GB2561355A - Pharmaceutical composition and a method for manufacturing the same - Google Patents

Pharmaceutical composition and a method for manufacturing the same Download PDF

Info

Publication number
GB2561355A
GB2561355A GB1705745.6A GB201705745A GB2561355A GB 2561355 A GB2561355 A GB 2561355A GB 201705745 A GB201705745 A GB 201705745A GB 2561355 A GB2561355 A GB 2561355A
Authority
GB
United Kingdom
Prior art keywords
vehicle
pharmaceutical composition
polyol
buffer
present
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
GB1705745.6A
Other versions
GB201705745D0 (en
Inventor
Ur Rehman Mahboob
Ahmad Waseem
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eaststone Ltd
Original Assignee
Eaststone Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eaststone Ltd filed Critical Eaststone Ltd
Priority to GB1705745.6A priority Critical patent/GB2561355A/en
Publication of GB201705745D0 publication Critical patent/GB201705745D0/en
Priority to GB1805951.9A priority patent/GB2564515B/en
Publication of GB2561355A publication Critical patent/GB2561355A/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/08—Solutions
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A vehicle for an active pharmaceutical ingredient is disclosed, wherein the vehicle comprises a viscosity enhancing component, a wetting agent, a pH buffer and a polyol. A pharmaceutical composition is also disclosed, comprising the vehicle and an active pharmaceutical ingredient, such as omeprazole. Furthermore, a method of manufacturing the same comprises the steps of mixing a viscosity enhancing component with a wetting agent to form a mixture and adding a pH buffer and a polyol to the mixture to form a vehicle. The vehicle can be mixed with an active pharmaceutical ingredient. The viscosity enhancing agent may be an alkali metal carboxymethyl cellulose, preferably sodium carboxymethyl cellulose. The wetting agent may be sorbitol, glycerine, a polysorbate or preferably propylene glycol. The pH buffer may be calcium bicarbonate, magnesium bicarbonate, calcium carbonate or preferably sodium bicarbonate. The polyol may be a sugar alcohol. Suitable sugar alcohols include sorbitol, mannitol, xylitol or preferably maltitol. The composition has an improved shelf-life.

