CA2666581A1 - Buprenorphine-containing non-pressurised spray composition for transmucosal administration - Google Patents
Buprenorphine-containing non-pressurised spray composition for transmucosal administration Download PDFInfo
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- CA2666581A1 CA2666581A1 CA002666581A CA2666581A CA2666581A1 CA 2666581 A1 CA2666581 A1 CA 2666581A1 CA 002666581 A CA002666581 A CA 002666581A CA 2666581 A CA2666581 A CA 2666581A CA 2666581 A1 CA2666581 A1 CA 2666581A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
Abstract
There is provided according to the invention a non-pressurised pharmaceutical liquid solution spray composition comprising: (i) buprenorphine; and 5 (ii) a solvent comprising ethanol which composition is substantially free of chloride.
Description
BUPRENORPHINE-CONTAINING NON-PRESSURISED SPRAY COMPOSITION
FOR TRANSMUCOSAL ADMINISTRATION
This invention relates to compositions of buprenorphine especially pump spray compositions suitable for transmucosal, particularly sublingual, delivery.
Buprenorphine, with structure shown below, is a partial agonist of opiate receptors which is widely used for the treatment of moderate to severe pain or in the treatment of opiate dependence.
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Buprenorphine is often described as a partial agonist (receptor stimulator)/antagonist (prevents receptor stimulation). It has important actions on two types of opiate receptors in the brain.
Many of the most common opioid effects, such as euphoria, respiratory effects and reduced pain sensation, are caused by stimulation of the mu receptor. Buprenorphine stimulates this receptor, albeit at lower intensity than other opiates such as heroin or methadone. This lower level of stimulation is of benefit clinically in people with respiratory compromise but require opioid medication, such as the elderly.
Buprenorphine is also an antagonist of the kappa opioid receptor, which is associated with some of the negative effects experienced in withdrawal, particularly depression. As buprenorphine inhibits stimulation of this receptor it may produce feelings of well-being. Finally, its disassociation from these receptors is slow, leading to a long duration of action, allowing once daily dosing and sometimes dosing every two days, making buprenorphine a versatile treatment option in treatment of drug addiction.
A number of presentations of buprenorphine are currently available. Low-dose sub-lingual tablets, containing 0.2-0.4 mg of the drug as hydrochloride, are sold under the brand name Temgesic and are normally used for analgesic purposes. Temgesic brand of buprenorphine hydrochloride is also available as ampoules for intramuscular or slow intravenous injection. The most common formulation of buprenorphine used for the treatment of opiate dependence is sublingual tablets containing 0.4, 2 and 8 mg buprenorphine hydrochloride and available under the brand name Subutex. Using a combination of tablets, doses of up to 32 mg may be administered. These tablets are specifically intended for the treatment of problem drug use in patients who are being maintained in medically assisted treatment; in the case of patients undergoing withdrawal treatment, they are administered in a gradually reducing dose. Low-dose sublingual tablets are sometimes used for the treatment of opiate dependence, in which case multiple tablets are prescribed in order to achieve the desired dose.
A liquid formulation for sub-lingual administration is described in GB2100985 (Todd).
Specifically, this document describes formulations containing buprenorphine or a non-toxic salt thereof, but especially buprenorphine hydrochloride, dissolved in 20-30% v/v ethanol in water buffered to a pH of between 4.5-5.5 with 0.05-0.2 molar concentration of a buffering agent selected from citric acid/disodium hydrogen phosphate, sodium citrate/hydrochloric acid, lactic acid/disodium hydrogen phosphate, lactic acid/sodium lactate, sodium citrate/citric acid and sodium acetate/acetic acid, the concentration of buprenorphine being between 0.8 and 10 mg/ml (i.e. around 0.08-1.0% w/v) of the composition. The Examples relate to buprenorphine hydrochloride solutions containing various different concentrations of ethanol and a variety of buffers. The compositions do not appear to be sprays as the document refers to the volume of liquid that a patient can hold sublingually for a reasonable amount of time.
It is well known that the application of carefully chosen medicaments to mucosa, for example the sublingual mucosa, offers a route of administration which is capable of resulting in very rapid transmission of medicament to the bloodstream with consequent fast onset of effect. Other mucosa to which medicaments may be administered include the nasal mucosa and buccal mucosa. A number of ways of administering compositions sublingually are known.
For example, tablets or liquids may be held under the tongue prior to swallowing.
Another method is spray delivery. Of these various types of sublingual administration, spray delivery is preferred as it does not involve holding the composition under the tongue for an extended period of time as, for example, with a lozenge and it reduces the amount of material which is swallowed (and may enter the blood stream in a delayed manner via the gastrointestinal tract).
However it is not considered desirable to spray large volumes of liquid (eg greater than around 500 uL) to the sublingual cavity.
WO01/97780 (Ross) describes a pharmaceutical composition comprising a solution of an opioid analgesic (especially fentanyl, although buprenorphine is referred to) and a propellant, for sublingual aerosol administration. The example formulations are pressurized and therefore require complex packaging and actuation technology. Also they employ halogenated propellants which may not be environmentally friendly.
Weinberg et al (1988) Clin Pharmacol Ther 44, 335-342 discusses the adsorption of various opioids including buprenorphine (presented in an aqueous phosphate buffer at pH 6.5) when administered by pipette in liquid form to the sublingual cavity.
WO01/89476 (Pinney et al) discloses buffered compositons for transmucosal delivery.
Buprenorphine is mentioned in a very long list of possible active agents and is not exemplified.
Presently there are no spray compositions containing buprenorphine which have been made available commercially.
Thus an object of the present invention is to provide a spray composition containing buprenorphine for transmucosal, particularly sublingual, administration.
Further objects of the invention are to provide a spray composition containing buprenorphine for transmucosal (eg sublingual) administration with good physical properties, especially good stability and low environmental impact, and good biological properties, especially rapid onset of activity and efficacy at relatively low doses. Such a composition would mitigate many of the disadvantages of prior art compositions containing buprenorphine.
Thus according to a first aspect of the invention there is provided a non-pressurised pharmaceutical liquid solution spray composition comprising:
(i) buprenorphine; and (ii) a solvent comprising ethanol;
characterised in that the composition is substantially free of chloride.
The composition is non-pressurised i.e. is substantially free of any propellant. Exemplary propellants to be substantially avoided include volatile substances which develop significant vapour pressure at ambient temperature and pressure such as lower alkanes (eg propane, butane and the like) and halogenated hydrocarbons such as CFCs (P12 etc) and hydrofluorocarbons (P134a, P227 etc) as well as other propellants commonly used in aerosol presentations. Use of P11 is also preferably substantially avoided. By "substantially free" or "substantially avoided" is meant that an amount of less than 5% w/w based on weight of composition is employed, suitably less than 2% eg less than 0.1% w/w.
Preferably propellants are avoided altogether.
FOR TRANSMUCOSAL ADMINISTRATION
This invention relates to compositions of buprenorphine especially pump spray compositions suitable for transmucosal, particularly sublingual, delivery.
Buprenorphine, with structure shown below, is a partial agonist of opiate receptors which is widely used for the treatment of moderate to severe pain or in the treatment of opiate dependence.
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........ ..ti,, , . ,..
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.,,. ,,..
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Buprenorphine is often described as a partial agonist (receptor stimulator)/antagonist (prevents receptor stimulation). It has important actions on two types of opiate receptors in the brain.
Many of the most common opioid effects, such as euphoria, respiratory effects and reduced pain sensation, are caused by stimulation of the mu receptor. Buprenorphine stimulates this receptor, albeit at lower intensity than other opiates such as heroin or methadone. This lower level of stimulation is of benefit clinically in people with respiratory compromise but require opioid medication, such as the elderly.
Buprenorphine is also an antagonist of the kappa opioid receptor, which is associated with some of the negative effects experienced in withdrawal, particularly depression. As buprenorphine inhibits stimulation of this receptor it may produce feelings of well-being. Finally, its disassociation from these receptors is slow, leading to a long duration of action, allowing once daily dosing and sometimes dosing every two days, making buprenorphine a versatile treatment option in treatment of drug addiction.
A number of presentations of buprenorphine are currently available. Low-dose sub-lingual tablets, containing 0.2-0.4 mg of the drug as hydrochloride, are sold under the brand name Temgesic and are normally used for analgesic purposes. Temgesic brand of buprenorphine hydrochloride is also available as ampoules for intramuscular or slow intravenous injection. The most common formulation of buprenorphine used for the treatment of opiate dependence is sublingual tablets containing 0.4, 2 and 8 mg buprenorphine hydrochloride and available under the brand name Subutex. Using a combination of tablets, doses of up to 32 mg may be administered. These tablets are specifically intended for the treatment of problem drug use in patients who are being maintained in medically assisted treatment; in the case of patients undergoing withdrawal treatment, they are administered in a gradually reducing dose. Low-dose sublingual tablets are sometimes used for the treatment of opiate dependence, in which case multiple tablets are prescribed in order to achieve the desired dose.
A liquid formulation for sub-lingual administration is described in GB2100985 (Todd).
