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WO2010045682A1 - Compositions stables au stockage et leurs méthodes d'élaboration - Google Patents

Compositions stables au stockage et leurs méthodes d'élaboration Download PDF

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Publication number
WO2010045682A1
WO2010045682A1 PCT/AU2009/001386 AU2009001386W WO2010045682A1 WO 2010045682 A1 WO2010045682 A1 WO 2010045682A1 AU 2009001386 W AU2009001386 W AU 2009001386W WO 2010045682 A1 WO2010045682 A1 WO 2010045682A1
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WO
WIPO (PCT)
Prior art keywords
composition
physiological
initial
anaesthetic
months
Prior art date
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Ceased
Application number
PCT/AU2009/001386
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English (en)
Inventor
Jeff Stanborough
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.)
JEFF STANBOROUGH Pty Ltd
Original Assignee
JEFF STANBOROUGH Pty 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
Priority claimed from AU2008905429A external-priority patent/AU2008905429A0/en
Application filed by JEFF STANBOROUGH Pty Ltd filed Critical JEFF STANBOROUGH Pty Ltd
Publication of WO2010045682A1 publication Critical patent/WO2010045682A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics

Definitions

  • the present invention relates to methods for preparing storage stable compositions, and in particular pharmaceutical compositions.
  • the invention also relates to storage stable compositions and methods for minimising the pain and discomfort associated with injections.
  • compositions such as vaccines and anaesthetics are often commercially available as acidic solutions. The reason for this is to ensure the solubility and/or stability of the active compounds which are not stable and/or not soluble at a higher pH.
  • buffering agents such as bicarbonate are not readily available in a form suitable for this purpose.
  • a further disadvantage lies in the fact that the person giving the injection must measure out a precise amount of buffering agent to add to the anaesthetic composition and perform the addition whilst maintaining sterility of the composition shortly before every injection. This is because the active compounds are only stable and/or soluble for a limited time following addition of the base.
  • compositions which have a non-acidic pH, including physiological pH.
  • Such compositions are highly desirable as they could be administered by physicians without prior neutralisation and with minimal pain and discomfort to the patient. Accordingly, there is a need for compositions, in particular anaesthetic compositions, which are stable at non-acidic pH for example at physiological pH for an extended period of time.
  • the present invention provides a method for preparing a composition having a desired pH the method comprising:
  • the desired pH may be a non-acidic pH, for example physiological pH.
  • the initial composition may have a pH between about 4.5 and about 6.9.
  • the pH may be increased in step (ii) to a level between about 5.0 and about 7.0.
  • the pH may be increased in step (ii) by less than about 20%, or by less than about
  • Carbon dioxide may be added to the composition until the pH decreases by between about 0.1 and about 4 pH units.
  • the desired pH is a non-acidic pH, for example physiological pH
  • the initial composition has a pH between about 6.0 and about 6.8, base is added to increase the pH to below about 7.0 and carbon dioxide is added so as to decrease the pH by at least 0.5 pH units.
  • the desired pH is a non-acidic pH, for example physiological pH
  • the initial composition has a pH between about 6.0 and about 6.8, base is added to increase the pH to below about 7.0 and carbon dioxide is added so as to decrease the pH by between about 0.5 and about 2 pH units.
  • the desired pH is a non-acidic pH, for example physiological pH
  • the initial composition has a pH between about 6.2 and about 6.7
  • base is added to increase the pH to below about 7.0
  • carbon dioxide is added so as to decrease the pH by between about 0.5 and about 2 pH units.
  • the desired pH is a non-acidic pH, for example physiological pH
  • the initial composition has a pH between about 6.4 and about 6.7
  • base is added to increase the pH to below about 7.0
  • carbon dioxide is added so as to decrease the pH by between about 1 and about 2 pH units.
  • the desired pH is a non-acidic pH, for example physiological pH
  • the initial composition has a pH between about 6.5 and about 6.7
  • base is added to increase the pH to below about 7.0
  • carbon dioxide is added so as to decrease the pH by between about 1 and about 1.5 pH units.
  • the desired pH is a non-acidic pH, for example physiological pH
  • the initial composition has a pH between about 6.4 and about 6.7
  • base is added to increase the pH by less than about 10%, or less than about 5%
  • carbon dioxide is added so as to decrease the pH by between about 1 and about 2 pH units.
