydroxide suspension is widely known as an antacid or laxative in the form of milk of magnesia in the pharmaceutical industry. Magnesium hydroxide is used for a short time to treat occasional constipation. It is a laxative (osmotic-type) that is thought to work by drawing water into the intestines, an effect that helps to cause movement of the intestines. Magnesium hydroxide is further treat to prepare milk of magnesia which use to treat symptoms caused by too much stomach acid such as heartburn, upset stomach, or indigestion. It is an antacid that works by lowering the amount of acid in the stomach.
Magnesium hydroxide is insoluble in water and it is best known as the suspension “Milk of Magnesia” which contains 7 to 8.5% w/v of the compound. One gram of magnesium hydroxide neutralizes 32.6mEq of gastric acid and 1ml of milk of magnesia will neutralize approximately 2.7mEq of acid also 1gm of Magnesium oxide neutralizes approximately 87ml of 0.1 N HCl in 10 Minutes. The recommended dose of milk of magnesia is 5 to 15ml, and 300 to 600mg in tablet form but the solid oral dosage form requires time to show its responses.
Magnesium oxide (MgO) is converted to magnesium hydroxide in the presence of water. Magnesium oxide is present in light and heavy form. Most preferably Milk of magnesia is 6% aqueous suspension of Magnesium hydroxide in which made up of light Magnesium Oxide.
Sodium picosulfate is a prodrug. It is hydrolyzed by bacteria in the colon to the active metabolite 4,4'-dihydroxydiphenyl-(2-pyridyl)methane. Sodium picosulfate is the class stimulant laxative which speed up the movement of your bowels by stimulating the nerves that control the muscles lining your digestive tract. Its acts as laxative which has a dual action of stimulating the mucosa of both the large intestine causing colonic peristalsis and of the rectum causing increased motility and a feeling of rectal fullness.
Commercially available picosulphate laxatives are designed to deliver the picosulphate to the small intestine. Although these dose forms provide effective laxative activity, doses which produce maximal laxation also evoke undesirable side effects such as secondary episodes of diarrhea or repeat bowel movements. Although there was a need to develop such a combination of different class of laxative which capable to deliver the best action and balance the peristalsis movement. Using Sodium Picosulfate tend to alter the laxation benefits without secondary diarrhea commonly associated with conventional picosulphate compositions.
An advantage of the present invention where the sodium picosulphate along with other actives when dispensed in the finished form, it tends to achieve the better appearance, settling rates and stability with respect to earlier reported dosage forms.
Liquid paraffin or mineral oil is a transparent, colourless, odourless, or almost odourless, oily liquid composed of saturated hydrocarbons obtained from petroleum. The use of liquid paraffin introduces with the effort of after W. Arbuthnot Lane, Chief Surgeon of Guy’s Hospital in 1913, recommended its use as a treatment for intestinal stasis and chronic constipation. The popularity of liquid paraffin as a treatment for constipation and encopresis stems primarily from its tolerability and ease of titration.
Conversion of mineral oil to hydroxy fatty acids induces an osmotic effect, liquid paraffin appears to work primarily as a stool lubricant. Mechanism based conversion allowed paraffin particularly attractive for use in chronic constipation and encopresis of childhood, where large doses and prolonged administration commonly are necessary during the disimpaction and maintenance phases of treatment, respectively.
The combination of liquid paraffin, magnesium hydroxide and sodium picosulphate in an appropriate ratio has been approved in India on Jan 2009 for symptomatic treatment of constipation in adults. Thus, in view of the high demand for the combination desired to improve as finished dosage form for the appropriate indication and the as per the nature of the compatible excipients. There is a further need to optimize the stable oral pharmaceutical dosage forms comprising liquid paraffin, magnesium hydroxide and sodium picosulphate so that it is convenient to manufacture, administer, and simultaneously provide the requisite daily required dosage of liquid paraffin, magnesium hydroxide and sodium picosulphate for the patient sufferings.
It is also required that the liquid pharmaceutical compositions exhibit stability upon storage, as this is essential to ensure an adequate shelf life of the final dosage form. Further there is an apparent need to develop an optimized stable oral pharmaceutical compositions that contains an approved ratio of liquid paraffin, magnesium hydroxide and sodium picosulphate also exhibits stability throughout the shelf life with overcome from some limitation like settling, sedimentation, creaming, cracking, phase separation, phase inversion etc. reported in marketed form of such products.