Specifically, this document describes formulations containing buprenorphine or a non-toxic salt thereof, but especially buprenorphine hydrochloride, dissolved in 20-30% v/v ethanol in water buffered to a pH of between 4.5-5.5 with 0.05-0.2 molar concentration of a buffering agent selected from citric acid/disodium hydrogen phosphate, sodium citrate/hydrochloric acid, lactic acid/disodium hydrogen phosphate, lactic acid/sodium lactate, sodium citrate/citric acid and sodium acetate/acetic acid, the concentration of buprenorphine being between 0.8 and 10 mg/ml (i.e. around 0.08-1.0% w/v) of the composition. The Examples relate to buprenorphine hydrochloride solutions containing various different concentrations of ethanol and a variety of buffers. The compositions do not appear to be sprays as the document refers to the volume of liquid that a patient can hold sublingually for a reasonable amount of time.
It is well known that the application of carefully chosen medicaments to mucosa, for example the sublingual mucosa, offers a route of administration which is capable of resulting in very rapid transmission of medicament to the bloodstream with consequent fast onset of effect. Other mucosa to which medicaments may be administered include the nasal mucosa and buccal mucosa. A number of ways of administering compositions sublingually are known.
For example, tablets or liquids may be held under the tongue prior to swallowing.
Another method is spray delivery. Of these various types of sublingual administration, spray delivery is preferred as it does not involve holding the composition under the tongue for an extended period of time as, for example, with a lozenge and it reduces the amount of material which is swallowed (and may enter the blood stream in a delayed manner via the gastrointestinal tract).
However it is not considered desirable to spray large volumes of liquid (eg greater than around 500 uL) to the sublingual cavity.
WO01/97780 (Ross) describes a pharmaceutical composition comprising a solution of an opioid analgesic (especially fentanyl, although buprenorphine is referred to) and a propellant, for sublingual aerosol administration. The example formulations are pressurized and therefore require complex packaging and actuation technology. Also they employ halogenated propellants which may not be environmentally friendly.
Weinberg et al (1988) Clin Pharmacol Ther 44, 335-342 discusses the adsorption of various opioids including buprenorphine (presented in an aqueous phosphate buffer at pH 6.5) when administered by pipette in liquid form to the sublingual cavity.
WO01/89476 (Pinney et al) discloses buffered compositons for transmucosal delivery.
Buprenorphine is mentioned in a very long list of possible active agents and is not exemplified.
Presently there are no spray compositions containing buprenorphine which have been made available commercially.
Thus an object of the present invention is to provide a spray composition containing buprenorphine for transmucosal, particularly sublingual, administration.
Further objects of the invention are to provide a spray composition containing buprenorphine for transmucosal (eg sublingual) administration with good physical properties, especially good stability and low environmental impact, and good biological properties, especially rapid onset of activity and efficacy at relatively low doses. Such a composition would mitigate many of the disadvantages of prior art compositions containing buprenorphine.
Thus according to a first aspect of the invention there is provided a non-pressurised pharmaceutical liquid solution spray composition comprising:
(i) buprenorphine; and (ii) a solvent comprising ethanol;
characterised in that the composition is substantially free of chloride.
The composition is non-pressurised i.e. is substantially free of any propellant. Exemplary propellants to be substantially avoided include volatile substances which develop significant vapour pressure at ambient temperature and pressure such as lower alkanes (eg propane, butane and the like) and halogenated hydrocarbons such as CFCs (P12 etc) and hydrofluorocarbons (P134a, P227 etc) as well as other propellants commonly used in aerosol presentations. Use of P11 is also preferably substantially avoided. By "substantially free" or "substantially avoided" is meant that an amount of less than 5% w/w based on weight of composition is employed, suitably less than 2% eg less than 0.1% w/w.
Preferably propellants are avoided altogether.
The concentration of the buprenorphine in the composition may typically vary between 0.05 and 12% w/v, more suitably 0.1-10% w/v, eg 0.1-4% w/v or especially 2-8% w/v, for example 4-8%
w/v eg 4% or 8% w/v (all figures being based on weight of buprenorphine base relative to total weight of composition).
By "substantially free of chloride" is meant that the formulation has a substantial absence of chloride in ionised (i.e. such that CI- is formed in solution) or unionised form. The reason for the substantial absence of chloride is to avoid the precipitation of buprenorphine hydrochloride which is not highly soluble in aqueous or ethanolic solvents. Thus the amount of chloride in the composition is suitably less than 3% w/w based on weight of buprenorphine eg less than 1%
w/w, eg less than 0.5% w/w for example less than 0.1 % w/w, especially when the pH of the composition is less than 7.
Preferably the buprenorphine is employed as base or as citrate, particularly as base.
An advantage of the invention, and in particular of use of buprenorphine in a formulation which is substantially free of chloride, is that relatively concentrated compositions can be prepared which allows for administration of high doses of buprenorphine without using excessively large metering volumes. For example, as will be explained below, we have successfully prepared solutions of concentration 4 and 8% w/v, whereas buprenorphine hydrochloride has not proved soluble in water or ethanol at these concentrations. These higher concentrations of buprenorphine are achieved by using a solvent containing a significant amount of ethanol and the highest concentrations are achieved by lowering the pH with citric acid.
Some sprayable non-pressurised analgesic compositions are taught in the art, for example in W002/094234 (Rabinowitz), WO 03/080022 (Birch) and WO 2004/071491 (Blondino).
W002/094234 relates to an opioid-containing aerosol formulation for administration by inhalation. The formulations are all aqueous solutions with no other solvent being suggested.
WO 03/080022 relates to aqueous solutions comprising an analgesic for intranasal administration. The analgesic may be buprenorphine or a salt thereof but there is no teaching that the composition should not contain chloride and indeed the examples all relate to compositions comprising buprenorphine hydrochloride. There is no suggestion that ethanol could be included in the solvent. WO 2004/071491 relates to liquid aerosol formulations in which the solvent may contain ethanol. There is no suggestion that it would be advantageous to provide a chloride-free composition and all of the examples relate to formulations containing buprenorphine hydrochloride.
Generally speaking it will be desired to employ the least amount of solvent necessary (or a modest excess over that necessary) to adequately solubilise the buprenorphine such that the buprenorphine remains in solution under the conditions of likely usage or exposure.
Typically the solvent is selected from ethanol and ethanol/water mixtures. In a first embodiment of the invention ethanol is substantially the only solvent. For example the concentration of ethanol in the solvent is greater than 90% w/w eg greater than 95% w/w particularly greater than 98% w/w, for example around 100% w/w (i.e. the solvent is ethanol, the presence of any water as contaminant from the atmosphere being ignored). In this first embodiment of the invention use of water as solvent is substantially avoided, for example the water concentration is less than 10% w/w eg less than 5% w/w particularly less than 98% w/w, for example around 0% w/w (i.e.
the composition is substantially free of water). As noted below, avoidance of water can be advantageous especially in formulations of buprenorphine containing citrate since we have observed that such formulations have a tendency to turn pink on storage.
In a second embodiment of the invention the solvent comprises water as well as ethanol. For example the solvent consists of a water/ethanol mixture in which the concentration of ethanol is approximately 30-90% w/w (the balance being water) for example approximately 40-70% w/w eg around 50% w/w.
Preferably water when employed as solvent meets the USP (US Pharmacopoeia), EP
(European Pharmacopoeia) "Purified Water" standards.
The pH of the solution may typically be between around 4 and 9.5 however will preferably be between around 4.5 and 9. In a first embodiment of the invention the pH is between 4 and 6 eg between around 4.5 and 6 eg around 5 or between around 4 and 5 eg around 4.5.
In a second embodiment of the invention, the pH is greater than 7 for instance between around 8 and 9.5 eg between around 8 and 9 eg around 8.5. It is envisaged that compositions at this higher pH
will be more efficacious and/or have more rapid activity. Without being limited by theory it is envisaged by the inventors that buprenorphine will be more rapidly or efficiently adsorbed through the mucosa, especially the sublingual mucosa, at a pH close to the pKa of buprenorphine, which is 8.5 (Pharmaceutical Codex). Compositions of pH above 7 have not thus far been described in concrete terms, presumably due to the predominant use of buprenorphine hydrochloride and the problems of solubility of the active at higher pH. Such problems are substantially overcome by use of compositions of the invention.
By "pH" is meant the pH reading that would be obtained using a conventional pH
meter eg model pH 211 manufactured by Hanna Instruments Ltd and Orion 420A manufactured by Thermo Electron Corporation (i.e. in water free systems the word "pH" would be construed to mean "apparent pH").
In order to adjust the pH buffer salts can be employed, however we have found that careful attention must be paid to the concentration of these due to the insolubility of many organic and inorganic salts in substantially ethanolic solvents. When buffers are employed, the preferred buffer system for lower pH ranges is citrate (eg sodium citrate)/citric acid which does have adequate solubility in ethanolic solvents. However citrate/citric acid is itself problematic since we have found that compositions of the invention containing citrate/citric acid and water have a tendency to turn pink on storage especially at elevated temperature.
Accordingly use of buffer salts and even citrate/citric acid is preferably avoided.
Suitably the use of phosphate containing buffers (eg phosphate and protonated derivatives such as hydrogen and dihydrogen phosphate) is also avoided. Thus the amount of phosphate in the composition (eg as phosphate per se or as a protonated derivative such as hydrogen or dihydrogen phosphate) is suitably less than 3% w/w based on weight of buprenorphine eg less than 1% w/w, eg less than 0.5% w/w for example less than 0.1 % w/w especially when the pH of the composition is less than 7.