  • the base may be bicarbonate, for example sodium bicarbonate.
  • the composition may be a pharmaceutical composition.
  • the composition may be a pharmaceutical composition intended for injection.
  • the composition may be a food or drink composition.
  • the pharmaceutical composition may be an anaesthetic composition or a vaccine composition.
  • the pharmaceutical composition may be an anaesthetic composition or a vaccine composition intended for injection.
  • the anaesthetic composition may be any local anaesthetic composition. Examples include, but are not limited to: lignocaine, prilocaine, etidocaine, articaine, marcaine, carbocaine, bupivacaine and mepivacaine compositions.
  • the pH of the composition may increase over time and ultimately reach the desired pH by the release of carbon dioxide from the composition.
  • the method may further comprise the step of sterilising the composition.
  • the present invention provides a composition whenever prepared by the method of the first aspect.
  • the composition may have a non-acidic pH, for example physiological pH.
  • the present invention provides a stable composition comprising one or more compounds that are not stable and/or not soluble at physiological pH, said composition having a pH between about 7.1 and about 7.6.
  • the composition may be a pharmaceutical composition.
  • the composition may be a vaccine or anaesthetic composition.
  • the composition may be a local anaesthetic composition, for example a lignocaine composition.
  • the composition may have a pH between about 7.1 and about 7-.5, or between about 7.2 and about 7.6, or between about 7.2 and about 7.5.
  • composition may be stable for a period beyond three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, eighteen months or twenty-four months.
  • composition may be stable for at least three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, eighteen months or twenty-four months.
  • the composition may be stable for a period of up to three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, eighteen months or twenty-four months.
  • composition may be stable for the above noted periods at a temperature between about 15 °C and 25 °C.
  • the present invention provides a container comprising a stable anaesthetic composition including one or more compounds that are not stable and/or not soluble at physiological pH, said composition having a pH between about 7.1 and about 7.6.
  • the anaesthetic composition may be a local anaesthetic composition, for example a lignocaine composition.
  • the composition may have a pH between about 7.1 and about 7.5, or between about
  • the composition may be stable for a period beyond three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, eighteen months or twenty-four months.
  • the composition may be stable for at least three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, eighteen months or twenty-four months.
  • the composition may be stable for a period of up to three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, eighteen months or twenty-four months.
  • composition may be stable for the above noted periods at a temperature between about 15 °C and 25 °C.
  • the present invention provides a method for reducing and/or minimising the pain and/or sting experienced by a subject that is associated with an injection, said method comprising injection into the subject of a composition of the second aspect or third aspect.
  • the composition may be an anaesthetic or vaccine composition.
  • the method of the fifth aspect may involve reducing and/or minimising the pain and/or sting experienced by a subject that is associated with injection of an anaesthetic or vaccine composition having an acidic pH, the method comprising injection into the subject of a composition of the second or third aspects having a physiological pH.
  • the subject may be an animal, for example a human.
  • an element means one element or more than one element.
  • stable is understood to mean that active compound(s) included in the composition do not irreversibly precipitate out of solution, and/or do not decompose (for example to a level such that administration of the composition does not produce the desired effect or activity) and/or that the solution does not irreversibly form precipitates (such as crystals) or become turbid.
  • stable may also mean that one or more compounds included in the composition do not undergo undesired physical and/or chemical changes which adversely affect the properties or use of the composition.
  • physiological pH means a pH in the range of about 7.1 to about 7.6, or a pH in the range of about 7.2 to about 7.6
  • the present invention relates to a method for preparing stable compositions comprising compounds that are not normally stable and/or not normally soluble at the pH of the compositions.
  • the invention further relates to compositions prepared by the method, and also methods for reducing and/or minimising the pain and/or sting associated with compositions administered by injection.
  • the first aspect of the invention provides a method for preparing a composition having a desired pH the method comprising:
  • the desired pH is physiological pH, however it is to be understood that the desired pH may be any pH that is above the pH of the initial composition.
  • the desired pH may be a pH in the range of about 6.5 and about 8.0.
  • the desired pH may be in the range of about 5.5 and about 6.5.
  • the initial composition may be any composition that comprises one or more active compounds that are not normally stable and/or not normally soluble at the desired pH.
  • the composition may, for example, be an anaesthetic composition or a vaccine composition, or any composition that is intended for injection.
  • the composition may be a food or drink composition.