The present invention particularly provides a stable oral pharmaceutical compositions of liquid paraffin, magnesium hydroxide and sodium picosulphate wherein magnesium hydroxide is further treated to prepare milk of magnesia. The active pharmaceutical ingredient (API) in the composition of stable oral pharmaceutical compositions according to present invention may be liquid paraffin, milk of magnesia and sodium picosulphate.
In one of the specific embodiment, liquid paraffin, milk of magnesia and sodium picosulphate as active material was utilized.
The invention provides that the stable oral pharmaceutical composition comprising stabilizing agent wherein stabilizing agent is selected from fatty acid ester e.g. glyceryl monostearate, glyceryl monostearate, PEG 7 glyceryl cocoate, glycol stearate, glycol distearate, other fractionated lecithin e.g. lecithin, hydrogenated lecithin, surfactants e.g. sodium cocoyl glycinate, sodium dodecyl sulphate, dodecylhexaoxyethylene glycol ether, oil derivatives e.g. 12-hydroxy stearic acid, hydrogenated castor oil, fatty alcohol e.g. cetyl alcohol, ceto stearyl alcohol, behenyl alcohol, fatty acids e.g. lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid , sodium alginate, agar, carboxymethylcellulose sodium, colloidal anhydrous silica, xanthan gum, carrageenan, glyceryl monostearate.
In a specific embodiment according to present invention the stabilizing agent used in the liquid pharmaceutical composition was colloidal anhydrous silica.
The present invention also provides the stable oral pharmaceutical composition comprising surfactant wherein surfactant is selected from acacia, carbomer copolymer, carbomer interpolymer, cholesterol, coconut oil, diethylene glycol stearates, ethylene glycol stearates, glyceryl distearate, glyceryl monolinoleate, glyceryl monooleate, glyceryl monostearate, lanolin alcohols, lecithin, mono- and di-glycerides, poloxamer, polyoxyethylene 50 stearate, polyoxyl 10 oleyl-ether, polyoxyl 20 cetostearyl ether, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, polyoxyl lauryl ether, polyoxyl stearyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (tween 80), propylene glycol monostearate, sorbitan monooleate (span 80), sodium cetostearyl sulfate, sodium lauryl sulfate, sodium stearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, stearic acid.
The pharmaceutical composition of liquid paraffin, magnesium hydroxide and sodium picosulphate comprising the addition of surfactant distributed in preparation of aqueous phase or oil phase or both phases of composition.
In one of the embodiments embodiment according to present invention, it provides a stable oral pharmaceutical composition wherein non-ionic surfactant comprising sorbitan monooleate (span 80) or polysorbate 80 (tween 80) or mixture thereof.
Inventors of the present invention successfully optimized the ratio of surfactants particularly addition of tween 80 and span 80 during preparation of aqueous and oil both phases.
The available marketed products having such combination of actives specially in the form of bi-phasic liquid dosage form, particularly suspension facing the issues like settling, caking, discoloration, sedimentation and separation of layers. The motivation behind the present invention introduces with a stable bi-phasic liquid pharmaceutical composition which is physically stable particularly in the form of o/w emulsion without any separation issues between solid, aqueous and oil phases to make it uniform. Although it is recommended prior to use the said composition as “Shake Well Before Use”.
The invention, provides a process for preparing stable oral pharmaceutical composition comprising magnesium hydroxide, liquid paraffin and sodium picosulfate, the process particularly comprises preparation of milk of magnesia slurry from magnesium hydroxide using suitable mill. e.g. high pressure homogenizer or colloidal mills, followed by preparing aqueous phase and oil phase separately.
In yet another embodiment of the present invention, it provides to a process of preparing stable oral pharmaceutical composition of magnesium hydroxide, liquid paraffin and sodium picosulfate wherein the process comprising the steps of:
i) preparation of milk of magnesia by mixing purified water, sorbitol solution and magnesium hydroxide at the temperature ranges between 60-70°C.
ii) process the liquid in colloidal mill for time duration ranging between 15 to 45 min.
iii) cooling the processed liquid of step (ii) up to temperature ranging between 20-40°C.
iv) adding preservative and taste masking agent in solution.
v) combining sodium picosulfate in to the liquid.
vi) optionally adding coloring agent to the above solution.
vii) mixing colloidal anhydrous silica (aerosil) for the time duration ranging between 15-45 min.
viii) adding 30-50% of non-ionic surfactant in to above step during stirring.
ix) mixing liquid paraffin and 35-35% of non-ionic surfactant followed by stirring
x) adding the mixture of step (ix) in to the material prepared in step (viii).
xi) adding remaining surfactant in above step followed by stirring.
