CN101573116A - 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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- CN101573116A CN101573116A CNA2007800387417A CN200780038741A CN101573116A CN 101573116 A CN101573116 A CN 101573116A CN A2007800387417 A CNA2007800387417 A CN A2007800387417A CN 200780038741 A CN200780038741 A CN 200780038741A CN 101573116 A CN101573116 A CN 101573116A
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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 (ii) a solvent comprising ethanol which composition is substantially free of chloride.
Description
The present invention relates to the compositions of buprenorphine, especially be suitable for the particularly pump spray composite sent of Sublingual of mucosa.
Buprenorphine with structure shown below is the partial agonist of opiate receptor, and it is widely used in treatment moderate to severe pain or treatment opium and relies on.
Buprenorphine is described to partial agonist (receptor for stimulating thing)/antagonist (stoping the receptor excitement) usually.It has important function to two opioid receptors in the brain.The pain of many modal opioid effects such as sense of euphoria, cell breath and minimizing all is that the stimulation by the μ receptor causes.Buprenorphine stimulates this receptor, although its stimulus intensity is lower than other opiates such as heroin or methadone.This lower level stimulation is useful clinically in having the people (such as the old people) who breathes the damage but need the opioid medicine.
Buprenorphine still is the antagonist of kappa opioid receptor, and described kappa opioid receptor is particularly depressed relevant with some negative effects of giving up.Because buprenorphine suppresses the stimulation of this receptor, so it can produce good sensation.At last, it is low from dissociating of these receptors, causes long acting duration, makes administration once a day and carried out administration in per sometimes two days to make that buprenorphine is the general treatment option of medicine addiction.
The buprenorphine of current many existence forms is obtainable.Contain 0.2-0.4mg and sell with trade name Temgesic, and be generally used for the pain relieving purpose as the low dosage sublingual tablet of the medicine of hydrochlorate.The buprenorphine hydrochloride of commodity Temgesic by name also can be used as the ampulla that is used for intramuscular or slowly intravenous injection and obtains.The most common preparation that is used for the treatment of the buprenorphine that opium relies on is to contain 0.4,2 and the sublingual tablet of 8mg buprenorphine hydrochloride, and can obtain by trade name Subutex.Use the combination of tablet, can administration up to the dosage of 32mg.These tablets especially are intended to be used for the treatment of the patient's who just is maintained in the medical auxiliary treatment problem drug use; Under the patient's who just experiences withdrawal and treatment situation, use these tablets with the dosage that reduces gradually.Sometimes the sublingual tablet treatment opium of using low dosage relies on, and uses a plurality of tablets in this case to reach the dosage of expectation.
In GB2100985 (Todd), the liquid preparation that is used for sublingual administration has been described.Specifically, this document has been described and has been contained the buprenorphine that is dissolved in the alcoholic acid aqueous solution of 20-30%v/v or its non-toxic salt but the preparation of buprenorphine hydrochloride especially, described alcoholic acid aqueous solution is buffered to the pH of 4.5-5.5 with the buffer agent that is selected from citric acid/sodium hydrogen phosphate, sodium citrate/hydrochloric acid, lactic acid/sodium hydrogen phosphate, lactic acid/sodium lactate, sodium citrate/citric acid and acetate/acetic of 0.05-0.2 molar concentration, and the concentration of buprenorphine is 0.8 to 10mg/ml (promptly about 0.08-1.0%w/v) compositions.Embodiment relates to the buprenorphine hydrochloride solution that contains various Different concentrations of alcohol and various buffer agents.As if said composition is not a spray, because this document relates to the liquid volume that the patient can keep the reasonable time amount in the Sublingual.
Known medicine to the mucosa (for example hypoglossis mucous membrane) of using careful selection provides and can cause medicine very rapidly to be transferred to the blood flow and the route of administration of fast-acting subsequently.Other mucosa (can administration medicine to this mucosa) comprises nasal mucosa and buccal mucosa.Many methods of sublingual administration compositions are known.For example, before swallowing, tablet or liquid can be remained on the Sublingual.Other method is that spraying is sent.In these various types of sublingual administrations, it is preferred that spraying is sent, because it does not relate to compositions is not kept the long time (for example as using lozenge) in the Sublingual, and it has reduced the amount of substance of swallowing (and may enter blood in the mode that delays by intestines and stomach).Yet, think that a large amount of liquid of spraying (for example surpassing about 500uL) is unfavorable to the chamber, Sublingual.
WO01/97780 (Ross) has described the pharmaceutical composition that contains opioid analgesic (especially fentanyl, although also relate to buprenorphine) solution and be used for the propellant of Sublingual aerosol drug delivery.Example preparation pressurizes, and therefore needs complicated packing and actuation technique.They have also been used may be to the disagreeableness halogenation propellant of environment.
Weinberg etc. (1988) Clin Pharmacol Ther 44,335-342 has discussed when being administered to the chamber, Sublingual with pipette with liquid form, comprises the absorption of the various opioids (being present in the phosphate-buffered aqueous solution of pH6.5) of buprenorphine.
WO01/89476 (Pinney etc.) discloses the buffered compositions that is used for mucosal delivery.In very long possible active substance tabulation, mentioned buprenorphine, but do not illustrated.
At present, there is not the commercial obtainable spray composite that contains buprenorphine.