Description

(54) Title of the Invention: Pharmaceutical composition and a method for manufacturing the same Abstract Title: A vehicle for an active pharmaceutical ingredient (57) A vehicle for an active pharmaceutical ingredient is disclosed, wherein the vehicle comprises a viscosity enhancing component, a wetting agent, a pH buffer and a polyol. A pharmaceutical composition is also disclosed, comprising the vehicle and an active pharmaceutical ingredient, such as omeprazole. Furthermore, a method of manufacturing the same comprises the steps of mixing a viscosity enhancing component with a wetting agent to form a mixture and adding a pH buffer and a polyol to the mixture to form a vehicle. The vehicle can be mixed with an active pharmaceutical ingredient. The viscosity enhancing agent may be an alkali metal carboxymethyl cellulose, preferably sodium carboxymethyl cellulose. The wetting agent may be sorbitol, glycerine, a polysorbate or preferably propylene glycol. The pH buffer may be calcium bicarbonate, magnesium bicarbonate, calcium carbonate or preferably sodium bicarbonate. The polyol may be a sugar alcohol. Suitable sugar alcohols include sorbitol, mannitol, xylitol or preferably maltitol. The composition has an improved shelf-life.
PHARMACEUTICAL COMPOSITION AND A METHOD FOR MANUFACTURING THE SAME
Technical Field
The present invention relates to a pharmaceutical composition and, more specifically, to a pharmaceutical composition comprising omeprazole that has an improved shelf-life and a method for manufacturing the same.
Background
Omeprazole is a proton pump inhibitor that is able to decrease the amount of acid produced in the stomach. It has therapeutic application in treating conditions such as the symptoms of gastroesophageal reflux disease (GERD) and other conditions caused by excess stomach acid. It can also be used to assist in the healing of erosive esophagitis, treatment of peptic ulcer disease and
Zollinger-Ellison syndrome.
Omeprazole is prone to degradation, particularly hydrolytic degradation. The process of degradation has a significant impact on the shelf-life of omeprazole formulations. In some instances, omeprazole formulations have a short shelf-life of only a few days.
It is therefore an object of the present invention to provide a composition comprising omeprazole as an active pharmaceutical ingredient that has an extended shelf-life as compared to existing omeprazole containing compositions.
The present invention has been devised with the aforementioned problems in mind.
Summary of the Invention
According to a first aspect of the present invention, there is provided a vehicle for an active pharmaceutical ingredient, the vehicle comprising a viscosity enhancing component, a wetting agent, a pH buffer and a polyol.
The vehicle may be mixed with an active pharmaceutical ingredient. The active pharmaceutical ingredient typically comprises omeprazole.
According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a vehicle as described herein and an active pharmaceutical ingredient.
The vehicle of the present invention has been found to increase the shelf-life of an active pharmaceutical ingredient. The pharmaceutical composition of the present invention has been found in testing to have a shelf-life of up to around 6 months or more, up to around 12 months or more and, in some instances, up to around 24 months or more. This is significantly longer than the shelf-life of existing pharmaceutical compositions containing omeprazole, which can be as short as a few days. Thus, beneficially, compositions of the present invention can be stored for use for a greater length of time than compositions currently known, resulting in reduced waste and manufacturing costs.
According to a further aspect of the present invention, there is provided a method of manufacturing a vehicle, the method comprising the steps of:
(a) mixing a viscosity enhancing component with a wetting agent to form a mixture; and (b) adding a pH buffer and a polyol to the mixture.
According to a further aspect of the present invention, there is provided a method of manufacturing a pharmaceutical composition, the method comprising the step of mixing a vehicle as described herein with an active pharmaceutical ingredient. The active pharmaceutical ingredient may be omeprazole.
According to a further aspect of the present invention, there is provided a pharmaceutical composition as described herein for use in therapy.
According to a further aspect of the present invention, there is provided a pharmaceutical composition as described herein for use in the treatment of duodenal ulcers including duodenal ulcers caused by /7.
pylori, gastric ulcers, NSAID-associated gastric and duodenal ulcers, peptic ulcer disease, reflux oesophagitis, Zollinger-Ellison syndrome, gastro-oesophagitis reflux disease including heartburn and acid regurgitation in gastro-oesophageal reflux disease.
According to a further aspect of the present invention, there is provided a pharmaceutical composition as described herein for use in the prevention of relapse of duodenal ulcers and relapse of gastric ulcers, including NSAID-associated gastric and duodenal ulcers; and in the management of patients with healed reflux oesophagitis.
According to a further aspect of the present invention, there is provided a vehicle as described herein for use in the manufacture of a medicament. Further, the invention also provides a vehicle for use in the manufacture of a medicament for the treatment of duodenal ulcers including duodenal ulcers caused by /7. pylori, gastric ulcers, NSAID-associated gastric and duodenal ulcers, peptic ulcer disease, reflux oesophagitis, Zollinger-Ellison syndrome, gastro-oesophagitis reflux disease including heartburn and acid regurgitation in gastro-oesophageal reflux disease. According to a further aspect of the present invention, there is provided a use of a vehicle as described herein in the manufacture of a medicament. Further, the invention also provides a use of a vehicle in the manufacture of a medicament for the treatment of duodenal ulcers including duodenal ulcers caused by /7. pylori, gastric ulcers,
NSAID-associated gastric and duodenal ulcers, peptic ulcer disease, reflux oesophagitis, ZollingerEllison syndrome, gastro-oesophagitis reflux disease including heartburn and acid regurgitation in gastro-oesophageal reflux disease