We have found nevertheless that citric acid is useful to enhance the solubility of buprenorphine base in ethanolic solvents (eg to concentrations of 4% w/v or higher eg 4-8%
w/w (based on total weight of composition) particularly 5-8% w/w). In such compositions the solvent may (most suitably) be essentially ethanol (eg 100% ethanol) or may (alternatively) contain water (eg ethanol/water 1:1). In order to achieve these higher concentrations typically citric acid may be employed at a concentration of around 0.1-10% w/w eg 0.2-5% w/v eg 0.2-2% w/w.
In order to address the issue of pH adjustment of buprenorphine solutions and in particular without use of conventional buffer salts or use of chloride (eg as HCI) the inventors have appreciated that it may be possible to achieve this by the use of other organic formulation components. Accordingly we undertook a careful assessment of the impact on pH
on buprenorphine solutions by addition of saccharin or sodium saccharin optionally together with certain other formulation components such as menthol (eg L-menthol) or peppermint oil.
As a result of our investigations we discovered that the pH of buprenorphine base in ethanol is not significantly affected by buprenorphine concentration. However we surprisingly discovered that saccharin may be effectively employed to lower the pH of buprenorphine base compositions, and is particularly useful in achieving a pH in the range 4-6, particularly 4.5-6 eg around 5. The pH lowering effect of saccharin lessens with increased buprenorphine concentration. Addition of menthol (eg L-menthol) or peppermint oil has relatively little impact on pH when in conjunction with saccharin.
We also discovered that saccharin sodium as well as menthol (eg L-menthol) and peppermint oil all have a modest but potentially useful effect on raising the pH of buprenorphine base compositions in ethanol, and is particularly useful in achieving a pH in the range between about 8 and 9.5 eg between around 8 and 9 eg around 8.5.
The above mentioned results are illustrated in Figures 1 and 2.
As well as their above mentioned useful properties in modifying the pH of the compositions, saccharin and saccharin sodium are useful as sweeteners which improve patient acceptability.
As well as their above mentioned useful properties in modifying the pH of the compositions, menthol (eg L-menthol) and/or peppermint oil are useful as flavourings and moisturing agents which may have penetration enhancing activity.
The properties of the claimed compositions may be further improved by including therein a number of additional formulation components.
It may be desirable to include one or more of the following components in the composition - sweeteners such as saccharin, saccharin sodium, sucrose, flavouring or taste-masking agents (to improve patient acceptability), -moisturising agents (to improve patient comfort and overcome the drying tendency of ethanol and other polar organic solvents) for example peppermint oil, menthol (eg L-menthol) pineapple extract, lanolin, polypropylene glycol, polyethylene glycol.
-mucoadherents (in order to increase residency time on the mucosa) for example carboxyvinyl polymers, chitosans, polyacrylic acid, gelatin, polyvinyl pyrrolidone.
-preservatives (to improve long term resistance to microbial contamination) for example sodium metabisulphite, benzalkonium, Nipas.
-antioxidants for example alkyl gallates, butylated hydroxyanisole butylated hydroxytoluene, nordihydroguaiaretic acid, tocopherols, Ascorbic acid, sodium metabisulphite -anionic surfactants for example magnesium stearate, sodium cetostearyl sulphate, sodium lauryl sulphate, sodium oleate, sodium stearyl fumarate, sodium tetradecyl sulphate -nonionic surfactants for example glyceryl monostearate, Macrogol cetostearyl ethers, Poloxamers, polyoxyl stearates, Polysorbates, sorbitan esters, sucrose esters, Tyloxapol, propylene glycol monostearate, Quillaia, polyoxyl, caster oils, nonoxinols, lecithins and derivatives, oleic acid and derivatives, oleyl alcohol and derivatives -foaming agents for example alginic acid and salts, propylene glycol alginate, sodium lauryl sulphate, sodium cetostearyl sulphate, carbomers, hydroxyethylcellulose Amongst the above mentioned possible additional components, it may be remarked that a preservative should not normally be necessary in view of the ethanol content of the compositions.
In accordance with best pharmaceutical principles, additional components will be avoided if not necessary.
We have observed that compositions according to the invention which are of higher strength (eg 4 % w/v or above), especially those containing saccharin, have a tendency to yellow on storage, especially at higher temperatures. Accordingly a stabiliser selected from anti-oxidants (eg ascorbic acid/ascorbate) and/or a chelating agent (eg EDTA/sodium edetate) may suitably be employed.
Some of the components proposed above may already be included in the composition of the present invention for other purposes. Suitable moisturising agents include, for example, the polar organic solvents such as glycols, especially propylene glycol, and the liquid polyethylene glycols, glycerol, methylcellulose, hypromellose, hydroxypropylcellulose, and many other substituted celluloses.
As mentioned above, a versatile component, which improves the acceptability and other properties of the composition, is menthol especially L-menthol. Menthol (eg L-menthol), as well as flavouring the composition, has moisturising effect. It may also have effect as a penetration enhancer. Preferably menthol (eg L-menthol) is employed in a concentration range of 0.1 % to 0.75% w/w eg around 0.2% w/w.
Peppermint oil is an alternative component which may be used in place of menthol. Peppermint is known to have incompatibilities with certain actives (eg fentanyl) however it appears to be compatible with buprenorphine. Suitably peppermint oil is employed in a concentration range of 0.1 % to 0.75% w/w eg around 0.5% w/w.
In preferred embodiments of the invention, the composition contains a sweetener. In one embodiment of the invention, the sweetener is saccharin sodium. Suitably the concentration of saccharin sodium is around 0.1-0.9% w/w eg around 0.45% w/w.
In another embodiment of the invention, the composition contains saccharin.
Suitably the concentration of saccharin is around 0.025-0.75% w/w, for example around 0.05-0.4% w/w eg around 0.05-0.1 % w/w. As pointed out above the concentration of saccharin may be varied depending on the eventual pH desired (see Figure 2).
A number of compositions of the invention are considered to be especially suitable.
A suitable example composition comprises (or consists essentially of (eg consists of)):
-buprenorphine as base;
-a solvent selected from ethanol and ethanol/water mixtures;
wherein the composition is substantially free of chloride; and wherein the pH of the composition is greater than 7.
The pH of the composition may, for instance, be between around 8 and 9.5 eg between around 8 and 9 eg around 8.5.
The solvent may suitably be ethanol.
Optionally (and advantageously) such compositions comprise saccharin sodium.
Optionally (and advantageously) such compositions comprise a flavouring agent selected from menthol (eg L-menthol), peppermint oil and mixtures thereof.
Optionally such compositions comprise a chelating agent (eg EDTA or sodium edetate).
Optionally such compositions comprise an anti-oxidant.
Optionally hydroxide (eg NaOH, KOH) may be used to raise the pH if needed.
Suitably the concentration of buprenorphine base is 0.1-4% w/v.
Another suitable example composition comprises (or consist essentially of (eg consist of)):
-buprenorphine as base;
-a solvent selected from ethanol and ethanol/water mixtures;
-saccharin;
wherein the composition is substantially free of chloride; and wherein the pH
of the composition is between around 4 and 6 eg between around 4.5 and 6 eg around 5.
The solvent may suitably be ethanol.
Optionally (and advantageously) such compositions comprise a flavouring agent selected from menthol (eg L-menthol), peppermint oil and mixtures thereof.
Optionally such compositions comprise a chelating agent (eg EDTA or sodium edetate).
Optionally such compositions comprise an anti-oxidant.
Suitably the concentration of buprenorphine base is 0.1-4% w/v.
Another suitable example composition comprises (or consist essentially of (eg consist of)):
-buprenorphine as base at a concentration of 4% w/v or more;
-a solvent selected from ethanol and ethanol/water mixtures;
-citric acid;
wherein the composition is substantially free of chloride; and wherein the pH
of the composition is between around 4 and 6 eg between around 4 and 5 eg around 4.5.
The solvent may suitably be ethanol.
Optionally (and advantageously) such compositions comprise a flavouring agent selected from menthol (eg L-menthol), peppermint oil and mixtures thereof.
Optionally (and advantageously) such compositions comprise saccharin.
Optionally such compositions comprise a chelating agent (eg EDTA or sodium edetate).
Optionally such compositions comprise an anti-oxidant.
Suitably the concentration of buprenorphine base is 4-8% w/v.
A process for preparation of compositions of the invention comprises:
(a) taking buprenorphine as base and a solvent comprising ethanol optionally containing the other formulation ingredients (eg saccharin, saccharin sodium, menthol, peppermint oil etc) and dissolving the buprenorphine in the solvent; or (b) taking buprenorphine as base and a solvent comprising ethanol and dissolving the buprenorphine in the solvent, then adding the other formulation ingredients (eg saccharin, saccharin sodium, menthol, peppermint oil etc); or (c) the process of (a) or (b) in which the pH of the solvent is adjusted (eg with citric acid) once all the other formulation ingredients are mixed together.
Amongst the advantages of the claimed compositions is the fact that by being non-pressurised they avoid the issues associated with using propellant, such as their manufacturing disadvantages and their potential environmental impact (many propellants are "greenhouse gasses"). The solution compositions of the invention are homogenous and have limited or no susceptibility to dose-to-dose variation. Furthermore compositions of the present invention are characterised by good long-term physical and chemical stability.
The compositions of the invention are preferably administered transmucosally (particularly sublingually) as a spray. The compositions are expected to be well tolerated when administered to the sensitive sublingual mucosa and the sublingual spray administration will result in rapid onset of the therapeutic effect of the buprenorphine.
Thus according to a second aspect of the invention there is provided a metered dose dispensing system comprising a sealed container containing a composition of the invention fitted with a metering pump, an actuator and a channelling device. The metered dose dispensing system is preferably adapted for transmucosal (particularly sublingual) administration.