Therefore, the purpose of this invention is to provide and be used for the particularly spray composite that contains buprenorphine of sublingual administration of transmucosal administration.Other purpose of the present invention provides the spray composite that contains buprenorphine that is used for mucosa (for example, Sublingual) administration of have good physical properties (especially good stable and low environmental effect) and good biological property (performance active and in the effectiveness of relative low dosage) especially fast.This based composition will alleviate the many shortcomings that contain the compositions of buprenorphine of the prior art.
Therefore, according to a first aspect of the invention, provide non-pressurised medicinal fluid solution spray compositions, it comprises:
(i) buprenorphine; With
(ii) comprise alcoholic acid solvent;
It is characterized in that the essentially no chloride of said composition.
Described compositions is non-pressurised, promptly essentially no any propellant.Basically the exemplary propellant of being avoided is included in the volatile substances that produces remarkable vapour pressure under ambient temperature and the pressure, for example CFCs (P12 etc.) and hydrogen fluorohydrocarbon (P134a, P227 etc.) and other are generally used for the propellant that aerosol is presented such as lower paraffin hydrocarbon (for example, propane, butane etc.) and halogenated hydrocarbon.Also preferably avoid using P11 basically." do not have basically " or the meaning of " avoiding basically " is to use the amount that is less than 5%w/w (based on composition weight), be less than 2% aptly, for example be less than 0.1%w/w.Preferably avoid propellant fully.
The concentration of buprenorphine in compositions usually can be 0.05 to 12%w/v, 0.1-10%w/v preferably for example 0.1-4%w/v or especially 2-8%w/v (4-8%w/v for example, for example 4% or 8%w/v) change between (all data are all based on the weight with respect to the buprenorphine alkali of compositions gross weight).
The meaning of " essentially no chloride " is that said preparation does not exist ionizing (promptly to form Cl thus in solution basically
-) or the chloride of nonionic form.Basically not having muriatic reason is for fear of buprenorphine hydrochloride precipitation that can not high dissolution in aqueous or alcohol solvent.Therefore, calculate according to the weight of buprenorphine, in the compositions muriatic amount suitable be less than 3%w/w, for example be less than 1%w/w, for example be less than 0.5%w/w, for example be less than 0.1%w/w, especially when the pH of compositions is lower than 7.
Advantageous applications is as alkali or as the buprenorphine of citrate (particularly as alkali).
Advantage of the present invention is particularly used the advantage of the buprenorphine in the essentially no muriatic preparation, is to prepare dense relatively compositions, its make can be under the situation of not using very large metered volume the buprenorphine of administration high dose.For example, as will making an explanation below, we have successfully prepared 4 and the solution of 8%w/v concentration, yet do not prove that also buprenorphine hydrochloride can be dissolved in water or the ethanol with these concentration.The higher concentration of these buprenorphines contains the alcoholic acid solvent of significant quantity by application to be realized, and has realized the highest concentration by reducing pH with citric acid.
Some sprayable non-pressurised analgesic compositions for example are disclosed among WO02/094234 (Rabinowitz), WO 03/080022 (Birch) and the WO 2004/071491 (Blondino) openly in the prior art.WO02/094234 relates to and being used for by opioid aerosol formulation of containing of inhalation.These preparations all are the aqueous solutions that does not contain other solvent that is suggested.WO03/080022 relates to the aqueous solution that contains analgesic that is used for intranasal administration.Analgesic can be buprenorphine or its salt, but does not instruct not chloride of said composition, and in fact embodiment all relates to the compositions that comprises buprenorphine hydrochloride.Do not propose to comprise ethanol in the solvent.WO2004/071491 relates to the liquid aerosol formulation, and wherein solvent can contain ethanol.It will be favourable not providing no muriatic compositions, and all embodiment all relate to the preparation that contains buprenorphine hydrochloride.
Generally speaking, the solvent of the minimum of the abundant dissolving of expectation application buprenorphine essential (or appropriateness is essential above being somebody's turn to do) is so that buprenorphine remains in the solution under possible use or exposure condition.
Usually, solvent is selected from ethanol and ethanol/water mixture.In first embodiment of the present invention, ethanol is unique solvent basically.For example, in the solvent concentration of ethanol surpass 90%w/w, for example surpass 95%w/w, particularly surpass 98%w/w, about 100%w/w (that is, solvent is an ethanol, is left in the basket from the existence of atmospheric any water as pollutant) for example.In first embodiment of the present invention, avoid application basically as the water of solvent, for example, the concentration of water less than 10%w/w, for example less than 5%w/w, particularly less than 98%w/w, about 0%w/w (that is, compositions does not have water basically) for example.As pointing out below, special in containing the buprenorphine formulation of citrate water to avoid be favourable in storage, have and become peach tendency because we have observed this type of preparation.
In second embodiment of the present invention, solvent comprises water and ethanol.For example, solvent is made up of water/alcohol mixture, and wherein concentration of ethanol is about 30-90%w/w (surplus is a water), for example about 40-70%w/w, about 50%w/w for example.
When using as solvent, water preferably meets USP (American Pharmacopeia), EP (European Pharmacopoeia) " pure water " standard.