The step i) of preparing slurry of milk of magnesia according to the present invention carried out by mixing purified water in to sorbitol solution 70%-80% and heated for the temperature ranges between 60-70°C by addition of magnesium hydroxide.
The step ii) of preparing slurry of milk of magnesia according to the present invention, the resultant prepare slurry transferred in colloidal mill and processed for 45-60 min.
The step iii) of preparing slurry of milk of magnesia, the colloidal processed material resulting for increase in temperature. It is preferred to cooled it for the temperature ranges between 35-40° C and shifting the material in a mixer tank for further processing.
It is required that the stable oral pharmaceutical composition of the present invention provide adequate self-life for long term desired activity. For the preservation of stable pharmaceutical composition preparing in present invention wherein preservative selected from Benzalkonium Chloride, Benzalkonium Chloride Solution, Benzethonium Chloride, Benzoic Acid, Benzyl Alcohol, Butylparaben, Cetrimonium Bromide, Cetylpyridinium Chloride, Chlorobutanol, Chlorocresol, Cresol, Ethylparaben, Methylparaben, Methylparaben Sodium, Phenol, Phenoxyethanol, Phenylethyl Alcohol, Phenylmercuric Acetate, Phenylmercuric Nitrate, Potassium Benzoate, Potassium Sorbate, Propylparaben, Propylparaben Sodium, Sodium Benzoate, Sodium Dehydroacetate, Sodium Propionate, Sorbic Acid, Thimerosal, Thymol.
In specific embodiments according to the present invention wherein preservative used for preparing stable oral pharmaceutical composition are Sodium Benzoate, Methylparaben Sodium, Propylparaben Sodium alone or in combination.
In particular embodiments according to the present invention wherein preservative used for preparing stable oral pharmaceutical composition are Sodium Benzoate, Methylparaben Sodium, Propylparaben Sodium used in combination having a specific ratio of 0.5:0.3:0.4-1.
The step iv) of adding preservative and taste masking agent according to the present invention carried out by continue mixing for 10-20 min.
The step v) of adding sodium picosulfate according to the present invention, carried out for 10-20 min by continue mixing.
The step vi) of adding coloring agent according to the present invention.
Mixing step vii) according to the present invention carried out with anhydrous silica (aerosil) in to the solution for 30-40 min. As advantage of adding, inventors of the present application found that this kind of step has satisfactory outcome and betterment of further step and alter the physical stability of the formulation.
Addition of 30-50% of surfactant step viii) according to the present invention carried out with tween 80 with continue stirring for 5-10 min.
Preparing liquid paraffin and 35-35% of surfactant e.g. span 80 separately step ix) according to the present invention carried out for 10-15 min.
Addition of step viii) and step ix) according to the present invention carried out in step x) for 30-40 min.
Adding surfactant tween 80 step xi) according to the present invention carried out by continue stirring for 5-15 min in mixture tank. However, inventors found that separate addition of surfactant at different steps gives better HLB value and provide adequate stability to formulation.
Inventors of the present application additionally found the advantage of addition of surfactant which upon addition separately in aqueous and oil phase give the improved HLB value and change the viscosity of the pharmaceutical composition while transferred the prepared composition in to PET boltless.
In yet different embodiments of the present invention, it relates to a process of preparing stable oral pharmaceutical composition of magnesium hydroxide, liquid paraffin and sodium picosulfate wherein the process comprising the steps of:
i) preparation of milk of magnesia by mixing purified water, sorbitol solution and magnesium hydroxide at the temperature ranges between 60-70°C.
ii) process the liquid in colloidal mill for time duration ranging between 05 to 35 min.
iii) adding the preservative and chelating agent with sweetener on aqueous phase at the temperature ranging of 70-90°C.
iv) optionally adding coloring agent to the above solution.
v) adding thickening agent in to above solution by continue stirring for the time duration ranges 10-30min.
vi) mixing liquid paraffin and 35-35% of non-ionic surfactant followed by stirring
vii) adding the mixture of step (v) in to the material prepared in step (vi)
viii) mixing colloidal anhydrous silica (aerosil) for the time duration ranging between 15-45 min.
ix) combining sodium picosulfate at the temperature ranges 25-45°C.
The step i) of preparing slurry of milk of magnesia according to the present invention carried out by mixing purified water in to sorbitol solution 70%-80% and heated for the temperature ranges between 60-70°C by addition of magnesium hydroxide.
The step ii) of preparing slurry of milk of magnesia according to the present invention, the resultant prepare slurry transferred in colloidal mill and processed for 05-35 min.