  • the desired pH will be dependent on the nature of the initial .composition and its intended use. For example, if the composition is to be injected, then the desired pH may be physiological pH, or a pH that is near physiological pH. Alternatively, if the composition is a beverage composition then the desired pH may be lower, for example in the range of about 5.0 to about 6.0.
  • the initial composition may have a pH of between about 4.5 and about 6.9, or between about 5.0 and about 6.9, or between about 5.5 and about 6.9, or between about 6.0 and about 6.9, or between about 6.2 and about 6.9, or between about 6.3 and about 6.9, or between about 6.4 and about 6.9, or between about 6.5 and about 6.9, or between about 6.6 and about 6.9, or between about 6.6 and about 6.85.
  • the initial composition has a pH between about 6.5 and about 6.8.
  • Step (ii) of the method involves adding a base to the composition so as to increase the pH of the composition to a pH below the desired pH. Where the pH is increased to the desired pH or above by addition of a base, the resulting composition will become turbid and/or exhibit precipitation within a matter of a few days to weeks after the composition is allowed to stand.
  • the amount of base added to the composition may be an amount sufficient to increase the pH by less than about 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%, of the pH of the initial composition.
  • the amount of base added to the composition may be an amount sufficient to increase the pH by between about 1% and about 30%, or between about 1% and about 20%, or between about 1% and about 15%, or between about 1% and about 10%, or between about 1% and about 8%, or between about 1% and about 6%, or between about 2% and about 10%, or between about 3% and about 10%, or between about 2% and about 8%, or between about 2% and about 6%, or between about 0.1% and about 10%, or between about 0.1% and about 8%, or between about 0.1% and about 7%, or between about 0.1% and about 6%, or between about 0.5% and about 8%, or between about 0.5% and about 6%, or between about 0.5% and about 5%, or between about 0.5% and about 4%, or between about 0.75% and about 4%, or between about 1% and about 5% of the pH of the initial composition.
  • the pH may be raised to a level between about 5.0 and about 7.0, or between about 5.0 and about 6.95, or between about 5.5 and about 6.95, or between about 6.0 and about 6.95, or between about 6.2 and about 6.95, or between about 6.3 and about 6.95, or between about 6.4 and about 6.95, or between about 6.5 and about 6.95, or between about 6.6 and about 6.95, or between about 6.7 and about 6.9, or between about 6.75 and about 6.95, or between about 6.75 and about 6.9, or between about 6.7 and about 7.0.
  • the pH may be raised to a level below about 7.0, 6.95, 6.9, 6.85, 6.8, 6.75, 6.7, 6.65, 6.6, 6.55, 6.5, 6.4, 6.3, 6.2 or 6.1. In one embodiment, the pH may be raised to between about 6.7 and about 6.95.
  • the base may be, for example, any physiologically acceptable base.
  • the base is bicarbonate which may be present as either 'an alkali or alkali earth metal salt, for example sodium bicarbonate, magnesium bicarbonate or potassium bicarbonate.
  • Step (iii) of the method involves introducing carbon dioxide into the composition so as to decrease the pH of the composition. Introduction of carbon dioxide may be achieved by bubbling carbon dioxide gas into the composition, or alternatively by adding a compound to the composition that liberates carbon dioxide in solution.
  • Carbon dioxide may be introduced into the composition until the pH decreases by between about 0.1 and about 4 pH units, or between about 0.1 and about 3 pH units, or between about 0.1 and about 2 pH units, or between about 0.2 and about 3 pH units, or between about 0.3 and about 3 pH units, or between about 0.4 and about 3 pH units or between about 0.5 and about 3 pH units or between about 0.6 and about 3 pH units, or between about 0.7 and about 3 pH units, or between about 0.8 and about 3 pH units, or between about 0.9 and about 3 pH units, or between about 1 and about 3 pH units or between about 1 and about 2.5 pH units, or between about 1.25 and about 2.5 pH units, or between about 1 and about 1.5 pH units.
  • carbon dioxide may be introduced into the composition until the pH decreases by between about 1 and about 2 pH units.
  • Steps (ii) and (iii) may be performed in any order, i.e. the base may be added before or after the carbon dioxide is added to the composition.
  • carbon dioxide may be added to the initial composition so as to decrease the pH by at least 0.5 pH units, followed by addition of base so as to increase the pH by less than about 5% of the pH of the initial composition.