The pH of solution can be about 4 to 9.5 usually, but preferably about 4.5 to 9.In one embodiment of the invention, pH is 4 to 6, for example about 4.5 to 6 for example about 5 or about 4 to 5 for example about 4.5.In another embodiment of the present invention, pH for example is about 8 to 9.5, for example about 8 to 9, for example about 8.5 greater than 7.It is believed that the compositions general with higher pH is more effective and/or have active faster.Bound by theory not, the inventor intends thinking, near the pH (it is 8.5 (pharmacy pharmacopeia (Pharmaceutical Codex))) of the pKa of buprenorphine down buprenorphine will be quicker or be absorbed by mucosa especially hypoglossis mucous membrane effectively.Be not that compositions more than 7 specifically describes so far to pH, infer this be since main use buprenorphine hydrochloride and under higher pH the solubility of this active component cause.By using compositions of the present invention, overcome this type of problem basically.
" pH " means and uses the pH reading that conventional pH meter can obtain, described pH meter for example be pH 211 types made by Hanna Instruments Ltd and the Orion 420A that makes by Thermo ElectronCorporation (promptly, in anhydrous system, word " pH " can be interpreted as meaning " apparent pH ").
For adjusting pH, can use buffer salt, yet because the many organic and indissolubility of inorganic salt in being essentially alcoholic acid solvent, we find to note carefully their concentration.When using buffer agent, the preferred buffer system that is used for low pH scope is citrate (for example sodium citrate)/citric acid, and it has enough dissolubility in alcohol solvent.Yet citrate/citric acid itself is problematic, has when storing and becomes peach tendency because we have found to contain the compositions of the present invention of citrate/citric acid and water, and is all the more so especially at elevated temperatures.Therefore, preferably avoid using buffer salt, citrate/citric acid especially.
Suitably, also avoid application to contain phosphatic buffer agent (for example, phosphate and protonated derivative are such as hydrophosphate and dihydric phosphate).Therefore, weight according to buprenorphine is calculated, the amount of phosphate in the compositions (for example for phosphate itself or protonated derivative such as hydrophosphate and dihydric phosphate) suit to be less than 3%w/w, for example be less than 1%w/w, for example be less than 0.5%w/w, for example be less than 0.1%w/w, especially when the pH of compositions less than 7 the time.
Yet we have found that citric acid can be used to increase buprenorphine alkali the dissolubility of alcohol solvent (for example to 4%w/v or higher for example 4-8%w/w concentration (based on the gross weight of compositions), particularly 5-8%w/w).In this based composition, solvent can (optimum) be ethanol (for example, 100% ethanol) or can contain (selectively) water (for example, ethanol/water is 1: 1) basically.For reaching these higher concentration, usually can about 0.1-10%w/w, for example 0.2-5%w/v for example the concentration of 0.2-2%w/w use citric acid.
For understanding the pH regulator problem of buprenorphine solution, and particularly under the situation of not using conventional buffer salt or chloride (for example being HCl), the inventor recognizes and can realize this purpose by using other organic formulations component.Therefore, by adding glucide or saccharin sodium and optional some other formulation components such as menthol (for example, the L-menthol) or Oleum menthae, we assess its influence to the pH of buprenorphine solution carefully.
As our result of study, we find that the pH of the buprenorphine alkali in the ethanol is not subjected to the appreciable impact of buprenorphine concentration.Yet we are surprised to find glucide can be used to reduce the pH of buprenorphine alkali composition effectively, and is used in particular for realizing the particularly pH of 4.5-6 for example about 5 of 4-6.Along with the rising of buprenorphine concentration, the effect that glucide reduces pH reduces.When with the glucide coupling, the adding of menthol (for example, L-menthol) or Oleum menthae is to relatively almost not influence of pH.
We (for example also find saccharin sodium and menthol, the L-menthol) or Oleum menthae all for the pH of the buprenorphine alkali composition in the rising ethanol, have effect medium but potentially useful, and it is used in particular for realizing about 8 to 9.5, for example about 8-9, about 8.5 pH for example.
The above results is shown among Fig. 1 and 2.
Except their above-mentioned useful qualitys in the pH that changes compositions, glucide and saccharin sodium also can be used as the sweeting agent that improves patient's acceptability.
Except their above-mentioned useful qualitys in the pH that changes compositions, the wetting agent that menthol (for example, L-menthol) and/or Oleum menthae also can be used as correctives and may have the enhanced activity of penetrating.
By many additional formulation components being included in the character that wherein can further improve compositions required for protection.
It may be desirable in the compositions that one or more following components are included in:
-sweeting agent is such as glucide, saccharin sodium, sucrose, correctives or taste screening agent (to improve patient's acceptability);
-wetting agent (to improve patient's comfort level and to overcome ethanol and the drying of other polar organic solvent tendency), for example Oleum menthae, menthol (for example, L-menthol), pineapple extract, lanoline, polypropylene glycol, Polyethylene Glycol.
-mucosa adhesive agent (to be increased in the time of staying on the mucosa), for example polycarboxy ethene, chitosan, polyacrylic acid, gelatin, polyvinylpyrrolidone.
-antiseptic (to improve long-term resistance) to microbial contamination, for example, sodium pyrosulfite, benzalkonium, Nipas.
-antioxidant, for example alkyl gallates class, butylated hydroxyanisol, Yoshinox BHT, nordihydroguaiaretic acid, tocopherols, ascorbic acid, sodium pyrosulfite
-anion surfactant, for example magnesium stearate, 16 octadecyls (cetostearyl) sodium sulfate, sodium lauryl sulphate, enuatrol, sodium stearyl fumarate, sodium tetradecyl sulfate
-nonionic surfactant, for example, glyceryl monostearate, Polyethylene Glycol 16 octadecyl ethers, poloxamer, KIKKOL MYS-40, polysorbate esters, sorbitan ester class, sucrose ester, tyloxapol, propylene glycolmonostearate, soapbark (Quillaia), poly-oxyl, Semen Ricini oils, nonoxynolum class, lecithin class and derivant, oleic acid and derivant, oleyl alcohol and derivant
-foaming agent, for example, alginic acid and salt, propylene glycol alginate, sodium lauryl sulphate, sodium cetostearylsulphate, carbomer, hydroxyethyl-cellulose.