Preparing slurry of milk of magnesia as per step ii), the colloidal processed material resulting for increase in temperature. It is preferred to maintain the temperature ranges between 55-75° C and shifting the material in a mixer tank for further processing. The inventors of the present invention optimized temperature as one of the critical parameter for increase the stability of the composition.
Preparing the aqueous phase as per step iii) by adding the preservative and chelating agent with sweetener at the temperature ranging of 70-90°C by continue stirring for the time ranges between 05-35 minutes.
The inventors found addition of chelating agent is useful to reduced or prevented droplet aggregation while preparing the emulsion. The advantage of using chelating agent in present invention is observed as reduction of droplet aggregation which results in decreases the particle size, shear-thinning behavior, apparent viscosity, and creaming behavior of composition. Chelating agent used in preparing stable oral pharmaceutical composition of the present invention is selected from Nitrilotriacetic acid, Pentetic acid or ethylenediaminetetraacetic acid (EDTA).
In a specific embodiment according to present invention the chelating agent used in the pharmaceutical composition was EDTA.
The step iv) of adding coloring agent according to the present invention.
Improve the viscosity of preparing solution as per step v) by adding thickening agent by continue stirring. The thickening agent used as per present invention is pre-socked with glycerol.
The thickening agent used in present invention is Xanthum Gum (Novaxa & Alvol).
Preparing the oil phase as per step vi) by using liquid paraffin and non-ionic surfactant with continue stirring.
Preparing the emulsion phase by addition of prepared aqueous phase into the oil phase as per step vii).
Mixing a per step viii) according to the present invention carried out with anhydrous silica (aerosil) in to the solution for 30-40 min. As advantage of adding, inventors of the present application found that this kind of step has satisfactory outcome and betterment of further step and alter the physical stability of the composition.
Addition of sodium picosulfate as per step ix) is carried out by continue stirring at the temperature ranges between 25-45°C.
It has been observed by present inventors that various composition available in market suffer a disadvantage of either not meeting physical parameters or non-uniform multilayers, appearance which may results as phase separation, caking, creaming, phase seperation or the like.
The inventors of the present invention of stable oral pharmaceutical composition of liquid paraffin, magnesium hydroxide and sodium picosulphate gives the advantages over aforementioned difficulties of composition when introduces in market. The prepared composition of the present invention is capable to deliver the medication consistently without affecting the physical properties of the liquid composition.
Present invention provides the patient compliance, easy to use liquid composition with taste masking adjuvant which allowing the stable oral composition to ingest orally without any bitterness or unpleasant characteristics.
Inventors of the present invention also used flavoring agents optionally to enhance the taste of the composition. Addition of flavors according to the present invention carried out using alone or in combination of cardamom or mint, most probably both.
The term "stable oral composition" or " stable pharmaceutical composition "comprises suspension, emulsion (flocculated, deflocculated suspension, W/O emulsion, O/W emulsion, W/O/W emulsion, O/W/O emulsion).
The term "about" is a value that can be considered ±5% of the given value.
Based on context of discussion, the term “% w/v” refers to the relative value to total weight of liquid base or to total weight of pharmaceutical composition and “% v/v” refer to volume by total volume percentage.
In one of embodiments, the application provides stable oral pharmaceutical composition of liquid paraffin, magnesium hydroxide and sodium picosulphate having assay under the limits as per Indian Pharmacopoeia, British Pharmacopoeia with pH value of not more than 09. In embodiments, the invention relates to stable liquid pharmaceutical composition having the viscosity of 105-115 cP using 50rpm (spindle size 61) at room temperature. In embodiments, the invention relates to stable oral pharmaceutical composition having density not more than about 1.1gm/ml.
Usage of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to, not more than, In between") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The term wt % refers to percent by weight. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g. "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
Particular embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those particular embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in best possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.