  • Step (iv) involves allowing the composition to stand such that the pH increases over time and ultimately reaches the desired pH. This may be achieved by allowing the composition to stand in a container such that carbon dioxide is able to escape from the composition.
  • the container may be a permeable or semi-permeable container. In an alternative embodiment, it is possible to allow the composition to stand in a non-permeable container so as to achieve the pH increase.
  • the composition may be allowed to stand at room temperature (approximately 15 0 C to 25 °C), or alternatively may be stored at reduced temperature, for example in a refrigerator. Where the composition is allowed to stand in a permeable or semi-permeable container, the time required for the composition to reach the desired pH may be reduced by subjecting the composition to reduced pressure and/or to heat, thereby increasing the rate at which carbon dioxide escapes from the composition.
  • the method of the first aspect may further comprise the step of sterilising the composition.
  • Sterilisation may be performed at any stage of the method, for example after step (iii).
  • Methods for sterilisation are well known to those skilled in the art and may include, for example, filtration (for example microfiltration), UV radiation, gamma radiation, some other form of sterilising radiation or some other form of sterilisation.
  • the sterilisation may be conducted so as not to damage or degrade any of the active compounds in the composition.
  • sterilising radiation UV, gamma or other
  • the present invention provides a method for preparing a composition having a desired pH which is physiological pH comprising:
  • an anaesthetic composition comprising one or more compounds that are not stable and/or not soluble at physiological pH, the composition having an initial pH of between about 6.4 and about 6.7; (ii) adding a base to the composition to increase the pH thereof by an amount that is less than about 10% of the initial pH;
  • Step (ii) may comprise adding a base to the composition to increase the pH thereof by an amount that is less than about 3%, 4%, 5%, 6%, 7%, 8% or 9% of the initial pH.
  • Step (ii) may comprise adding a base to the composition to increase the pH thereof by an amount between about 0.5% and about 10%, or between about 0.5.% and about 5%, of the initial pH.
  • Step (iii) may comprise decreasing the pH of the composition by between about 0.5 and about 2, or by between about 1 and about 2, pH units.
  • the pH of the composition may increase over time and ultimately reach physiological pH by release of carbon dioxide from the composition.
  • the present invention provides a method for preparing a composition having a desired pH which is physiological pH comprising: (i) providing an anaesthetic composition comprising one or more compounds that are not stable and/or not soluble at physiological pH, the composition having an initial pH of between about 6.4 and about 6.75;
  • Step (iii) decreasing the pH of the composition by at least 0.5 pH units by adding carbon dioxide thereto; and (iv) allowing the pH of the composition to increase over time -and ultimately reach physiological pH.
  • Step (iii) may comprise decreasing the pH of the composition by between about 0.5 and about 2, or by between about 1 and about 2, pH units.
  • the pH of the composition may increase over time and ultimately reach physiological pH by release of carbon dioxide from the composition.
  • the anaesthetic composition may be a local anaesthetic composition comprising lignocaine, for example Xylocaine® (AstraZeneca).
  • Local anaesthetic compositions prepared in accordance with the method of the first aspect have surprisingly been found to be stable on storage at room temperature (about 15 °C to 25 °C) for a period up to and exceeding twelve months.
  • compositions prepared using combinations of base and carbon dioxide by methods other than the" method of the first aspect show a marked reduction in anaesthetic efficacy and often exhibit turbidity and/or precipitation within a matter of a few days to a few weeks following preparation.
  • the inventor believes that the combination of increasing the pH of the composition to a pH below the desired pH in the presence of carbon dioxide creates a unique set of conditions wherein compounds not normally stable and/or not normally soluble at the desired pH are effectively stabilised at such a pH.
  • compositions prepared in accordance with the methods of the invention having a physiological pH result in a significantly reduced stinging sensation as compared to injection of the same composition having a lower pH.
  • the method of the first aspect may be carried out as follows:
  • Aim is to prepare a beverage composition having a desired pH which is between about 5.5 and about 6.0; (ii) providing a beverage composition comprising one or more compounds that are susceptible to discolouration and/or precipitation at increased pH, the composition having an initial pH of between about 4.0 and about 4.5;
  • the method of the first aspect may be carried out as follows:
  • Aim is to prepare a local anaesthetic composition having a desired pH which is physiological pH;
  • the composition obtained typically reaches a pH of about 7.2 after 1 to 2 months and is stable for a period up to and beyond twelve months whilst at the same time maintaining anaesthetic activity throughout this period. Because of its increased pH, injection of the composition results in significantly less pain and stinging when injected into a patient as compared to injection of a commercial -caine anaesthetic having a pH of less than 6.8.