Among above-mentioned possible annexing ingredient, can notice that in view of the ethanol content of compositions, antiseptic usually should be optional.
According to best pharmacy principle,, should avoid using annexing ingredient if not essential.
We observed higher-strength (for example, 4%w/v or more than) according to compositions of the present invention, especially contain those of glucide, have the tendency of yellowing when storing, especially all the more so under higher temperature.Therefore, can use the stabilizing agent that is selected from antioxidant (for example ascorbic acid/Ascorbate) and/or chelating agen (for example EDTA/ edetate sodium) aptly.
Some components of proposing above may be included in the middle of the compositions of the present invention, are used for other purpose.Suitable wetting agent comprises for example polar organic solvent, such as the cellulose family of glycols especially propylene glycol and liquid macrogol class, glycerol, methylcellulose, hypromellose, hydroxypropyl cellulose and many other replacements.
As mentioned above, improving the acceptability of compositions and the multipurpose component of other character is especially L-menthol of menthol.Except to the compositions flavoring, menthol (for example, L-menthol) is gone back Carboxymethyl Chitin.It can also have the effect of penetration enhancer.Preferably with 0.1% to 0.75%w/w, for example the concentration of about 0.2%w/w is used menthol (for example L-menthol).
Oleum menthae is the alternative component that can be used for replacing menthol.Known Oleum menthae and some active substance (for example fentanyl) are incompatible, yet, its it seems with buprenorphine be compatible.Aptly, with 0.1% to 0.75%w/w, for example the concentration of about 0.5%w/w is used Oleum menthae.
In a preferred embodiment of the invention, compositions contains sweeting agent.In one embodiment of the invention, sweeting agent is a saccharin sodium.The concentration of saccharin sodium is suitably about 0.1-0.9%w/w, about 0.45%w/w for example.
In another embodiment of the invention, compositions contains glucide.The concentration of glucide is suitably about 0.025-0.75%w/w, for example about 0.05-0.4%w/w, about 0.05-0.1%w/w for example.As noted above such, the concentration of glucide can change (referring to Fig. 2) according to the final pH of expectation.
Think that many compositionss of the present invention are especially suitable.
Suitable exemplified composition comprises (or forming (for example being made up of following material) by following material basically):
-as the buprenorphine of alkali;
-be selected from the solvent of ethanol and ethanol/water mixture;
The essentially no chloride of wherein said compositions; And
The pH of wherein said compositions is greater than 7.
The pH of compositions for example can be about 8 to 9.5, for example about 8 to 9, for example about 8.5.
Solvent is ethanol suitably.
This based composition optional (and advantageously) comprises saccharin sodium.
This based composition optional (and advantageously) comprises the correctives that is selected from menthol (for example L-menthol), Oleum menthae and composition thereof.
The optional chelating agen (for example DETA or edetate sodium) that comprises of this based composition.
The optional antioxidant that comprises of this based composition.
If necessary, can optional use hydroxide (for example NaOH, KOH) to improve pH.
The concentration of buprenorphine alkali is 0.1-4%w/v aptly.
Another suitable exemplified composition comprises (or forming (for example being made up of following material) by following material basically):
-as the buprenorphine of alkali;
-be selected from the solvent of ethanol and ethanol/water mixture;
-glucide;
The essentially no chloride of wherein said compositions; And the pH of wherein said compositions is about 4 to 6, for example about 4.5 to 6, for example about 5.
Solvent is ethanol suitably.
This based composition optional (and advantageously) comprises the correctives that is selected from menthol (for example L-menthol), Oleum menthae and composition thereof.
The optional chelating agen (for example DETA or edetate sodium) that comprises of this based composition.
The optional antioxidant that comprises of this based composition.
The concentration of buprenorphine alkali is 0.1-4%w/v aptly.
Another suitable exemplified composition comprises (or forming (for example being made up of following material) by following material basically):
The buprenorphine as alkali of-4%w/v or above concentration;
-be selected from the solvent of ethanol and ethanol/water mixture;
-citric acid;
The essentially no chloride of wherein said compositions; And the pH of wherein said compositions is about 4 to 6, for example about 4 to 5, for example about 4.5.
Solvent is ethanol suitably.
This based composition optional (and advantageously) comprises the correctives that is selected from menthol (for example L-menthol), Oleum menthae and composition thereof.
This based composition optional (and advantageously) comprises glucide.
The optional chelating agen (for example DETA or edetate sodium) that comprises of this based composition.
The optional antioxidant that comprises of this based composition.
The concentration of buprenorphine alkali is 4-8%w/v aptly.
Be used to prepare the method for the present composition, this method comprises:
(a) obtain as the buprenorphine of alkali and comprise ethanol, randomly contain the solvent of other preparation composition (for example glucide, saccharin sodium, menthol, Herba Menthae wet goods), and buprenorphine is dissolved in the described solvent; Or
(b) obtain as the buprenorphine of alkali and comprise alcoholic acid solvent, and buprenorphine is dissolved in the described solvent, add other preparation composition (for example glucide, saccharin sodium, menthol, Herba Menthae wet goods) then; Or
(c) (a) or method (b), wherein in case after all other preparation compositions are mixed together, regulate the pH of (for example using citric acid) solvent.