According to a further aspect of the present invention, there is provided a method for the treatment of duodenal ulcers including duodenal ulcers caused by /7. pylori, gastric ulcers, NSAID-associated gastric and duodenal ulcers, peptic ulcer disease, reflux oesophagitis, Zollinger-Ellison syndrome, gastro25 oesophagitis reflux disease including heartburn and acid regurgitation in gastro-oesophageal reflux disease, comprising the steps of administering to a mammal a pharmaceutical composition as described herein. Further, the invention also provides a use of a pharmaceutical composition as described herein for the treatment of duodenal ulcers including duodenal ulcers caused by /7. pylori, gastric ulcers,
NSAID-associated gastric and duodenal ulcers, peptic ulcer disease, reflux oesophagitis, Zollinger4
Ellison syndrome, gastro-oesophagitis reflux disease including heartburn and acid regurgitation in gastro-oesophageal reflux disease.
Reference to the treatment of duodenal ulcers caused by /7. pylori may include a combination of a pharmaceutical composition or vehicle as described herein in combination with one or more antibiotics.
Detailed description of the invention
Unless defined otherwise in this specification, all technical and scientific terms are used herein according to their conventional definitions.
The active pharmaceutical ingredient omeprazole is prone to hydrolytic degradation, that is the cleaving of chemical bonds by the addition of water. This has the effect of reducing the length of time for which omeprazole remains usable, fit for use and/or fit for sale, referred to herein as ‘shelf-life’.
It has been discovered that a vehicle comprising a viscosity enhancing component, a wetting agent, a pH buffer and a polyol has the advantageous effect of increasing the shelf-life of the active pharmaceutical ingredient omeprazole.
It has been found that lowering the water content of the vehicle, lowering the dielectric constant of the vehicle and adjusting the pH of the vehicle have the effect of lowering the degradation rate of the active pharmaceutical ingredient and, consequently, extending the shelf-life.
The vehicle may be in the form of a liquid, typically a solution or suspension. The vehicle is preferably in the form of a homogenised solution or suspension.
The vehicle may have a pH of at least 8. It has been found that omeprazole formulations exhibit improved stability at higher pH. For example, omeprazole exhibits good stability at pH 11 and can be prone to decomposition below pH 7.8. Typically, the pH of the vehicle is in the range of 8 to 11, more preferably 8 to 9.
The vehicle comprises a viscosity enhancing component. It has been found that increasing the viscosity of the vehicle can have the effect of decreasing the rate of degradation of an active pharmaceutical ingredient. Increasing the viscosity of the vehicle has also been shown to have a preservative effect on the active pharmaceutical ingredient.
The viscosity enhancing component may be an alkali metal cellulose derivative, such as an alkali metal carboxymethyl cellulose. The alkali metal may be sodium or calcium, preferably sodium. Thus, the viscosity enhancing component may be sodium carboxymethyl cellulose.
The viscosity enhancing component may be in the form of a solid, e.g. particulate, granular, powder, flake. Preferably, the viscosity enhancing component is in the form of a powder.
The viscosity enhancing component may be present in an amount of from 0.3 to 0.6% v/v of the vehicle. Good results have been observed with a viscosity enhancing component in an amount of 0.4% v/v of the vehicle. The viscosity enhancing component may have a strength of around 500mps 600mps.
The vehicle comprises a wetting agent. The wetting agent may comprise a component that is capable of reducing the dielectric constant of the vehicle and/or act as a preservative. The wetting agent may be selected from one or more of the group consisting of propylene glycol, sorbitol, glycerine and polysorbates. Preferably, the wetting agent is propylene glycol.
Propylene glycol is typically used in the form of a liquid and has the dual effect of functioning as a wetting agent and a preservative, whilst also reducing the dielectric constant of the vehicle. The dielectric constant value of propylene glycol is 32.1 at 20°C.
The wetting agent may be present in an amount of from 2 to 10% v/v of the vehicle. Good results have been observed with a wetting agent, such as propylene glycol, present in an amount of 2.5% v/v.
In preparing the vehicle, the viscosity enhancing component and the wetting agent may be mixed together to form a homogenous mixture. The alkali metal carbonate and the polyol may be added to the homogenous mixture.
An important factor in the preparation of the vehicle is the reduction of the dielectric constant, as it has been found that a lower dielectric constant can improve the shelf-life of the active pharmaceutical ingredient in the pharmaceutical composition. For example, lowering the dielectric constant value improved the shelf life of omeprazole. Without wishing to be bound by theory, it is believed that, in some instances, the rate of a chemical reaction is dependent on the dielectric constant value of the environment. By lowering the dielectric constant value of the environment, it is possible to decrease the rate of hydrolytic degradation and hence improve the shelf life. Water has a dielectric constant of over
80. Preferably, the dielectric constant of the vehicle of the present invention is less than 80.
The vehicle of the present invention comprises a polyol. The polyol serves to reduce the dielectric constant of the vehicle by acting as a substitute for a volume of the water present in the vehicle. Typically, the vehicle has a water content of around 45%. Further, together with the viscosity enhancing component, the polyol acts to further increase the viscosity of the vehicle.
The polyol may be a sugar alcohol. Suitable sugar alcohols include maltitol, sorbitol, mannitol and xylitol.
Preferably, the polyol is maltitol. The maltitol may be in the form of a liquid.
The polyol may be present in an amount of from 40 to 60% v/v of the vehicle. Good results have been observed with a polyol present in an amount of around 50% v/v.
The vehicle of the present invention comprises a pH buffer. The term ‘pH buffer’ is used herein to refer to a chemical substance capable of adjusting the pH value of a composition, solution and the like to a certain value or to a certain pH range.
The pH buffer may be an alkali metal carbonate. Suitable alkali metal carbonates include sodium bicarbonate, calcium bicarbonate and magnesium bicarbonate and calcium carbonate. It has been observed that calcium carbonate has a detrimental effect on taste and is therefore not preferred.