Although in principle the container for the pharmaceutical liquid composition may contain a single dose of buprenorphine (which may, nevertheless be a divided dose), preferably the container will contain a plurality of doses (eg 20 to 200 doses) of buprenorphine.
Although the composition could be packaged in a suitable pharmaceutical grade, plastics container, such a container would be relatively easy to open for abuse of the product. Therefore a glass container would be more suitable. Glass would shatter if attempts were made to open the pack, rendering the contents either lost or unusable due to glass fragments. Preferably the glass container will be coated on the exterior with a suitable moulded film of plastic to protect against shattering. For example the film may be of polypropylene. The material may be coloured and contain a UV absorber. The container glass may be colourless or more suitably may be provided with a UV protective colouring, for example amber colouring.
Optionally, the interior of the container can be coated to enhance stability of the product.
Coatings include polymers and lacquers but also silicone dioxide as an unreactive coating can be used to line the inside of the container.
Since the composition is non-pressurised, it is suitably administered to the patient by pump action. Thus the metering dose dispensing system suitably contains a metering pump permitting a metered dose of the composition to be administered as a spray.
Suitable metering pumps include those adapted for dispensation with the container in the upright or inverted orientation. Preferably the metering chamber is adapted for dispensation with the container in the upright orientation since this facilitates administration under the tongue.
Accordingly the metering chamber will be in communication with the composition by means of a dip-tube.
The metering pump is suitably a non-venting type. Suitable materials of construction include polypropylene and polyethylene. Example metering pumps are those manufactured by Valois (eg VP3, VP6, VP7 and VP7D) and for example those illustrated in International Patent Application No. WO01/66089. Other conventional pumps include those from Rexam (eg SP270) and Calmar (eg Accupump or Mistette Mk II).
Preferably the actuator will be designed to deliver a transmucosally (particularly a sublingually) effective dose. The pump may suitably be manually actuated, although assisted actuation using stored energy (eg spring or gas) may be contemplated.
For a secure seal, the pump is suitably crimped onto the container neck.
Suitable sealing materials eg thermo plastic crimp gaskets suitable for the purpose will be employed. In addition, a suitable aluminium ferrule purposely designed for crimping on to glass containers may suitably be employed. Suitable grade stainless steel springs will preferably be adopted.
The metering pump will administer a metered volume of composition. Suitable metering volumes are 10-1000 uL, more suitably 50-250 uL, eg 100uL or 200 uL, particularly 200 uL.
A channelling device is provided to direct the liquid sprayed from the metered dose dispensing area to the appropriate part of the mouth e.g. to the sublingual cavity or if desired to the nose.
Channelling devices are suitably fabricated from moulded plastics. A number of channelling devices adapted to administer sprays to the mouth or nose are known to persons skilled in the art eg Valois Spray Buttons Nasal Actuators Throat Actuators Dental Actuators 165 GPC CB 18 NEC 139 foldable Calmar Spray Buttons Nasal Actuators Throat Actuators Dental Actuators Standard Head 2-piece Nasal Short Throat Capillary Tube 3-piece Nasal Medium Throat Long Throat Articulated Throat Rexam Spray Buttons Nasal Actuators Throat Actuators Dental Actuators Compositions of the invention are useful in treatment or prevention of opiate dependency and abuse, particularly in the treatment or prevention of dependency on opiates such as heroin and for analgesic purposes eg for the treatment of moderate to severe pain. Thus in a further aspect of the invention there is provided a method of treatment or prevention of opiate dependency and abuse or pain which comprises administering to a subject in need thereof an effective amount of a composition of the invention. In a further aspect of the invention, there is provided the use of a composition according to the invention in the manufacture of a medicament for the treatment or prevention of opiate dependency and abuse or pain. In a further aspect, there is provided a composition of the invention for use in the treatment or prevention of opiate dependency and abuse or pain.
In order to lessen the risk of abuse with the product, suitably the container or the dispensing system may be provided with features to prevent tampering. In particular, the container or the dispensing system may suitably be provided with features to prevent or discourage access to the reservoir and/or to prevent administration of more than one dose of buprenorphine at one time.
The dispensing system, in particular the actuator, may, for example, be provided with a lock-out feature to prevent administration of a second dose within a specified time interval of the first.
Lock-out features are, for example, described in US2006191532, W003097141 and W00232487.
Typically a patient is treated by administration transmucosally (eg sublingually) of 1 to 4 actuations eg 1 or 2 actuations from the spray pump. Another advantage of mucosal spray delivery is the ability to easily titrate patients by 1 or 2 doses as required by a single actuation.
This is not the case with other forms of drug delivery (patches, lozenges, tablets, suppositories).
Pharmaceutical compositions of the invention are useful in the treatment of animals, particularly non-human mammals (for example domestic or livestock animals) as well as humans.
Accordingly pharmaceutical uses, for example uses in the treatment of pain, may be extended to veterinary uses. Dosages and methods of administration (eg the spray actuator design) will be adapted for the intended recipient as would be known to a skilled person.
Examples Examples 1-4 Compositions were prepared as follows:
Ex 1 Ex 2 Ex 3 Ex 4 Buprenorphine base (% w/v 0.2 0.1 0.1 0.1 Levomenthol (% w/w) 0.2 0.2 - -Peppermint oil (% w/w) - - - 0.5 Sodium saccharin (% w/w) 0.45 - 0.45 -Ethanol anhydrous (%) to 100 to 100 to 100 to 100 Measured pH 8.38 9.08 8.36 8.43 The compositions formed a clear colourless solution at 4, 25 and 40 C and remained so after 1 month storage at these temperatures.
Examples 5-8 Compositions were prepared as follows:
Ex 5 Ex 6 Ex 7 Ex 8 Buprenorphine base (% w/v 0.2 0.2 0.2 0.1 Levomenthol (% w/w) - 0.2 - -Peppermint oil (% w/w) - - 0.5 0.5 Saccharin (% w/w) 0.05 0.05 0.05 0.40 Ethanol anhydrous (%) to 100 to 100 to 100 to 100 Measured pH 4.92 4.93 4.97 2.94 The compositions formed a clear colourless solution at 4, 25 and 40 C and remained so after 2 weeks storage (Example 8) or 1 month storage (Examples 5-7) at these temperatures.
Examples 9-12 Compositions were prepared as follows:
Ex 9 Ex 10 Ex 11 Ex 12 Buprenorphine base (% w/v 0.1 0.1 0.2 0.1 Levomenthol (% w/w) 0.2 - - -Peppermint oil (% w/w) - 0.5 0.5 -Sodium saccharin (% w/w) 0.45 0.45 0.45 -Ethanol anhydrous (%) to 100 to 100 to 100 to 100 Measured pH 8.36 7.98 8.08 9.04 The compositions formed a clear colourless solution at 4, 25 and 40 C and remained so after 1 month storage at these temperatures.
Examples 13-16 Compositions were prepared as follows:
Ex 13 Ex 14 Ex 15 Ex 16 Buprenorphine base (% w/v 4 4 4 4 Levomenthol (% w/w) 0.2 - - 0.2 Peppermint oil (% w/w) - 0.5 - -Sodium saccharin (% w/w) - - - -Saccharin (% w/w) - - - -Ethanol anhydrous (%) to 100 to 100 to 100 to 100 Measured pH 8.63 8.35 8.67 NM
NM not measured Example 13: the composition formed a clear colourless solution at 4, 25 and 40 C. and remained so after 2 months storage at these temperatures.
Example 14: the composition formed a clear colourless solution at 4 and 25 C
and a clear very light yellow solution at 40 C after 2 months storage at these temperatures.
Examples 15, 16: the compositions formed a clear colourless solution at 4 and 25 C and a clear light yellow solution at 40 C after 3.5 months storage at these temperatures.
Examples 17-20 Compositions were prepared as follows:
Ex 17 Ex 18 Ex 19 Ex 20 Buprenorphine base (% w/v) 4 4 4 4 Levomenthol (% w/w) - 0.2 - 0.2 Peppermint oil (% w/w) - - 0.5 -Sodium saccharin (% w/w) - - - 0.45 Saccharin (% w/w) 0.40 0.40 0.40 Ethanol anhydrous (%) to 100 to 100 to 100 to 100 Measured pH 5.89 5.85 5.87 8.77 NM not measured Examples 17 and 18: the compositions formed a clear colourless solution at 4 and 25 C and a dark yellow solution at 40 C after 3.5 months storage at these temperatures.
Example 19: the composition formed a clear light yellow solution at 4 C, a clear yellow solution at 25 C and a clear dark yellow solution at 400C after 3.5 months storage at these temperatures.
Example 20: the composition formed a clear colourless solution at 4 C, a clear light yellow solution at 25 C and a clear yellow solution at 40 C after 2 months storage at these temperatures.
Examples 21-24 Compositions were prepared as follows:
Ex 21 Ex 22 Ex 23 Ex 24 Buprenorphine base (% w/v) 8 8 8 4 Levomenthol (% w/w) - - - -Peppermint oil (% w/w) - - - -Sodium saccharin (% w/w) - - - -Saccharin (% w/w) - - - -Citric acid % w/w 4.13 8.22 4.11 2.05 Water/ethanol 1:1 w/w (% to 100 to 100 w/w) Ethanol anhydrous % w/w to 100 to 100 - -Measured pH 4.83 4.20 4.55 4.64 Examples 21 and 22: the compositions formed a clear colourless solution at 4, a light yellow solution at 25 C and a yellow solution at 40 C after 3 months storage at these temperatures.