In the middle of the advantage of compositions required for protection, there is the following fact; promptly owing to be non-pressurised; they have been avoided and have used the relevant problem of propellant, such as their production shortcoming and their potential environmental effects (many propellant are " greenhouse gases ").Liquid composite of the present invention is to change uniformly and to dosage-to-dosage to have limited or do not have sensitivity.In addition, the present composition is characterised in that good long term physics and chemical stability.
Compositions of the present invention is preferably as the saturating mucosa of spray (particularly Sublingual) administration.When being administered to responsive hypoglossis mucous membrane, the expection said composition can be tolerated well, and the sublingual spraying administration will cause buprenorphine to bring into play curative effect fast.
Therefore, according to another aspect of the present invention, provide rationed system, it comprises the sealed container that contains the present composition, and described container is furnished with dosing pump, actuator (actuator) and passage (channelling) device.This rationed optimum system choosing is suitable for mucosa (particularly Sublingual) administration.
Although the container that is used for medicinal fluid composition in principle can contain the buprenorphine of single dose (it still can be a fractionated dose), this container preferably contains (for example 20 to 200 dosage) buprenorphine of multiple dose.
Although compositions can be packaged in the suitable pharmaceutical grades plastic containers, thereby this type of container is relatively easily opened the abuse product.Therefore, glass container will be more suitably.If attempt to unpack, glass is fragmentation, causes inclusions forfeiture or because glass fragment and can not using.Preferably be coated on this glass container outside, prevent fragmentation with protection with suitable molded plastics thin film.For example, this thin film can be polyacrylic.Described material can be colored and contain the UV absorbent.Container glass can be colourless or can more suitably be provided with UV protection pigment, for example amber colour.Randomly, can wrap by internal tank to improve the stability of product.Coating comprises polymer and lacquer, but is used for ruling in container inside as the silicon dioxide (silicone dioxide) of inert coatings.
Because described compositions is non-pressurised, suit to be administered to the patient by pumping action.Therefore, rationed system suitable contain allow quantitative compositions as spray by the dosing pump of administration.
Suitable dosing pump comprises and being suitable for described container with vertically or be inverted those that direction is used to distribute.Preferably, measuring room is suitable for being used for distributing with vertical direction with container, because this is beneficial to sublingual administration.Therefore, this measuring room is got in touch by soaking tube side formula and compositions.
It is non-ventilation type that dosing pump suits.The suitable material of construction comprises polypropylene and polyethylene.The example dosing pump is those (for example VP3, VP6, VP7 and VP7D) that made by Valois, and for example in international patent application no WO01/66089, illustrate those.Other pump commonly used comprises from those of Rexam (for example SP270) and Calmar (for example Accupump or Mistette Mk II).
Actuator decision design is used to send effectively dosage of mucosa (particularly Sublingual).Pump can manually be started aptly, although it is also conceivable that auxiliary the starting of using the energy of storing (for example spring or gas).
For security seal, pump is crimped onto on the container neck aptly.Can use the suitable seal material that is suitable for this purpose, for example the curling packing ring of thermoplasticity.In addition, can use aptly and specially be designed for the suitable aluminum lasso that is crimped onto on the glass container.The preferred stainless steel spring that adopts suitable grade.
Dosing pump is with the compositions of administration metered volume.Suitable metered volume is 10-1000uL, and preferably is 50-250uL, for example 100uL or 200uL, particularly 200uL.
Provide the lane device guiding liquids to be sprayed to the suitable part of mouth from rationed zone,, or if necessary, be sprayed to nose for example to the chamber, Sublingual.Lane device is suitably by the molded plastics manufacturing.Many to be suitable for administration spray to the lane device of mouth or nose be well known to a person skilled in the art, for example
| Valois | |||
| The spraying button | The nose actuator | The larynx actuator | The tooth actuator |
| 155GPC | CB 18NAC | 132C GP | 251EB 406 |
| 155GPCS | CB 18NAL | 132L GP | 251EB 407 |
| 165GPC | CB 18NEC | 139 is folding | |
| 165GPCS | CB 18W NAC | 137C | |
| 852 | CB 19 | 137L | |
| A3 | 147NE | 251EB 408 | |
| Calmar | |||
| The spraying button | The nose actuator | The larynx actuator | The tooth actuator |
| Standard header | 2-saves (piece) nose | Short larynx | Capillary tube |
| 3-saves nose | Middle larynx | ||
| Long larynx | |||
| The larynx that the joint connects | |||
| Rexam |
| The spraying button | The nose actuator | The larynx actuator | The tooth actuator |
| 9590 | 4345 | 9180 | 9410 |
| AA5733 | 4234 | 5200 | |
| AB3960 | AA9994 | ||
| 5561 | 5860 | ||
| 4095 | 585 | ||
| AA8238 | 4325 |
Compositions of the present invention can be used for treatment or dependence of prevention opium and abuse, particularly treatment or the prevention dependency for opiates such as heroin, and is used for the pain relieving purpose, for example is used for the treatment of moderate to severe pain.Therefore, in another aspect of this invention, provide the method for treatment or prevention opium dependence and abuse or pain, this method comprises the individuality that the compositions of the present invention of effective dose is administered to its needs.In another aspect of this invention, provide compositions according to the present invention to be used for the treatment of or to prevent purposes in the medicine of opium dependence and abuse or pain in preparation.On the other hand, provide the compositions of the present invention that is used for the treatment of or prevents opium dependence and abuse or pain.