Preferably, the alkali metal carbonate is sodium bicarbonate. The sodium bicarbonate may be dissolved in water to form a sodium bicarbonate solution. The concentration of the sodium bicarbonate solution may be any concentration sufficient to adjust the pH of the vehicle into the desirable range. Good results have been observed using a concentration of up to 8.4% sodium bicarbonate solution. It has been observed that concentrations higher than this are less desirable due to a reduced solubility of the sodium bicarbonate and higher resistance to pH changes.
The pH buffer may be present in an amount of from 30 to 50% v/v of the vehicle. Good results have been observed with a pH buffer present in an amount of around 47.5% v/v.
The vehicle of the present invention may comprise additional components as desired or as appropriate. Such additional components may include one or more preservatives.
Suitable preservatives include disodium edetate and/or propylene glycol. It has been observed that disodium edetate is operable as a preservative at alkaline pH, such as pH 8.5 or above. Further, it has also been observed that microbes are less active at alkaline pH.
In preparing the vehicle, the pH buffer may be added to the mixture before the polyol. Preferably, the pH buffer is added to the mixture of the viscosity enhancing component and propylene glycol and mixed until substantially all of the solids have dissolved.
The polyol may be added to the solution comprising the viscosity enhancing component, the propylene glycol and the pH to form the vehicle. The vehicle may be mixed to form a homogenous mixture.
The vehicle of the present invention may comprise from 0.3 to 0.6% v/v of a viscosity enhancing component, from 2 to 10% v/v propylene glycol, from 30 to 50% v/v of a pH buffer and from 40 to 60% v/v of a polyol.
The vehicle of the present invention may comprise from 0.3 to 0.6% v/v sodium carboxymethyl cellulose, from 2 to 10% v/v propylene glycol, from 30 to 50% v/v sodium bicarbonate solution and from 40 to 60% v/v maltitol.
The pharmaceutical composition of the present invention comprises the vehicle of the present invention and an active pharmaceutical ingredient.
In preparing the pharmaceutical composition, the vehicle may be added to the active pharmaceutical ingredient. The vehicle may be added gradually to the active pharmaceutical ingredient. The term ‘gradual’ is used herein to refer to the addition of the active pharmaceutical ingredient over a set timespan. Whilst not wishing to be bound by theory, it is believed that the active pharmaceutical ingredient is cohesive in nature. If the vehicle is added all at once, it will take more time to achieve a homogeneous suspension. The longer the mixing time required to achieve a homogeneous suspension, the greater the temperature rise in the environment. This can have the effect of increasing the temperature of the active pharmaceutical ingredient during processing, which is not desirable. Preferably, the product should be maintained at a temperature of from 2 to 8°C for optimum stability. Consequently, it is beneficial to add the vehicle gradually over a set time-span.
Once the vehicle has been combined with the active pharmaceutical ingredient to form the pharmaceutical composition, the pharmaceutical composition may be mixed until homogenous.
The pharmaceutical composition comprising the vehicle and the active pharmaceutical ingredient may be in the form of a suspension, a solution or a solid. Preferably, the composition is in the form of a suspension. Preferably still, the composition is in the form of a homogenous suspension.
The active pharmaceutical ingredient may be omeprazole. The pharmaceutical composition may be in the form of a suspension comprising a mixture of omeprazole and the vehicle. The pharmaceutical composition may comprise a homogenous suspension of omeprazole and the vehicle.
Omeprazole may be in the form of a solid, e.g. particulate, granular, powder, flake. Preferably, omeprazole is in the form of a powder.
Omeprazole may be present in the pharmaceutical composition in an amount of from at least 0.04% v/v of the pharmaceutical composition. Omeprazole may be present in an amount of from 0.04 to 0.4% v/v of the pharmaceutical composition. Good results have been observed for amounts of omeprazole of around 0.1%, 0.2% and 0.4% v/v of the pharmaceutical composition.
It has been discovered that the stability of pharmaceutical composition is partially dependent upon the concentration of omeprazole. It has been found that the lower the concentration of omeprazole, the greater the rate of degradation. For the pharmaceutical compositions of the present invention, it has been found that compositions having a concentration of less than 2mg/5ml are not sufficiently stable.
Concentrations of omeprazole in the pharmaceutical compositions of the present invention may be at least 2mg/5ml. Concentrations of omeprazole in the pharmaceutical composition may be from 2mg/5ml to 40mg/5ml. Example concentrations include 5mg/5ml (0.1% v/v), 10mg/5ml (0.2% v/v) and 20mg/5ml (0.4% v/v) and 40mg/5ml (0.8% v/v).
The pharmaceutical composition of the present invention may comprise from 0.3 to 0.6% v/v of a viscosity enhancing component, from 2 to 10% v/v propylene glycol, from 30 to 50% v/v of a pH buffer and from 40 to 60% v/v of a polyol and from 0.04 to 0.8% v/v omeprazole.
The pharmaceutical composition of the present invention may comprise from 0.3 to 0.6% v/v sodium carboxymethyl cellulose, from 2 to 10% v/v propylene glycol, from 30 to 50% v/v sodium bicarbonate solution and from 40 to 60% v/v maltitol and from 0.04 to 0.8% v/v omeprazole.
The pharmaceutical composition of the present invention may be placed in one or more labelled vessels for storage and transport. It has been observed that the pharmaceutical composition can display some sensitivity to light. As such, the pharmaceutical composition may be stored in coloured vessels, such as amber glass bottles.
A pharmaceutical composition of the present invention has been found in testing to have a shelf-life of up to around 6 months or more, up to around 12 months or more and, in some instances, up to around months or more. This is significantly longer than the shelf-life of certain pharmaceutical compositions containing omeprazole, which can be as short as a few days. Thus, beneficially, compositions of the present invention can be stored for use for a greater length of time than compositions currently known, resulting in reduced waste and manufacturing costs.
It has been found that good results for shelf-life have been obtained when the pharmaceutical composition is stored at a temperature in the range of 2 to 8°C. Particularly good results have been observed when the pharmaceutical composition is stored at around 5°C. Thus, the method of the present invention may comprise refrigerating the pharmaceutical composition.