Example 23: the composition formed a clear colourless solution at 4 C and 25 C and a clear pink solution at 40 C after 3 months storage at these temperatures.
Example 24: the composition formed a clear colourless solution at 4 C and 25 C and a clear light pink solution at 40 C after 3 months storage at these temperatures.
Example 25 The dependence of apparent pH on buprenorphine base concentration in ethanol solution was investigated for various compositions. The results are shown in Figure 1.
The most striking observation is that saccharin has a significant effect on the composition apparent pH, which decreases with buprenorphine base concentration. The overlapping profiles at markedly lower pH was obtained from the 3 compositions containing (i) saccharin; (ii) saccharin with peppermint oil; and (iii) saccharin with L-menthol.
Example 26 The dependence of apparent pH on saccharin concentration in buprenorphine base (0.2% w/v) /
ethanol solution was investigated for various compositions. The results are shown in Figure 2.
Throughout the specification and the claims which follow, unless the context requires otherwise, the word `comprise', and variations such as `comprises' and `comprising', will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.
The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein.
They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims:
w/v eg 4% or 8% w/v (all figures being based on weight of buprenorphine base relative to total weight of composition).
By "substantially free of chloride" is meant that the formulation has a substantial absence of chloride in ionised (i.e. such that CI- is formed in solution) or unionised form. The reason for the substantial absence of chloride is to avoid the precipitation of buprenorphine hydrochloride which is not highly soluble in aqueous or ethanolic solvents. Thus the amount of chloride in the composition is suitably less than 3% w/w based on weight of buprenorphine eg less than 1%
w/w, eg less than 0.5% w/w for example less than 0.1 % w/w, especially when the pH of the composition is less than 7.
Preferably the buprenorphine is employed as base or as citrate, particularly as base.
An advantage of the invention, and in particular of use of buprenorphine in a formulation which is substantially free of chloride, is that relatively concentrated compositions can be prepared which allows for administration of high doses of buprenorphine without using excessively large metering volumes. For example, as will be explained below, we have successfully prepared solutions of concentration 4 and 8% w/v, whereas buprenorphine hydrochloride has not proved soluble in water or ethanol at these concentrations. These higher concentrations of buprenorphine are achieved by using a solvent containing a significant amount of ethanol and the highest concentrations are achieved by lowering the pH with citric acid.
Some sprayable non-pressurised analgesic compositions are taught in the art, for example in W002/094234 (Rabinowitz), WO 03/080022 (Birch) and WO 2004/071491 (Blondino).
W002/094234 relates to an opioid-containing aerosol formulation for administration by inhalation. The formulations are all aqueous solutions with no other solvent being suggested.
WO 03/080022 relates to aqueous solutions comprising an analgesic for intranasal administration. The analgesic may be buprenorphine or a salt thereof but there is no teaching that the composition should not contain chloride and indeed the examples all relate to compositions comprising buprenorphine hydrochloride. There is no suggestion that ethanol could be included in the solvent. WO 2004/071491 relates to liquid aerosol formulations in which the solvent may contain ethanol. There is no suggestion that it would be advantageous to provide a chloride-free composition and all of the examples relate to formulations containing buprenorphine hydrochloride.
Generally speaking it will be desired to employ the least amount of solvent necessary (or a modest excess over that necessary) to adequately solubilise the buprenorphine such that the buprenorphine remains in solution under the conditions of likely usage or exposure.
Typically the solvent is selected from ethanol and ethanol/water mixtures. In a first embodiment of the invention ethanol is substantially the only solvent. For example the concentration of ethanol in the solvent is greater than 90% w/w eg greater than 95% w/w particularly greater than 98% w/w, for example around 100% w/w (i.e. the solvent is ethanol, the presence of any water as contaminant from the atmosphere being ignored). In this first embodiment of the invention use of water as solvent is substantially avoided, for example the water concentration is less than 10% w/w eg less than 5% w/w particularly less than 98% w/w, for example around 0% w/w (i.e.
the composition is substantially free of water). As noted below, avoidance of water can be advantageous especially in formulations of buprenorphine containing citrate since we have observed that such formulations have a tendency to turn pink on storage.
In a second embodiment of the invention the solvent comprises water as well as ethanol. For example the solvent consists of a water/ethanol mixture in which the concentration of ethanol is approximately 30-90% w/w (the balance being water) for example approximately 40-70% w/w eg around 50% w/w.
Preferably water when employed as solvent meets the USP (US Pharmacopoeia), EP
(European Pharmacopoeia) "Purified Water" standards.
The pH of the solution may typically be between around 4 and 9.5 however will preferably be between around 4.5 and 9. In a first embodiment of the invention the pH is between 4 and 6 eg between around 4.5 and 6 eg around 5 or between around 4 and 5 eg around 4.5.
In a second embodiment of the invention, the pH is greater than 7 for instance between around 8 and 9.5 eg between around 8 and 9 eg around 8.5. It is envisaged that compositions at this higher pH
will be more efficacious and/or have more rapid activity. Without being limited by theory it is envisaged by the inventors that buprenorphine will be more rapidly or efficiently adsorbed through the mucosa, especially the sublingual mucosa, at a pH close to the pKa of buprenorphine, which is 8.5 (Pharmaceutical Codex). Compositions of pH above 7 have not thus far been described in concrete terms, presumably due to the predominant use of buprenorphine hydrochloride and the problems of solubility of the active at higher pH. Such problems are substantially overcome by use of compositions of the invention.
By "pH" is meant the pH reading that would be obtained using a conventional pH
meter eg model pH 211 manufactured by Hanna Instruments Ltd and Orion 420A manufactured by Thermo Electron Corporation (i.e. in water free systems the word "pH" would be construed to mean "apparent pH").
In order to adjust the pH buffer salts can be employed, however we have found that careful attention must be paid to the concentration of these due to the insolubility of many organic and inorganic salts in substantially ethanolic solvents. When buffers are employed, the preferred buffer system for lower pH ranges is citrate (eg sodium citrate)/citric acid which does have adequate solubility in ethanolic solvents. However citrate/citric acid is itself problematic since we have found that compositions of the invention containing citrate/citric acid and water have a tendency to turn pink on storage especially at elevated temperature.
Accordingly use of buffer salts and even citrate/citric acid is preferably avoided.
Suitably the use of phosphate containing buffers (eg phosphate and protonated derivatives such as hydrogen and dihydrogen phosphate) is also avoided. Thus the amount of phosphate in the composition (eg as phosphate per se or as a protonated derivative such as hydrogen or dihydrogen phosphate) is suitably less than 3% w/w based on weight of buprenorphine eg less than 1% w/w, eg less than 0.5% w/w for example less than 0.1 % w/w especially when the pH of the composition is less than 7.
We have found nevertheless that citric acid is useful to enhance the solubility of buprenorphine base in ethanolic solvents (eg to concentrations of 4% w/v or higher eg 4-8%
w/w (based on total weight of composition) particularly 5-8% w/w). In such compositions the solvent may (most suitably) be essentially ethanol (eg 100% ethanol) or may (alternatively) contain water (eg ethanol/water 1:1). In order to achieve these higher concentrations typically citric acid may be employed at a concentration of around 0.1-10% w/w eg 0.2-5% w/v eg 0.2-2% w/w.
In order to address the issue of pH adjustment of buprenorphine solutions and in particular without use of conventional buffer salts or use of chloride (eg as HCI) the inventors have appreciated that it may be possible to achieve this by the use of other organic formulation components. Accordingly we undertook a careful assessment of the impact on pH
on buprenorphine solutions by addition of saccharin or sodium saccharin optionally together with certain other formulation components such as menthol (eg L-menthol) or peppermint oil.
As a result of our investigations we discovered that the pH of buprenorphine base in ethanol is not significantly affected by buprenorphine concentration. However we surprisingly discovered that saccharin may be effectively employed to lower the pH of buprenorphine base compositions, and is particularly useful in achieving a pH in the range 4-6, particularly 4.5-6 eg around 5. The pH lowering effect of saccharin lessens with increased buprenorphine concentration. Addition of menthol (eg L-menthol) or peppermint oil has relatively little impact on pH when in conjunction with saccharin.
We also discovered that saccharin sodium as well as menthol (eg L-menthol) and peppermint oil all have a modest but potentially useful effect on raising the pH of buprenorphine base compositions in ethanol, and is particularly useful in achieving a pH in the range between about 8 and 9.5 eg between around 8 and 9 eg around 8.5.
The above mentioned results are illustrated in Figures 1 and 2.
As well as their above mentioned useful properties in modifying the pH of the compositions, saccharin and saccharin sodium are useful as sweeteners which improve patient acceptability.
As well as their above mentioned useful properties in modifying the pH of the compositions, menthol (eg L-menthol) and/or peppermint oil are useful as flavourings and moisturing agents which may have penetration enhancing activity.
The properties of the claimed compositions may be further improved by including therein a number of additional formulation components.
It may be desirable to include one or more of the following components in the composition - sweeteners such as saccharin, saccharin sodium, sucrose, flavouring or taste-masking agents (to improve patient acceptability), -moisturising agents (to improve patient comfort and overcome the drying tendency of ethanol and other polar organic solvents) for example peppermint oil, menthol (eg L-menthol) pineapple extract, lanolin, polypropylene glycol, polyethylene glycol.