For reducing the risk of the described product of abuse, described container or distribution system can be provided the feature of pre-tamperproof (tampering) suitably.Specifically, described container or distribution system can be provided prevention suitably or stop and enter storage storehouse and/or the prevention feature at a buprenorphine more than the dosage of a time administration.
Distribution system, particularly actuator for example can be provided lock-in feature with prevention second dosage of administration in the specified time interval of first dosage.Lock-in feature for example is described in US2006191532, WO03097141 and WO0232487.
Usually, saturating mucosa (for example Sublingual) the drug treatment patient by starting, for example start for 1 or 2 time from 1 to 4 time of atomizing pump.Another advantage that the mucosa spraying is sent is can easily start by single to send 1 or 2 required dosage to the patient.This is with different with other medicines delivery form (patch, lozenge, tablet and suppository).
Pharmaceutical composition of the present invention can be used for treating the animal particularly non-human animal (for example domestic animal or domestic animal) and the mankind.Therefore, medicinal usage (for example purposes in treatment pain) can extend to veterinary's application.The dosage of administration and method (for example, spraying actuator design) will be suitable for the receiver that expects as known to the skilled person.
Embodiment
Embodiment 1-4
Be prepared as follows compositions:
| Embodiment 1 | |
Embodiment 3 | |
|
| Buprenorphine alkali (%w/v) | 0.2 | 0.1 | 0.1 | 0.1 |
| Left side menthol (%w/w) | 0.2 | 0.2 | - | - |
| Oleum menthae (%w/w) | - | - | - | 0.5 |
| Saccharin sodium (%w/w) | 0.45 | - | 0.45 | - |
| Dehydrated alcohol (%) | To 100 | To 100 | To 100 | To 100 |
| The pH that measures | 8.38 | 9.08 | 8.36 | 8.43 |
Said composition forms the colourless solution of clarification down at 4,25 and 40 ℃, and still keeps so after storing 1 month under these temperature.
Embodiment 5-8
Be prepared as follows compositions:
| Embodiment 5 | |
Embodiment 7 | |
|
| Buprenorphine alkali (%w/v) | 0.2 | 0.2 | 0.2 | 0.1 |
| Left side menthol (%w/w) | - | 0.2 | - | - |
| Oleum menthae (%w/w) | - | - | 0.5 | 0.5 |
| Glucide (%w/w) | 0.05 | 0.05 | 0.05 | 0.40 |
| Dehydrated alcohol (%) | To 100 | To 100 | To 100 | To 100 |
| The pH that measures | 4.92 | 4.93 | 4.97 | 2.94 |
Said composition forms the colourless solution of clarification down at 4,25 and 40 ℃, and still keeps so after storing 2 weeks (embodiment 8) or 1 month (embodiment 5-7) under these temperature.
Embodiment 9-12
Be prepared as follows compositions:
| Embodiment 9 | |
Embodiment 11 | Embodiment 12 | |
| Buprenorphine alkali (%w/v) | 0.1 | 0.1 | 0.2 | 0.1 |
| Left side menthol (%w/w) | 0.2 | - | - | - |
| Oleum menthae (%w/w) | - | 0.5 | 0.5 | - |
| Saccharin sodium (%w/w) | 0.45 | 0.45 | 0.45 | - |
| Dehydrated alcohol (%) | To 100 | To 100 | To 100 | To 100 |
| The pH that measures | 8.36 | 7.98 | 8.08 | 9.04 |
Said composition forms the colourless solution of clarification down at 4,25 and 40 ℃, and still keeps so after storing 1 month under these temperature.
Embodiment 13-16
Be prepared as follows compositions:
| Embodiment 13 | Embodiment 14 | Embodiment 15 | Embodiment 16 | |
| Buprenorphine alkali (%w/v) | 4 | 4 | 4 | 4 |
| Left side menthol (%w/w) | 0.2 | - | - | 0.2 |
| Oleum menthae (%w/w) | - | 0.5 | - | - |
| Saccharin sodium (%w/w) | - | - | - | - |
| Glucide (%w/w) | - | - | - | - |
| Dehydrated alcohol (%) | To 100 | To 100 | To 100 | To 100 |
| The pH that measures | 8.63 | 8.35 | 8.67 | NM |
NM: do not measure
Embodiment 13: compositions forms the colourless solution of clarification down at 4,25 and 40 ℃, and still keeps so after storing 2 months under these temperature.
Embodiment 14: after storing 2 months under following those temperature, compositions forms the colourless solution of clarification down at 4 and 25 ℃, forms the extremely lurid solution of clarification down at 40 ℃.
Embodiment 15,16: after storing 3.5 months under following those temperature, compositions forms the colourless solution of clarification down at 4 and 25 ℃, forms the lurid solution of clarification down at 40 ℃.