EXAMPLES
Example 01: Liquid Composition of liquid paraffin, magnesium hydroxide and sodium picosulphate
Ingredients Quantity
(mg/ml, ml/ml)
Trial -01 Trial -02 Trial -03 Trial -04
Magnesium Hydroxide IP 63.898 63.898 63.898 63.898
Liquid paraffin IP 0.250 0.250 0.250 0.250
Sodium Picosulfate BP* 0.710 0.710 0.710 0.710
Sodium Benzoate BP 4.000 4.000 4.000 4.000
Sod. Methyl paraben BP 2.000 2.000 2.000 2.000
Sod. Propyl paraben BP 0.300 0.300 0.300 0.300
Saccharin sod. BP 0.300 0.300 0.300 0.300
Span 80 10.560 10.560 10.560 10.560
Tween- 80 BP 14.48 14.48 14.48 21.98
Aerosil BP 5.000 10.000 15.000 15.000
Sorbitol Solution (70%) (Non-Crystallising ) IP 200.000 200.000 200.000 200.000
Cardamom Flaour(Liq.) 0.0045 0.0045 0.0045 0.0045
Col. Carmoisine supra 0.050 0.050 0.050 0.050
Col. Ponceau 4R supra 0.025 0.025 0.025 0.025
Cool mint Flavour (Liq.) 0.0045 0.0045 0.0045 0.0045
Purified water 0.537 0.537 0.537 0.537

Manufacturing process of liquid paraffin, magnesium hydroxide and sodium picosulphate liquid composition:
Step A: Preparation of milk of magnesia:
i) preparation of milk of magnesia by mixing purified water, sorbitol solution and magnesium hydroxide at the temperature ranges between 60-70°C.
ii) process the liquid in colloidal mill for time duration ranging between 15 to 45 min.
iii) cooling the processed liquid of step (ii) up to temperature ranging between 20-40°C.
Step-B: Preparation of aqueous phase
i) combining sodium picosulfate in to the liquid.
ii) optionally adding coloring agent to the above solution.
iii) mixing colloidal anhydrous silica (aerosil) for the time duration ranging between 15-45 min.
iv) adding 30-50% of non-ionic surfactant in to above step during stirring.
Step-C: Preparation of oil phase:
i) mixing liquid paraffin and 35-35% of non-ionic surfactant followed by stirring
Step-D: Preparation of emulsion phase
i) adding the mixture of step (b) in to the material prepared in step (c).
ii) adding remaining surfactant in above step followed by stirring.
iii) adding Cool mint flavor and cardamom flavor with continuous stir and mixed for 20-30 minutes in mixture tank at 400rpm.
Example 02:
Ingredients Quantity
(mg/ml, ml/ml)
Trial -05
Magnesium Hydroxide IP 63.898
Liquid paraffin IP 0.250
Sodium Picosulfate BP* 0.710
Sodium Benzoate BP 4.000
Sod. Methyl paraben BP 2.000
Sod. Propyl paraben BP 0.300
Saccharin sod. BP 0.300
Disodium edetate 10.560
Tween- 80 BP 21.98
Aerosil BP 3.000
Glycerol BP 30.000
Sorbitol Solution (70%) (Non-Crystallising ) IP 200.000
Xanthum Gum (Alvol) 0.714
Xanthum Gum (Novaxan) 1.250
Cardamom Flaour (Liq.) 0.0045
Col. Brilliant blue supra 0.009
Col. Tartrazine supra 0.046
Cool mint Flavour (Liq.) 0.0045
Purified water 0.537

Trial 05: Manufacturing process of liquid paraffin, magnesium hydroxide and sodium picosulphate liquid composition:
Step A: Preparation of milk of magnesia:
i) preparation of milk of magnesia by mixing purified water, sorbitol solution and magnesium hydroxide at the temperature ranges between 60-70°C.
ii) process the liquid in colloidal mill for time duration ranging between 05 to 35 min.
Step-B: Preparation of aqueous phase
i) adding preservative and chelating agent with sweetener in aqueous phase at the temperature ranging between 80-90°C
ii) optionally adding coloring agent to the above solution by continue stirring for 15-30 min.
iii) adding thickening agent (pre-socked) in to above step during stirring.
Step-C: Preparation of oil phase:
i) mixing liquid paraffin and 35-35% of non-ionic surfactant followed by stirring
Step-D: Preparation of emulsion phase
i) adding the mixture of step (A) (iii) in to the material prepared in step (C) (i) by continue stirring.
ii) adding stabilizer to above phase at the temperature ranges between 30-50°C.
iii) combining sodium picosulfate at the temperature below 40°C
iv) adding Cool mint flavor and cardamom flavor with continuous stir and mixed for 10-30 minutes in mixture tank at 400rpm.
Final product cooled at room temperature and packed in glass or PET bottle with metal caps or plastic rigid container (jar) made of HDPE with slowly mixing.
Emulsion prepared as in Example 01 of Trail 04 is packaged by slowly mixing in closed glass or PET bottle with metal caps or plastic rigid container (jar) made of HDPE and stored at three different conditions: 25°C and 60% relative humidity (Condition 1), 30°C and 75% RH (Condition 2) or 40°C and 75% RH (Condition 3) for one adequate time.