The present invention provides a method of manufacturing a pharmaceutical composition, the method comprising the steps of:
(a) mixing a viscosity enhancing component with a wetting agent to form a mixture;
(b) adding a pH buffer and a polyol to the mixture to form a vehicle (c) adding the vehicle to an active pharmaceutical ingredient.
The mixture of the viscosity enhancing component and the wetting agent may be mixed until homogenous.
In the step of adding a pH buffer and a polyol to the mixture, the pH buffer may be added to the mixture before, after or at the same time as the polyol. Preferably, the pH buffer is added to the mixture before the polyol. The mixture of the viscosity enhancing component, wetting agent and the pH buffer may be mixed until the solids have dissolved. The solids may comprise the viscosity enhancing component, which is preferably added in powder form.
In the step of adding a pH buffer and a polyol to the mixture, the polyol may be added to the mixture before, after or at the same time as the pH buffer. Preferably, the pH buffer is added to the mixture after the pH buffer. The vehicle comprising the viscosity enhancing component, the wetting agent, pH buffer and polyol may be mixed until homogenous.
The step of adding the vehicle to an active pharmaceutical ingredient, the active pharmaceutical ingredient, such as omeprazole, may be in a separate vessel. The active pharmaceutical composition may be in the form of a powder. The vehicle may be added to the vessel gradually. The resulting pharmaceutical composition may be mixed until homogenous. The pharmaceutical composition may be in the form of a suspension for oral administration.
The method of manufacturing a pharmaceutical composition may comprise the further step of refrigerating the pharmaceutical composition. Preferably, the composition is refrigerated at a temperature in the range 2 to 8°C.
The method may further comprise the step of transferring the pharmaceutical composition to a UV light resistant vessel. The UV light resistance vessel may comprise a coloured glass, such as amber glass.
Embodiments of the present invention will now be further described with reference to the following nonlimiting examples.
The vehicle of the present invention may be prepared according to the following general processing steps:
(a) Add propylene glycol to sodium carboxymethyl cellulose and mix to form a homogenous mixture;
(b) Add sodium bicarbonate solution and mix until solids have dissolved;
(c) Add liquid maltitol and mix to form a homogenous mixture.
The pharmaceutical composition of the present invention may be prepared by gradually adding the homogenous vehicle to omeprazole, preferably in powder form, and mix to form a homogenous suspension.
Example 1:
Component Strength Amount v/v
Sodium carboxymethyl cellulose 500mps 0.4g 0.4%
Propylene glycol N/A 2.5ml 2.5%
Sodium bicarbonate solution 8.4% 47ml 47%
Maltitol (liquid) N/A 50ml 50%
Omeprazole N/A 0.1g 0.1%
Table 1: Pharmaceutical composition comprising a concentration of 5mg/5ml omeprazole
The general processing steps for preparing a pharmaceutical composition were followed. The resulting pharmaceutical composition was in the form of an off-white, opaque suspension and free from any visual contamination.
Example 2:
Component Strength Amount v/v
Sodium carboxymethyl cellulose 500mps 0.4g 0.4%
Propylene glycol N/A 2.5ml 2.5%
Sodium bicarbonate solution 8.4% 47ml 46.9%
Maltitol (liquid) N/A 50ml 50%
Omeprazole N/A 0.2g 0.2%
Table 2: Pharmaceutical composition comprising a concentration of 10mg/5ml omeprazole The general processing steps for preparing a pharmaceutical composition were followed. The resulting pharmaceutical composition was in the form of an off-white, opaque suspension and free from any visual contamination.
Example 3:
Component Strength Amount v/v
Sodium carboxymethyl cellulose 500mps 0.4g 0.4%
Propylene glycol N/A 2.5ml 2.5%
Sodium bicarbonate solution 8.4% 47ml 46.7%
Maltitol (liquid) N/A 50ml 50%
Omeprazole N/A 0.4g 0.4%
Table 3: Pharmaceutical composition comprising a concentration of 20mg/5ml omeprazole
The general processing steps for preparing a pharmaceutical composition were followed. The resulting pharmaceutical composition was in the form of a cream coloured, opaque suspension and free from any visual contamination.
Stability trial tests
The pharmaceutical composition may go through formal stability trial tests, where the composition is stored at 4°C, 25°C and 40°C in final packaging. The stability trial tests run for 24 months and typically time points are 0 months, 1 month, 3 months, 6 months, 9 months, 12 months, 18 months and 24 months. At each time point, the product is analysed as shown in the table below.
Time point (months)
0 1 2.8 3 4 5 6 9
Appearance Pass Pass Pass Pass Pass Pass Pass Pass
Colour Off-white Pale Grey- yellow Peach- Pink Pale Beige Dark Beige Beige Beige Dark Beige
pH 8.3 8.3 9.0 8.3 8.4 8.6 8.5 8.5
Assay (%) 100.4 98.1 99.6 97.0 91.6 95.1 94.5 87.7
Impurity D (%) 0 0.07 0 0 1.2 0.07 0 0
Microbiology Pass N/A N/A N/A N/A N/A N/A N/A
Table 4: Stability results for the pharmaceutical composition of Example 1 - stored at 5°C
Time point (months)
0 1 2.8 3 4 5 6 9 12 24
Appearance Pass Pass Pass Pass Pass Pass Pass Pass Pass Pass
Colour Off- white Pale Grey- yellow Peach- pink Pale beige Dark beige Beige Beige Dark Beige Beige Beige
pH 8.4 8.3 9.0 8.4 8.4 8.7 8.5 8.5 8.4 8.6
Assay (%) 100.7 95.3 102.0 97.9 95.4 97.6 98.4 91.8 91.6 91.7
Impurity D (%) 0 0.05 0 0 0.12 0 0 0 0 0
Microbiology Pass N/A N/A N/A N/A N/A N/A N/A Pass Pass
Table 5: Stability results for the pharmaceutical composition of Example 2 - stored at 5°C
Time point (months)
0 1 3 5 6 9
Appearance Pass Pass Pass Pass Pass Pass
Colour Cream Pale-Grey Beige Dark beige Dark beige Mustard
pH N/A N/A N/A 8.5 8.5 8.7
Assay (%) 95.5 91.7 103.2 103.0 95.0 79.6
Impurity D N/A N/A N/A N/A 0 0
(%)
Microbiology Pass N/A Pass N/A N/A N/A
Table 6: Stability results for the pharmaceutical composition of Example 3 - stored at 5°C
Based on the stability results obtained, it is clear that the three omeprazole formulations have extended shelf-life. The omeprazole suspension of Example 1 is chemically and aesthetically stable for 6 months at 5°C storage; the omeprazole suspension of Example 2 is chemically and microbiologically stable for months at 5°C; and the omeprazole suspension of Example 3 is chemically and aesthetically stable for 6 months at 5°C storage.
It is of course to be understood that the present invention is not intended to be restricted to the foregoing examples which are described by way of example only.