Embodiment 17-20
Be prepared as follows compositions:
| Embodiment 17 | Embodiment 18 | Embodiment 19 | Embodiment 20 | |
| Buprenorphine alkali (%w/v) | 4 | 4 | 4 | 4 |
| Left side menthol (%w/w) | - | 0.2 | - | 0.2 |
| Oleum menthae (%w/w) | - | - | 0.5 | - |
| Saccharin sodium (%w/w) | - | - | - | 0.45 |
| Glucide (%w/w) | 0.40 | 0.40 | 0.40 | |
| Dehydrated alcohol (%) | To 100 | To 100 | To 100 | To 100 |
| The pH that measures | 5.89 | 5.85 | 5.87 | 8.77 |
NM: do not measure
Embodiment 17 and 18: after storing 3.5 months under following those temperature, compositions forms the colourless solution of clarification down at 4 and 25 ℃, forms dark yellow solution down at 40 ℃.
Embodiment 19: after storing 3.5 months under following those temperature, compositions forms the clarification pale yellow solution at 4 ℃, forms clear yellow solution down at 25 ℃, forms clarification dark yellow solution down at 40 ℃.
Embodiment 20: after storing 2 months under following those temperature, compositions forms clear colorless solution at 4 ℃, forms the clarification pale yellow solution down at 25 ℃, forms clear yellow solution down at 40 ℃.
Embodiment 21-24
Be prepared as follows compositions:
| Embodiment 21 | Embodiment 22 | Embodiment 23 | Embodiment 24 |
| Buprenorphine alkali (%w/v) | 8 | 8 | 8 | 4 |
| Left side menthol (%w/w) | - | - | - | - |
| Oleum menthae (%w/w) | - | - | - | - |
| Saccharin sodium (%w/w) | - | - | - | - |
| Glucide (%w/w) | - | - | - | - |
| Citric acid (%w/w) | 4.13 | 8.22 | 4.11 | 2.05 |
| Water/ethanol 1: 1w/w (% w/w) | To 100 | To 100 | ||
| Dehydrated alcohol (%w/w) | To 100 | To 100 | - | - |
| The pH that measures | 4.83 | 4.20 | 4.55 | 4.64 |
Embodiment 21 and 22: after storing 3 months under following those temperature, compositions forms clear colorless solution at 4 ℃, forms pale yellow solution down at 25 ℃, forms yellow solution down at 40 ℃.
Embodiment 23: after storing 3 months under following those temperature, compositions forms clear colorless solution down at 4 ℃ and 25 ℃, forms the pink solution of clarification down at 40 ℃.
Embodiment 24: after storing 3 months under following those temperature, compositions forms clear colorless solution down at 4 ℃ and 25 ℃, forms clarification baby pink solution down at 40 ℃.
Embodiment 25
For various compositionss, studied the dependence of apparent pH to buprenorphine alkali concn in the alcoholic solution.The result is presented among Fig. 1.
The most noticeable observed result is that glucide has remarkable influence to the apparent pH of compositions, and this influence reduces along with the buprenorphine alkali concn.Overlapping line chart at significantly low pH place derives from and contains (i) glucide; (ii) glucide and Oleum menthae; And (iii) 3 kinds of compositionss of glucide and L-menthol.
Embodiment 26
For various compositionss, studied the dependence of apparent pH to glucide concentration in buprenorphine alkali (0.2%w/v)/alcoholic solution.The result is presented among Fig. 2.
In this description and claims subsequently, unless the other requirement of context, word " comprises " and variation will be understood that to mean as " comprising " and " containing " and comprise described integral body, step, whole group or the group of step, but does not get rid of any other integral body, step, whole group or the group of step.
The application that this description and claims constitute its part can be used as the basis for priority of any subsequent application.The claim of this type of subsequent application can relate to any feature described herein or characteristics combination.They can take the form of product, compositions, method and purposes claim, and can be by example and comprise following claim without restriction:
Claims (36)
1. non-pressurised medicinal fluid solution spray compositions, it comprises
(i) buprenorphine; With
(ii) comprise alcoholic acid solvent
It is characterized in that the essentially no chloride of said composition.
2. the compositions of claim 1, wherein concentration of ethanol surpasses 90%w/w in the solvent.
3. the compositions of claim 1 or claim 2, it is anhydrous basically.
4. the compositions of claim 2 or claim 3, wherein concentration of ethanol is about 100%w/w in the solvent.
5. the compositions of claim 1, wherein concentration of ethanol is about 30-90%w/w in the solvent, surplus is a water.
6. each compositions among the claim 1-5, wherein the concentration of buprenorphine is about 0.05-12%w/v in the compositions.
7. the compositions of claim 6, wherein the concentration of buprenorphine is about 2-8%w/v in the compositions.
8. each compositions among the claim 1-7, the pH of wherein said compositions is about 4 to 6.
9. each compositions among the claim 1-7, the pH of wherein said compositions is about 8 to 9.5.
10. the compositions of claim 8, it contains glucide.
11. the compositions of claim 9, it contains saccharin sodium.
12. each compositions among the claim 1-11, it contains menthol.
13. each compositions among the claim 1-12, it contains Oleum menthae.
14. the compositions of claim 1, it comprises
-as the buprenorphine of alkali;
-be selected from the solvent of ethanol and ethanol/water mixture;
The essentially no chloride of wherein said compositions; And
The pH of wherein said compositions is greater than 7.
15. the compositions of claim 14, the pH of wherein said compositions is about 8 to 9.
16. the compositions of claim 14 or claim 15, it comprises saccharin sodium.
17. the compositions of claim 1, it comprises
-as the buprenorphine of alkali;
-be selected from the solvent of ethanol and ethanol/water mixture;
-glucide;
The essentially no chloride of wherein said compositions; And the pH of wherein said compositions is about 4 to 6.