-mucoadherents (in order to increase residency time on the mucosa) for example carboxyvinyl polymers, chitosans, polyacrylic acid, gelatin, polyvinyl pyrrolidone.
-preservatives (to improve long term resistance to microbial contamination) for example sodium metabisulphite, benzalkonium, Nipas.
-antioxidants for example alkyl gallates, butylated hydroxyanisole butylated hydroxytoluene, nordihydroguaiaretic acid, tocopherols, Ascorbic acid, sodium metabisulphite -anionic surfactants for example magnesium stearate, sodium cetostearyl sulphate, sodium lauryl sulphate, sodium oleate, sodium stearyl fumarate, sodium tetradecyl sulphate -nonionic surfactants for example glyceryl monostearate, Macrogol cetostearyl ethers, Poloxamers, polyoxyl stearates, Polysorbates, sorbitan esters, sucrose esters, Tyloxapol, propylene glycol monostearate, Quillaia, polyoxyl, caster oils, nonoxinols, lecithins and derivatives, oleic acid and derivatives, oleyl alcohol and derivatives -foaming agents for example alginic acid and salts, propylene glycol alginate, sodium lauryl sulphate, sodium cetostearyl sulphate, carbomers, hydroxyethylcellulose Amongst the above mentioned possible additional components, it may be remarked that a preservative should not normally be necessary in view of the ethanol content of the compositions.
In accordance with best pharmaceutical principles, additional components will be avoided if not necessary.
We have observed that compositions according to the invention which are of higher strength (eg 4 % w/v or above), especially those containing saccharin, have a tendency to yellow on storage, especially at higher temperatures. Accordingly a stabiliser selected from anti-oxidants (eg ascorbic acid/ascorbate) and/or a chelating agent (eg EDTA/sodium edetate) may suitably be employed.
Some of the components proposed above may already be included in the composition of the present invention for other purposes. Suitable moisturising agents include, for example, the polar organic solvents such as glycols, especially propylene glycol, and the liquid polyethylene glycols, glycerol, methylcellulose, hypromellose, hydroxypropylcellulose, and many other substituted celluloses.
As mentioned above, a versatile component, which improves the acceptability and other properties of the composition, is menthol especially L-menthol. Menthol (eg L-menthol), as well as flavouring the composition, has moisturising effect. It may also have effect as a penetration enhancer. Preferably menthol (eg L-menthol) is employed in a concentration range of 0.1 % to 0.75% w/w eg around 0.2% w/w.
Peppermint oil is an alternative component which may be used in place of menthol. Peppermint is known to have incompatibilities with certain actives (eg fentanyl) however it appears to be compatible with buprenorphine. Suitably peppermint oil is employed in a concentration range of 0.1 % to 0.75% w/w eg around 0.5% w/w.
In preferred embodiments of the invention, the composition contains a sweetener. In one embodiment of the invention, the sweetener is saccharin sodium. Suitably the concentration of saccharin sodium is around 0.1-0.9% w/w eg around 0.45% w/w.
In another embodiment of the invention, the composition contains saccharin.
Suitably the concentration of saccharin is around 0.025-0.75% w/w, for example around 0.05-0.4% w/w eg around 0.05-0.1 % w/w. As pointed out above the concentration of saccharin may be varied depending on the eventual pH desired (see Figure 2).
A number of compositions of the invention are considered to be especially suitable.
A suitable example composition comprises (or consists essentially of (eg consists of)):
-buprenorphine as base;
-a solvent selected from ethanol and ethanol/water mixtures;
wherein the composition is substantially free of chloride; and wherein the pH of the composition is greater than 7.
The pH of the composition may, for instance, be between around 8 and 9.5 eg between around 8 and 9 eg around 8.5.
The solvent may suitably be ethanol.
Optionally (and advantageously) such compositions comprise saccharin sodium.
Optionally (and advantageously) such compositions comprise a flavouring agent selected from menthol (eg L-menthol), peppermint oil and mixtures thereof.
Optionally such compositions comprise a chelating agent (eg EDTA or sodium edetate).
Optionally such compositions comprise an anti-oxidant.
Optionally hydroxide (eg NaOH, KOH) may be used to raise the pH if needed.
Suitably the concentration of buprenorphine base is 0.1-4% w/v.
Another suitable example composition comprises (or consist essentially of (eg consist of)):
-buprenorphine as base;
-a solvent selected from ethanol and ethanol/water mixtures;
-saccharin;
wherein the composition is substantially free of chloride; and wherein the pH
of the composition is between around 4 and 6 eg between around 4.5 and 6 eg around 5.
The solvent may suitably be ethanol.
Optionally (and advantageously) such compositions comprise a flavouring agent selected from menthol (eg L-menthol), peppermint oil and mixtures thereof.
Optionally such compositions comprise a chelating agent (eg EDTA or sodium edetate).
Optionally such compositions comprise an anti-oxidant.
Suitably the concentration of buprenorphine base is 0.1-4% w/v.
Another suitable example composition comprises (or consist essentially of (eg consist of)):
-buprenorphine as base at a concentration of 4% w/v or more;
-a solvent selected from ethanol and ethanol/water mixtures;
-citric acid;
wherein the composition is substantially free of chloride; and wherein the pH
of the composition is between around 4 and 6 eg between around 4 and 5 eg around 4.5.
The solvent may suitably be ethanol.
Optionally (and advantageously) such compositions comprise a flavouring agent selected from menthol (eg L-menthol), peppermint oil and mixtures thereof.
Optionally (and advantageously) such compositions comprise saccharin.
Optionally such compositions comprise a chelating agent (eg EDTA or sodium edetate).
Optionally such compositions comprise an anti-oxidant.
Suitably the concentration of buprenorphine base is 4-8% w/v.
A process for preparation of compositions of the invention comprises:
(a) taking buprenorphine as base and a solvent comprising ethanol optionally containing the other formulation ingredients (eg saccharin, saccharin sodium, menthol, peppermint oil etc) and dissolving the buprenorphine in the solvent; or (b) taking buprenorphine as base and a solvent comprising ethanol and dissolving the buprenorphine in the solvent, then adding the other formulation ingredients (eg saccharin, saccharin sodium, menthol, peppermint oil etc); or (c) the process of (a) or (b) in which the pH of the solvent is adjusted (eg with citric acid) once all the other formulation ingredients are mixed together.
Amongst the advantages of the claimed compositions is the fact that by being non-pressurised they avoid the issues associated with using propellant, such as their manufacturing disadvantages and their potential environmental impact (many propellants are "greenhouse gasses"). The solution compositions of the invention are homogenous and have limited or no susceptibility to dose-to-dose variation. Furthermore compositions of the present invention are characterised by good long-term physical and chemical stability.
The compositions of the invention are preferably administered transmucosally (particularly sublingually) as a spray. The compositions are expected to be well tolerated when administered to the sensitive sublingual mucosa and the sublingual spray administration will result in rapid onset of the therapeutic effect of the buprenorphine.
Thus according to a second aspect of the invention there is provided a metered dose dispensing system comprising a sealed container containing a composition of the invention fitted with a metering pump, an actuator and a channelling device. The metered dose dispensing system is preferably adapted for transmucosal (particularly sublingual) administration.
Although in principle the container for the pharmaceutical liquid composition may contain a single dose of buprenorphine (which may, nevertheless be a divided dose), preferably the container will contain a plurality of doses (eg 20 to 200 doses) of buprenorphine.
Although the composition could be packaged in a suitable pharmaceutical grade, plastics container, such a container would be relatively easy to open for abuse of the product. Therefore a glass container would be more suitable. Glass would shatter if attempts were made to open the pack, rendering the contents either lost or unusable due to glass fragments. Preferably the glass container will be coated on the exterior with a suitable moulded film of plastic to protect against shattering. For example the film may be of polypropylene. The material may be coloured and contain a UV absorber. The container glass may be colourless or more suitably may be provided with a UV protective colouring, for example amber colouring.
Optionally, the interior of the container can be coated to enhance stability of the product.
Coatings include polymers and lacquers but also silicone dioxide as an unreactive coating can be used to line the inside of the container.
Since the composition is non-pressurised, it is suitably administered to the patient by pump action. Thus the metering dose dispensing system suitably contains a metering pump permitting a metered dose of the composition to be administered as a spray.
Suitable metering pumps include those adapted for dispensation with the container in the upright or inverted orientation. Preferably the metering chamber is adapted for dispensation with the container in the upright orientation since this facilitates administration under the tongue.
Accordingly the metering chamber will be in communication with the composition by means of a dip-tube.
The metering pump is suitably a non-venting type. Suitable materials of construction include polypropylene and polyethylene. Example metering pumps are those manufactured by Valois (eg VP3, VP6, VP7 and VP7D) and for example those illustrated in International Patent Application No. WO01/66089. Other conventional pumps include those from Rexam (eg SP270) and Calmar (eg Accupump or Mistette Mk II).
Preferably the actuator will be designed to deliver a transmucosally (particularly a sublingually) effective dose. The pump may suitably be manually actuated, although assisted actuation using stored energy (eg spring or gas) may be contemplated.
For a secure seal, the pump is suitably crimped onto the container neck.
Suitable sealing materials eg thermo plastic crimp gaskets suitable for the purpose will be employed. In addition, a suitable aluminium ferrule purposely designed for crimping on to glass containers may suitably be employed. Suitable grade stainless steel springs will preferably be adopted.