Claims (27)

  1. Claims:
    I. A vehicle for an active pharmaceutical ingredient, the vehicle comprising a viscosity enhancing component, a wetting agent, a pH buffer and a polyol.
    5
  2. 2. A method of manufacturing a vehicle, the method comprising the steps of:
    (a) mixing a viscosity enhancing component with a wetting agent to form a mixture; and (b) adding a pH buffer and a polyol to the mixture.
  3. 3. A vehicle or method as claimed in claim 1 or claim 2, wherein the vehicle has a pH of at least
    8.
    10
  4. 4. A vehicle or method as claimed in any preceding claim, wherein the viscosity enhancing component comprises an alkali metal cellulose derivative.
  5. 5. A vehicle or method as claimed in claim 4, wherein the alkali metal cellulose derivative is an alkali metal carboxymethyl cellulose.
  6. 6. A vehicle or method as claimed in claim 5, wherein the alkali metal carboxymethyl cellulose is
    15 sodium carboxymethyl cellulose.
  7. 7. A vehicle or method as claimed in any preceding claim, wherein the viscosity enhancing component is present in an amount of from 0.3 to 0.6% v/v of the vehicle.
  8. 8. A vehicle or method as claimed in any preceding claim, wherein the wetting agent is propylene glycol.
    20
  9. 9. A vehicle or method as claimed in claim 8, wherein the propylene glycol is present in an amount of from 2 to 10% v/v of the vehicle.
  10. 10. A vehicle or method as claimed in any preceding claim, wherein the polyol is a sugar alcohol.
  11. II. A vehicle or method as claimed in claim 10, wherein the sugar alcohol is maltitol.
  12. 12. A vehicle or method as claimed in any preceding claim, wherein the polyol is present in an
    25 amount of from 40 to 60% v/v of the vehicle.
  13. 13. A vehicle or method as claimed in any preceding claim, wherein the pH buffer is an alkali metal carbonate.
  14. 14. A vehicle or method as claimed in any preceding claim, wherein the alkali metal carbonate is sodium bicarbonate.
  15. 15. A vehicle or method as claimed in any preceding claim, wherein the pH buffer is present in an amount of from 30 to 50% v/v of the vehicle.
  16. 16. A method as claimed in any one of claims 2 to 15, wherein the mixture of step (a) is mixed until homogenous.
  17. 17. A method as claimed in any one of claims 2 to 16, wherein the pH buffer is added to the mixture before the polyol.
  18. 18. A method as claimed in claim 17, wherein the mixture is mixed until the solids have dissolved.
  19. 19. A method as claimed in any one of claims 2 to 18, wherein step (b) further comprises mixing the vehicle until homogenous.
  20. 20. A pharmaceutical composition comprising a vehicle as claimed in any one of claims 1 and 3 to
    15 and an active pharmaceutical ingredient.
  21. 21. A method of manufacturing a pharmaceutical composition, the method comprising the step of mixing a vehicle as claimed in, or obtained by the method of, any one of claims 1 to 20 with an active pharmaceutical ingredient.
  22. 22. A pharmaceutical composition or method as claimed in claim 20 or claim 21, wherein the active pharmaceutical ingredient is omeprazole.
  23. 23. A pharmaceutical composition or method as claimed in any one of claims 20 to 22, wherein the omeprazole is present in the pharmaceutical composition in an amount of from at least 0.04% v/v of the pharmaceutical composition.
  24. 24. A method as claimed in any one of claims 21 to 23, wherein the vehicle is added to the active pharmaceutical ingredient.
  25. 25. A pharmaceutical composition as claimed in any one of claims 20 and 22 to 23 for use in therapy.
  26. 26. A pharmaceutical composition as claimed in any one of claims 20 and 22 to 23 for use in the treatment or prevention of duodenal ulcers including duodenal ulcers caused by H. pylori, gastric ulcers, NSAID-associated gastric and duodenal ulcers, peptic ulcer disease, reflux oesophagitis, Zollinger-Ellison syndrome, gastro-oesophagitis reflux disease including heartburn and acid regurgitation in gastro-oesophageal reflux disease.
  27. 27. A vehicle as claimed in any one of claims 1 and 3 to 15 for use in the manufacture of a medicament.
    Intellectual
    Property
    Office
    Application No: GB1705745.6 Examiner: Dr Alistair Longshaw
GB1705745.6A 2017-04-10 2017-04-10 Pharmaceutical composition and a method for manufacturing the same Withdrawn GB2561355A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
GB1705745.6A GB2561355A (en) 2017-04-10 2017-04-10 Pharmaceutical composition and a method for manufacturing the same
GB1805951.9A GB2564515B (en) 2017-04-10 2018-04-10 Pharmaceutical composition and a method for manufacturing the same