Trial -01: During experiment it was observed that phase separation occurred within hour.
Trial -02: During experiment it was observed that phase separation occurred within 4 hours.
Trial-03: During experiment it was observed that phase separation occurred within 10 days.
Trial-04: During experiment it was observed that finished formulation is stable.
Trial 05: During experiment it was observed that finished formulation is more stable.
The abovementioned examples, which are provided by way of illustration, should not be construed as limiting the scope of the invention with respect to parameter/s, ingredient/s and quantities used in any manner.
,CLAIMS:We Claims:
1. A stable oral pharmaceutical composition comprising 3-8% w/v of magnesium hydroxide, 15-40% v/v of liquid paraffin and 0.01-1.0% w/v of sodium picosulfate, wherein the composition contains 01-05% w/v of colloidal anhydrous silica as stabilizing agent and 1-4% w/v of non-ionic surfactant.
2. A stable oral pharmaceutical composition according to claim 1 wherein non-ionic surfactant comprising sorbitan monooleate (span 80) or polysorbate 80 (tween 80) or mixture thereof.
3. A process for preparing stable oral pharmaceutical composition according to the claim 1 wherein stable oral pharmaceutical composition is an emulsion or suspension.
4. A process of preparing stable oral pharmaceutical composition of magnesium hydroxide, liquid paraffin and sodium picosulfate, wherein the process comprising the steps of:
i) preparation of milk of magnesia by mixing purified water, sorbitol solution and magnesium hydroxide at the temperature ranges between 60-70°C.
ii) process the liquid in colloidal mill for time duration ranging between 15 to 45 min.
iii) cooling the processed liquid of step (ii) up to temperature ranging between 20-40°C.
iv) adding preservative and taste masking agent in solution.
v) combining sodium picosulfate in to the liquid.
vi) optionally adding coloring agent to the above solution.
vii) mixing colloidal anhydrous silica (aerosil) for the time duration ranging between 15-45 min.
viii) adding 30-50% of non-ionic surfactant in to above step during stirring.
ix) mixing liquid paraffin and 35-35% of non-ionic surfactant followed by stirring
x) adding the mixture of step (ix) in to the material prepared in step (viii).
xi) adding remaining surfactant in above step followed by stirring.
xii) optionally adding flavoring agent with continue stirring for 10-60 min.
5. A process for preparing the stable liquid pharmaceutical composition according to the claim 4, where ratio of sorbitan monooleate (span 80) and polysorbate 80 (tween 80) is 1-3:1
6. A stable oral pharmaceutical composition comprising 4-7% w/v of magnesium hydroxide, 22-27% v/v of liquid paraffin and 0.01-0.5% w/v of sodium picosulfate, wherein the composition contains 01-2.5% w/v of colloidal anhydrous silica, 2-4% w/v of sorbitan monooleate (span 80) and polysorbate 80 (tween 80).
7. A stable oral pharmaceutical composition according to claim 6 wherein preservative used are sodium benzoate, methylparaben sodium and propylparaben sodium alone or in combination.
8. A stable oral pharmaceutical composition according to claim 6 wherein preservative used are sodium benzoate, methylparaben sodium and propylparaben sodium in combination having the ratio of 0.4:0.2:0.3-1.
9. A process of preparing stable oral pharmaceutical composition of magnesium hydroxide, liquid paraffin and sodium picosulfate, wherein the process comprising the steps of:
i) preparation of milk of magnesia by mixing purified water, sorbitol solution and magnesium hydroxide at the temperature ranges between 60-70°C.
ii) process the liquid in colloidal mill for time duration ranging between 05 to 35 min.
iii) adding the preservative and chelating agent with sweetener on aqueous phase at the temperature ranging of 70-90°C.
iv) optionally adding coloring agent to the above solution.
v) adding thickening agent in to above solution by continue stirring for the time duration ranges 10-30min.
vi) mixing liquid paraffin and 35-35% of non-ionic surfactant followed by stirring
vii) adding the mixture of step (v) in to the material prepared in step (vi)
viii) mixing colloidal anhydrous silica (aerosil) for the time duration ranging between 15-45 min.
ix) combining sodium picosulfate at the temperature ranges 25-45°C.
x) optionally adding flavoring agent with continue stirring for 10-60 min.
10. A process for preparing the stable liquid pharmaceutical composition according to the claim 9, where the chelating agent and thickening agent is Disodium edetate and Xanthum Gum.