The metering pump will administer a metered volume of composition. Suitable metering volumes are 10-1000 uL, more suitably 50-250 uL, eg 100uL or 200 uL, particularly 200 uL.
A channelling device is provided to direct the liquid sprayed from the metered dose dispensing area to the appropriate part of the mouth e.g. to the sublingual cavity or if desired to the nose.
Channelling devices are suitably fabricated from moulded plastics. A number of channelling devices adapted to administer sprays to the mouth or nose are known to persons skilled in the art eg Valois Spray Buttons Nasal Actuators Throat Actuators Dental Actuators 165 GPC CB 18 NEC 139 foldable Calmar Spray Buttons Nasal Actuators Throat Actuators Dental Actuators Standard Head 2-piece Nasal Short Throat Capillary Tube 3-piece Nasal Medium Throat Long Throat Articulated Throat Rexam Spray Buttons Nasal Actuators Throat Actuators Dental Actuators Compositions of the invention are useful in treatment or prevention of opiate dependency and abuse, particularly in the treatment or prevention of dependency on opiates such as heroin and for analgesic purposes eg for the treatment of moderate to severe pain. Thus in a further aspect of the invention there is provided a method of treatment or prevention of opiate dependency and abuse or pain which comprises administering to a subject in need thereof an effective amount of a composition of the invention. In a further aspect of the invention, there is provided the use of a composition according to the invention in the manufacture of a medicament for the treatment or prevention of opiate dependency and abuse or pain. In a further aspect, there is provided a composition of the invention for use in the treatment or prevention of opiate dependency and abuse or pain.
In order to lessen the risk of abuse with the product, suitably the container or the dispensing system may be provided with features to prevent tampering. In particular, the container or the dispensing system may suitably be provided with features to prevent or discourage access to the reservoir and/or to prevent administration of more than one dose of buprenorphine at one time.
The dispensing system, in particular the actuator, may, for example, be provided with a lock-out feature to prevent administration of a second dose within a specified time interval of the first.
Lock-out features are, for example, described in US2006191532, W003097141 and W00232487.
Typically a patient is treated by administration transmucosally (eg sublingually) of 1 to 4 actuations eg 1 or 2 actuations from the spray pump. Another advantage of mucosal spray delivery is the ability to easily titrate patients by 1 or 2 doses as required by a single actuation.
This is not the case with other forms of drug delivery (patches, lozenges, tablets, suppositories).
Pharmaceutical compositions of the invention are useful in the treatment of animals, particularly non-human mammals (for example domestic or livestock animals) as well as humans.
Accordingly pharmaceutical uses, for example uses in the treatment of pain, may be extended to veterinary uses. Dosages and methods of administration (eg the spray actuator design) will be adapted for the intended recipient as would be known to a skilled person.
Examples Examples 1-4 Compositions were prepared as follows:
Ex 1 Ex 2 Ex 3 Ex 4 Buprenorphine base (% w/v 0.2 0.1 0.1 0.1 Levomenthol (% w/w) 0.2 0.2 - -Peppermint oil (% w/w) - - - 0.5 Sodium saccharin (% w/w) 0.45 - 0.45 -Ethanol anhydrous (%) to 100 to 100 to 100 to 100 Measured pH 8.38 9.08 8.36 8.43 The compositions formed a clear colourless solution at 4, 25 and 40 C and remained so after 1 month storage at these temperatures.
Examples 5-8 Compositions were prepared as follows:
Ex 5 Ex 6 Ex 7 Ex 8 Buprenorphine base (% w/v 0.2 0.2 0.2 0.1 Levomenthol (% w/w) - 0.2 - -Peppermint oil (% w/w) - - 0.5 0.5 Saccharin (% w/w) 0.05 0.05 0.05 0.40 Ethanol anhydrous (%) to 100 to 100 to 100 to 100 Measured pH 4.92 4.93 4.97 2.94 The compositions formed a clear colourless solution at 4, 25 and 40 C and remained so after 2 weeks storage (Example 8) or 1 month storage (Examples 5-7) at these temperatures.
Examples 9-12 Compositions were prepared as follows:
Ex 9 Ex 10 Ex 11 Ex 12 Buprenorphine base (% w/v 0.1 0.1 0.2 0.1 Levomenthol (% w/w) 0.2 - - -Peppermint oil (% w/w) - 0.5 0.5 -Sodium saccharin (% w/w) 0.45 0.45 0.45 -Ethanol anhydrous (%) to 100 to 100 to 100 to 100 Measured pH 8.36 7.98 8.08 9.04 The compositions formed a clear colourless solution at 4, 25 and 40 C and remained so after 1 month storage at these temperatures.
Examples 13-16 Compositions were prepared as follows:
Ex 13 Ex 14 Ex 15 Ex 16 Buprenorphine base (% w/v 4 4 4 4 Levomenthol (% w/w) 0.2 - - 0.2 Peppermint oil (% w/w) - 0.5 - -Sodium saccharin (% w/w) - - - -Saccharin (% w/w) - - - -Ethanol anhydrous (%) to 100 to 100 to 100 to 100 Measured pH 8.63 8.35 8.67 NM
NM not measured Example 13: the composition formed a clear colourless solution at 4, 25 and 40 C. and remained so after 2 months storage at these temperatures.
Example 14: the composition formed a clear colourless solution at 4 and 25 C
and a clear very light yellow solution at 40 C after 2 months storage at these temperatures.
Examples 15, 16: the compositions formed a clear colourless solution at 4 and 25 C and a clear light yellow solution at 40 C after 3.5 months storage at these temperatures.
Examples 17-20 Compositions were prepared as follows:
Ex 17 Ex 18 Ex 19 Ex 20 Buprenorphine base (% w/v) 4 4 4 4 Levomenthol (% w/w) - 0.2 - 0.2 Peppermint oil (% w/w) - - 0.5 -Sodium saccharin (% w/w) - - - 0.45 Saccharin (% w/w) 0.40 0.40 0.40 Ethanol anhydrous (%) to 100 to 100 to 100 to 100 Measured pH 5.89 5.85 5.87 8.77 NM not measured Examples 17 and 18: the compositions formed a clear colourless solution at 4 and 25 C and a dark yellow solution at 40 C after 3.5 months storage at these temperatures.
Example 19: the composition formed a clear light yellow solution at 4 C, a clear yellow solution at 25 C and a clear dark yellow solution at 400C after 3.5 months storage at these temperatures.
Example 20: the composition formed a clear colourless solution at 4 C, a clear light yellow solution at 25 C and a clear yellow solution at 40 C after 2 months storage at these temperatures.
Examples 21-24 Compositions were prepared as follows:
Ex 21 Ex 22 Ex 23 Ex 24 Buprenorphine base (% w/v) 8 8 8 4 Levomenthol (% w/w) - - - -Peppermint oil (% w/w) - - - -Sodium saccharin (% w/w) - - - -Saccharin (% w/w) - - - -Citric acid % w/w 4.13 8.22 4.11 2.05 Water/ethanol 1:1 w/w (% to 100 to 100 w/w) Ethanol anhydrous % w/w to 100 to 100 - -Measured pH 4.83 4.20 4.55 4.64 Examples 21 and 22: the compositions formed a clear colourless solution at 4, a light yellow solution at 25 C and a yellow solution at 40 C after 3 months storage at these temperatures.
Example 23: the composition formed a clear colourless solution at 4 C and 25 C and a clear pink solution at 40 C after 3 months storage at these temperatures.
Example 24: the composition formed a clear colourless solution at 4 C and 25 C and a clear light pink solution at 40 C after 3 months storage at these temperatures.
Example 25 The dependence of apparent pH on buprenorphine base concentration in ethanol solution was investigated for various compositions. The results are shown in Figure 1.
The most striking observation is that saccharin has a significant effect on the composition apparent pH, which decreases with buprenorphine base concentration. The overlapping profiles at markedly lower pH was obtained from the 3 compositions containing (i) saccharin; (ii) saccharin with peppermint oil; and (iii) saccharin with L-menthol.
Example 26 The dependence of apparent pH on saccharin concentration in buprenorphine base (0.2% w/v) /
ethanol solution was investigated for various compositions. The results are shown in Figure 2.
Throughout the specification and the claims which follow, unless the context requires otherwise, the word `comprise', and variations such as `comprises' and `comprising', will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.
The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein.
They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims:
Claims (36)
1. A non-pressurised pharmaceutical liquid solution spray composition comprising:
(i) buprenorphine; and (ii) a solvent comprising ethanol characterised in that the composition is substantially free of chloride.
(i) buprenorphine; and (ii) a solvent comprising ethanol characterised in that the composition is substantially free of chloride.
2. A composition according to claim 1 wherein the concentration of ethanol in the solvent is greater than 90% w/w.
3. A composition according to claim 1 or claim 2 which is substantially free of water.
4. A composition according to claim 2 or claim 3 wherein the concentration of ethanol in the solvent is around 100% w/w.
5. A composition according to claim 1 wherein the concentration of ethanol in the solvent is approximately 30-90% w/w, the balance being water.
6. A composition according to any one of claims 1-5 wherein the concentration of buprenorphine in the composition is around 0.05-12% w/v.