  • the above method may be repeated wherein the anaesthetic composition is replaced by another composition comprising a pharmacologically active compound or compounds, for example a vaccine composition.
  • the method is also applicable to any water-based composition that requires an acidic pH so as to maintain stability of the active compound(s).
  • the method may also be used to prepare a stable aqueous composition comprising genetic material at a higher pH than that which is currently achievable, whilst maintaining the structure, form and properties of the material.
  • the method may also find application generally in industrial processes wherein it is desired to prepare a stable aqueous solution at a higher pH than that which is currently achievable.
  • compositions comprising local anaesthetics at physiological pH Storage stable compositions comprising lignocaine were prepared in accordance with the method of the first aspect as follows:
  • Carbon dioxide gas is then introduced into each ampoule via syringe at a rate of about 1 to 2 litres per minute for a period of 60 seconds so as to reduce the pH by at least 0.5 pH units.
  • the pH values of each solution following addition of base are depicted in Table 2 below:
  • the ampoules were sealed using a soldering iron and hot melt glue applied.
  • the ampoules were then stored at room temperature (approximately 15 °C to 25 °C) in the absence of light.
  • the pH values of TTO, X2, 444 and XC8 were checked over a period of five months. Within two months, all samples had reached physiological pH whilst at the same time maintaining anaesthetic activity. Sample XC8 attained the highest pH during this period (7.36), whilst sample X2 attained the lowest pH (7.1). Where it is desired to increase the pH of a composition to the upper range of physiological pH, an increased amount of base addition may be necessary. Samples X2 and 444 reached pH's of 7.21 and 7.23 respectively after about the same -time period thereby confirming the reproducibility of the method of the invention.
  • samples XC8, X2 and 444 had pH values of 7.34, 7.16 and 7.23 respectively.
  • the samples did not contain any precipitate and all retained anaesthetic activity.
  • Sample XC8 was checked again after a period of twelve months and found to contain no precipitate nor turbidity.
  • the pH of the composition was 7.43. Surprisingly, the anaesthetic activity remained.
  • Sample ND was allowed to stand for a period of twelve months and the pH was not assessed prior to the expiry of this period. After twelve months the sample attained a pH of 7.43. Surprisingly, the anaesthetic activity remained and the sample appeared clear with no evidence of precipitation or turbidity.
  • the anaesthetic activity of all samples was tested qualitatively by comparing the anaesthetic effect resulting from subcutaneous injection (but not into the dermis) of 1 mL of the relevant sample and 1 mL of 2% lignocaine drawn from a new ampoule.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Anesthesiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des méthodes d'élaboration de compositions stables au stockage, et en particulier de compositions pharmaceutiques. La présente invention concerne également des compositions stables au stockage et des méthodes minimisant la douleur et l'inconfort associés aux injections.
PCT/AU2009/001386 2008-10-21 2009-10-19 Compositions stables au stockage et leurs méthodes d'élaboration Ceased WO2010045682A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2008905429A AU2008905429A0 (en) 2008-10-21 Storage stable compositions and methods for preparing same
AU2008905429 2008-10-21

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Publication Number Publication Date
WO2010045682A1 true WO2010045682A1 (fr) 2010-04-29

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5226901A (en) * 1988-04-11 1993-07-13 Dhaliwal Avtar S Composite anesthetic article and method of use
US5261903A (en) * 1988-04-11 1993-11-16 M.D. Inc. Composite anesthetic article and method of use
WO1996029103A1 (fr) * 1995-03-23 1996-09-26 Baxter International Inc. Procede de fabrication et de conservation de solutions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5226901A (en) * 1988-04-11 1993-07-13 Dhaliwal Avtar S Composite anesthetic article and method of use
US5261903A (en) * 1988-04-11 1993-11-16 M.D. Inc. Composite anesthetic article and method of use
WO1996029103A1 (fr) * 1995-03-23 1996-09-26 Baxter International Inc. Procede de fabrication et de conservation de solutions

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AU2009101067A4 (en) 2009-11-19

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