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB1705745.6A GB2561355A (en) 2017-04-10 2017-04-10 Pharmaceutical composition and a method for manufacturing the same

Publications (2)

Publication Number Publication Date
GB201705745D0 GB201705745D0 (en) 2017-05-24
GB2561355A true GB2561355A (en) 2018-10-17

Family

ID=58744775

Family Applications (2)

Application Number Title Priority Date Filing Date
GB1705745.6A Withdrawn GB2561355A (en) 2017-04-10 2017-04-10 Pharmaceutical composition and a method for manufacturing the same
GB1805951.9A Active GB2564515B (en) 2017-04-10 2018-04-10 Pharmaceutical composition and a method for manufacturing the same

Family Applications After (1)

Application Number Title Priority Date Filing Date
GB1805951.9A Active GB2564515B (en) 2017-04-10 2018-04-10 Pharmaceutical composition and a method for manufacturing the same

Country Status (1)

Country Link
GB (2) GB2561355A (en)

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4788220A (en) * 1987-07-08 1988-11-29 American Home Products Corporation (Del.) Pediatric ibuprofen compositions
US20060140989A1 (en) * 2004-12-22 2006-06-29 Schering Corporation Pharmaceutical formulations
US20080193548A1 (en) * 2007-02-09 2008-08-14 Claudio Zanichelli Pharmaceutical Compositions for Oral Administration in the Form of Stabilised Aqueous Suspensions
US20080260837A1 (en) * 2007-04-20 2008-10-23 Qpharma, L.L.C. Physically stable aqueous suspensions of active pharmaceuticals
US20100216754A1 (en) * 2007-11-13 2010-08-26 Meritage Pharma, Inc. Compositions for the treatment of inflammation of the gastrointestinal tract
US20110015233A1 (en) * 2009-07-20 2011-01-20 Vetegen, Llc Stable Pharmaceutical Omeprazole Formulation for Oral Administration
WO2014104412A1 (en) * 2012-12-28 2014-07-03 Otsuka Pharmaceutical Co., Ltd. Injectable depot formulation comprising optically active tolvaptan and process of producing the same
GB2513172A (en) * 2013-04-18 2014-10-22 Nupharm Lab Ltd Liquid dosage form and delivery system
US20140364392A1 (en) * 2013-06-06 2014-12-11 Novartis Ag Topical aqueous ophthalmic compositions containing a 1h-indole-1-carboxamide derivative and use thereof for treatment of ophthalmic disease
CN104523589A (en) * 2014-12-26 2015-04-22 万特制药(海南)有限公司 Oral suspension type medicine composition containing agomelatine
EP2926816A1 (en) * 2012-12-03 2015-10-07 Ems S.A. Pharmaceutical composition comprising desloratadine and prednisolone and use thereof
WO2017036118A1 (en) * 2015-08-31 2017-03-09 诺瑞特国际药业股份有限公司 Injectable aripiprazole suspension preparation having prolonged shelf life