7. A composition according to claim 6 wherein the concentration of buprenorphine in the composition is around 2-8% w/v.
8. A composition according to any one of claims 1-7 wherein the pH of the composition is between around 4 and 6.
9. A composition according to any one of claims 1-7 wherein the pH of the composition is between around 8 and 9.5.
10. A composition according to claim 8 which contains saccharin.
11. A composition according to claim 9 which contains saccharin sodium.
12. A composition according to any one of claims 1 to 11 which contains menthol.
13. A composition according to any one of claims 1 to 12 which contains peppermint oil.
14. A composition according to claim 1 comprising:
-buprenorphine as base;
-a solvent selected from ethanol and ethanol/water mixtures;
wherein the composition is substantially free of chloride; and wherein the pH of the composition is greater than 7.
-buprenorphine as base;
-a solvent selected from ethanol and ethanol/water mixtures;
wherein the composition is substantially free of chloride; and wherein the pH of the composition is greater than 7.
15. A composition according to claim 14 wherein the pH of the composition is between around 8 and 9.
16. A composition according to claim 14 or claim 15 which comprises saccharin sodium.
17. A composition according to claim 1 which comprises -buprenorphine as base;
-a solvent selected from ethanol and ethanol/water mixtures;
-saccharin;
wherein the composition is substantially free of chloride; and wherein the pH
of the composition is between around 4 and 6.
-a solvent selected from ethanol and ethanol/water mixtures;
-saccharin;
wherein the composition is substantially free of chloride; and wherein the pH
of the composition is between around 4 and 6.
18. A composition according to any one of claims 14 to 17 wherein the concentration of buprenorphine base is 0.1-4% w/v.
19. A composition according to claim 1 which comprises:
-buprenorphine as base at a concentration of 4% w/v or more;
-a solvent selected from ethanol and ethanol/water mixtures;
-citric acid;
wherein the composition is substantially free of chloride; and wherein the pH
of the composition is between around 4 and 6.
-buprenorphine as base at a concentration of 4% w/v or more;
-a solvent selected from ethanol and ethanol/water mixtures;
-citric acid;
wherein the composition is substantially free of chloride; and wherein the pH
of the composition is between around 4 and 6.
20. A composition according to claim 19 which comprises saccharin.
21. A composition according to any one of claims 14 to 20 wherein the solvent is ethanol.
22. A composition according to claim 19 or claim 20 wherein the solvent is an ethanol/water mixture.
23. A composition according to any one of claims 14 to 22 which comprises a flavouring agent selected from menthol, peppermint oil and mixtures thereof.
24. A composition according to any one of claims 14 to 23 which comprises a chelating agent.
25. A composition according to any one of claims 14 to 24 which comprises an anti-oxidant.
26. A composition according to any one of the preceding claims for transmucosal administration as a spray.
27. A composition according to claim 26 wherein the transmucosal administration is sublingual administration.
28. A composition according to any one of the preceding claims, for use in the treatment or prevention of opiate dependency or abuse or pain.
29. Use of a composition according to any one of claims 1 to 28 in the manufacture of a medicament for the treatment or prevention of opiate dependency or abuse or pain.
30. A sealed container containing a plurality of doses of a composition according to any one of claims 1 to 28.
31. A container according to claim 30 which is made out of glass.
32. A metered dose dispensing system comprising a sealed container according to claim 30 or claim 31 fitted with a metering pump, an actuator and a channelling device.
33. A metered dose dispensing system according to claim 32 containing a metering chamber which is adapted for dispensation with the container in the upright orientation and wherein the metering chamber is in communication with the composition by means of a dip-tube.
34. A metered dose dispensing system according to claim 32 or claim 33 adapted for transmucosal administration of the composition as a spray.
35. A metered dose dispensing system according to claim 34 wherein the transmucosal administration is sublingual administration.
36. A process for preparation a composition according to any one of claims 1 to 28 which comprises:
(a) taking buprenorphine as base and a solvent comprising ethanol optionally containing the other formulation ingredients and dissolving the buprenorphine in the solvent; or (b) taking buprenorphine as base and a solvent comprising ethanol and dissolving the buprenorphine in the solvent, then adding the other formulation ingredients;
or (c) the process of (a) or (b) in which the pH of the solvent is adjusted once all the other formulation ingredients are mixed together.
(a) taking buprenorphine as base and a solvent comprising ethanol optionally containing the other formulation ingredients and dissolving the buprenorphine in the solvent; or (b) taking buprenorphine as base and a solvent comprising ethanol and dissolving the buprenorphine in the solvent, then adding the other formulation ingredients;
or (c) the process of (a) or (b) in which the pH of the solvent is adjusted once all the other formulation ingredients are mixed together.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0620661.9 | 2006-10-18 | ||
| GBGB0620661.9A GB0620661D0 (en) | 2006-10-18 | 2006-10-18 | Novel compounds |
| PCT/GB2007/050639 WO2008047163A1 (en) | 2006-10-18 | 2007-10-17 | Buprenorphine-containing non-pressurised spray composition for transmucosal administration |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2666581A1 true CA2666581A1 (en) | 2008-04-24 |
Family
ID=37507923
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002666581A Abandoned CA2666581A1 (en) | 2006-10-18 | 2007-10-17 | Buprenorphine-containing non-pressurised spray composition for transmucosal administration |
Country Status (8)
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|---|---|
| EP (1) | EP2081574A1 (en) |
| CN (1) | CN101573116A (en) |
| AU (1) | AU2007311621A1 (en) |
| CA (1) | CA2666581A1 (en) |
| GB (2) | GB0620661D0 (en) |
| IL (1) | IL197908A0 (en) |
| WO (1) | WO2008047163A1 (en) |
| ZA (1) | ZA200902123B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8852638B2 (en) | 2005-09-30 | 2014-10-07 | Durect Corporation | Sustained release small molecule drug formulation |
| CN103550136B (en) | 2006-07-21 | 2016-04-13 | 生物递送科学国际公司 | The transmucosal delivery devices of influx and translocation |
| GB2461681A (en) * | 2008-04-17 | 2010-01-13 | Pharmasol Ltd | Buprenorphine liquid spray formulation with solvent and antioxidant |
| NZ581862A (en) | 2007-05-25 | 2012-06-29 | Tolmar Therapeutics Inc | Injectable subcutaneous formulation comprising risperidone capable of forming a solid, microporous implant in a patient |
| WO2010072398A2 (en) * | 2008-12-22 | 2010-07-01 | Boehringer Ingelheim Limited | Veterinary formulations |
| US9272044B2 (en) | 2010-06-08 | 2016-03-01 | Indivior Uk Limited | Injectable flowable composition buprenorphine |
| GB2481017B (en) | 2010-06-08 | 2015-01-07 | Rb Pharmaceuticals Ltd | Microparticle buprenorphine suspension |
| GB2481728B (en) * | 2010-06-30 | 2012-05-23 | Londonpharma Ltd | Formulations and delivery devices for the sublingual administration of opioids |
| US9901539B2 (en) | 2011-12-21 | 2018-02-27 | Biodelivery Sciences International, Inc. | Transmucosal drug delivery devices for use in chronic pain relief |
| IN2014DN06117A (en) * | 2011-12-21 | 2015-08-14 | Biodelivery Sciences Int Inc | |
| GB201404139D0 (en) | 2014-03-10 | 2014-04-23 | Rb Pharmaceuticals Ltd | Sustained release buprenorphine solution formulations |
| CA3003293A1 (en) | 2015-10-27 | 2017-05-04 | Insys Development Company, Inc. | Liquid buprenorphine formulations |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030190290A1 (en) * | 2000-06-22 | 2003-10-09 | Calvin Ross | Pharmaceutical compositions |
| US6737042B2 (en) * | 2001-05-24 | 2004-05-18 | Alexza Molecular Delivery Corporation | Delivery of drug esters through an inhalation route |
| JP2006516963A (en) * | 2003-02-04 | 2006-07-13 | クリサリス テクノロジーズ インコーポレイテッド | Aerosol formulation and aerosol delivery of buspirone, buprenorphine, triazolam, cyclobenzaprine and zolpidem |
| EP1745247B1 (en) * | 2004-04-23 | 2015-11-11 | Philip Morris Products S.a.s. | Aerosol generators and methods for producing aerosols |
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2006
- 2006-10-18 GB GBGB0620661.9A patent/GB0620661D0/en not_active Ceased
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2007
- 2007-10-17 WO PCT/GB2007/050639 patent/WO2008047163A1/en active Application Filing
- 2007-10-17 AU AU2007311621A patent/AU2007311621A1/en not_active Abandoned
- 2007-10-17 EP EP07824851A patent/EP2081574A1/en not_active Withdrawn
- 2007-10-17 CN CNA2007800387417A patent/CN101573116A/en active Pending
- 2007-10-17 CA CA002666581A patent/CA2666581A1/en not_active Abandoned
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- 2009-03-25 GB GB0905120A patent/GB2456434A/en not_active Withdrawn
- 2009-03-26 ZA ZA200902123A patent/ZA200902123B/en unknown
- 2009-04-05 IL IL197908A patent/IL197908A0/en unknown
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| Publication number | Publication date |
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| IL197908A0 (en) | 2009-12-24 |
| GB0620661D0 (en) | 2006-11-29 |
| WO2008047163A1 (en) | 2008-04-24 |
| GB2456434A (en) | 2009-07-22 |
| GB0905120D0 (en) | 2009-05-06 |
| EP2081574A1 (en) | 2009-07-29 |
| ZA200902123B (en) | 2010-04-28 |
| AU2007311621A1 (en) | 2008-04-24 |
| CN101573116A (en) | 2009-11-04 |
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