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013192066A1 (en) * 2012-06-19 2013-12-27 Intercontinental Great Brands Llc Chewing gum product and method of production thereof

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4788220A (en) * 1987-07-08 1988-11-29 American Home Products Corporation (Del.) Pediatric ibuprofen compositions
US20060140989A1 (en) * 2004-12-22 2006-06-29 Schering Corporation Pharmaceutical formulations
US20080193548A1 (en) * 2007-02-09 2008-08-14 Claudio Zanichelli Pharmaceutical Compositions for Oral Administration in the Form of Stabilised Aqueous Suspensions
US20080260837A1 (en) * 2007-04-20 2008-10-23 Qpharma, L.L.C. Physically stable aqueous suspensions of active pharmaceuticals
US20100216754A1 (en) * 2007-11-13 2010-08-26 Meritage Pharma, Inc. Compositions for the treatment of inflammation of the gastrointestinal tract
US20110015233A1 (en) * 2009-07-20 2011-01-20 Vetegen, Llc Stable Pharmaceutical Omeprazole Formulation for Oral Administration
EP2926816A1 (en) * 2012-12-03 2015-10-07 Ems S.A. Pharmaceutical composition comprising desloratadine and prednisolone and use thereof
WO2014104412A1 (en) * 2012-12-28 2014-07-03 Otsuka Pharmaceutical Co., Ltd. Injectable depot formulation comprising optically active tolvaptan and process of producing the same
GB2513172A (en) * 2013-04-18 2014-10-22 Nupharm Lab Ltd Liquid dosage form and delivery system
US20140364392A1 (en) * 2013-06-06 2014-12-11 Novartis Ag Topical aqueous ophthalmic compositions containing a 1h-indole-1-carboxamide derivative and use thereof for treatment of ophthalmic disease
CN104523589A (en) * 2014-12-26 2015-04-22 万特制药(海南)有限公司 Oral suspension type medicine composition containing agomelatine
WO2017036118A1 (en) * 2015-08-31 2017-03-09 诺瑞特国际药业股份有限公司 Injectable aripiprazole suspension preparation having prolonged shelf life

Also Published As

Publication number Publication date
GB201805951D0 (en) 2018-05-23
GB2564515A (en) 2019-01-16
GB2564515B (en) 2022-10-26
GB201705745D0 (en) 2017-05-24

Similar Documents

Publication Publication Date Title
EP0858329B1 (en) Novel stable liquid paracetamol compositions, and method for preparing same
US9943492B2 (en) Injectable liquid paracetamol formulation
KR950002883B1 (en) Process for preparing effervescent couples
HU224964B1 (en) Process for stabilization of naloxone and stable pharmaceutical compositions containing naloxone
AU2006322120B2 (en) Benzimidazole non-aqueous compositions
AU634271B2 (en) Stable solutions of mitomycin c
BE1026546A1 (en) READY-TO-USE INTRAVENOUS TRANEXAMIC ACID SOLUTION
US20080233196A1 (en) Injectable sterile pharmaceutical composition with piperacillin sodium and tazobactam sodium as active principles
DE60205125T2 (en) SOLID PREPARATIONS WITH RAMIPRIL
CZ292256B6 (en) Pharmaceutical mixture and process for preparing thereof
EP3181120A1 (en) Enema composition for treatment of ulcerative colitis having long term stability
AU2005210632B2 (en) Anthelmintic composition
JP5340493B2 (en) Nicorandil-containing pharmaceutical composition
GB2561355A (en) Pharmaceutical composition and a method for manufacturing the same
EP3057571B1 (en) Proton pump inhibitor paste compositions
WO2009112800A1 (en) Losartan composition
KR20190087039A (en) Oral emulsion formulation comprising Risedronic acid or its salts and vitamin D and the method for preparation thereof
AU2015326572A1 (en) A suspension
EP2918291A2 (en) Pharmaceutical composition of stabilized paracetamol, plastic bags and use of the pharmaceutical composition
EP1713468B9 (en) Anthelmintic composition
WO2024067094A1 (en) Clethodim composition, and emulsifiable concentrate and technical concentrate comprising same
JP2003095939A (en) Stable pravastatin sodium tablet
GB2573784A (en) A stable aqueous hydroxycarbamide solution
KR20050071437A (en) Method for dissolving an amprolium and ethopabate
KR20130055998A (en) The composition of ampicillin powder preparation to improve the solubility of the active substance

Legal Events

Date Code Title Description
WAP Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1)