18. each compositions among the claim 14-17, wherein the concentration of buprenorphine alkali is 0.1-4%w/v.
19. the compositions of claim 1, it comprises:
The buprenorphine as alkali of-4%w/v or above concentration;
-be selected from the solvent of ethanol and ethanol/water mixture;
-citric acid;
The essentially no chloride of wherein said compositions; And the pH of wherein said compositions is about 4 to 6.
20. the compositions of claim 19, it comprises glucide.
21. each compositions among the claim 14-20, wherein said solvent is an ethanol.
22. the compositions of claim 19 or claim 20, wherein said solvent is an ethanol/water mixture.
23. each compositions among the claim 14-22, it comprises the correctives that is selected from menthol, Oleum menthae and its mixture.
24. each compositions among the claim 14-23, it comprises chelating agen.
25. each compositions among the claim 14-24, it comprises antioxidant.
26. the compositions of aforementioned any one claim, it is used for as the spray transmucosal administration.
27. the compositions of claim 26, wherein said transmucosal administration is a sublingual administration.
28. the compositions of aforementioned any one claim, it is used for the treatment of or prevents opium dependence or abuse or pain.
29. each compositions is used for the treatment of or prevents purposes in the medicine of opium dependence or abuse or pain in preparation among the claim 1-28.
30. contain the sealed container of each compositions among the claim 1-28 of multiple dose.
31. the container of claim 30, it is made by glass.
32. rationed system, it comprise be furnished with dosing pump, actuator and the claim 30 of lane device or the sealed container of claim 31.
33. the rationed system of claim 32, it contains and is suitable for the measuring room that distributes with vertical direction with described container, and wherein said measuring room is got in touch by soaking tube side formula and compositions.
34. the rationed system of claim 32 or claim 33, it is suitable for the compositions of transmucosal administration as spray.
35. the rationed system of claim 34, wherein said transmucosal administration is a sublingual administration.
36. each method for compositions among the preparation claim 1-28, it comprises:
(a) obtain as the buprenorphine of alkali and comprise ethanol, randomly contain the solvent of other preparation composition, and buprenorphine is dissolved in the described solvent; Or
(b) obtain as the buprenorphine of alkali and comprise alcoholic acid solvent, and buprenorphine is dissolved in the described solvent, add other preparation composition then; Or
(c) (a) or method (b), wherein in case after all other preparation compositions are mixed together, regulate the pH of solvent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0620661.9A GB0620661D0 (en) | 2006-10-18 | 2006-10-18 | Novel compounds |
| GB0620661.9 | 2006-10-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101573116A true CN101573116A (en) | 2009-11-04 |
Family
ID=37507923
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800387417A Pending CN101573116A (en) | 2006-10-18 | 2007-10-17 | Buprenorphine-containing non-pressurised spray composition for transmucosal administration |
Country Status (8)
| Country | Link |
|---|---|
| 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) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8852638B2 (en) | 2005-09-30 | 2014-10-07 | Durect Corporation | Sustained release small molecule drug formulation |
| BRPI0714712B8 (en) | 2006-07-21 | 2021-05-25 | Biodelivery Sciences Int Inc | drug delivery device |
| GB2461681A (en) * | 2008-04-17 | 2010-01-13 | Pharmasol Ltd | Buprenorphine liquid spray formulation with solvent and antioxidant |
| MX337286B (en) | 2007-05-25 | 2016-02-22 | Indivior Uk Ltd | Sustained delivery formulations of risperidone compounds. |
| WO2010072398A2 (en) * | 2008-12-22 | 2010-07-01 | Boehringer Ingelheim Limited | Veterinary formulations |
| GB2513060B (en) | 2010-06-08 | 2015-01-07 | Rb Pharmaceuticals Ltd | Microparticle buprenorphine suspension |
| US9272044B2 (en) | 2010-06-08 | 2016-03-01 | Indivior Uk Limited | Injectable flowable composition buprenorphine |
| GB2481619B (en) * | 2010-06-30 | 2012-06-20 | 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 |
| SG11201403075XA (en) * | 2011-12-21 | 2014-07-30 | Biodelivery Sciences Int Inc | Transmucosal drug delivery devices for use in chronic pain relief |
| GB201404139D0 (en) | 2014-03-10 | 2014-04-23 | Rb Pharmaceuticals Ltd | Sustained release buprenorphine solution formulations |
| WO2017075256A1 (en) | 2015-10-27 | 2017-05-04 | Insys Development Company, Inc. | Liquid buprenorphine formulations |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030190290A1 (en) * | 2000-06-22 | 2003-10-09 | Calvin Ross | Pharmaceutical compositions |
| JP2005503425A (en) * | 2001-05-24 | 2005-02-03 | アレックザ モレキュラー デリヴァリー コーポレイション | Delivery of drug ester by the prescribed 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 |
| ES2559410T3 (en) * | 2004-04-23 | 2016-02-12 | Philip Morris Products S.A. | Aerosol generators and methods for producing aerosols |
-
2006
- 2006-10-18 GB GBGB0620661.9A patent/GB0620661D0/en not_active Ceased
-
2007
- 2007-10-17 CA CA002666581A patent/CA2666581A1/en not_active Abandoned
- 2007-10-17 AU AU2007311621A patent/AU2007311621A1/en not_active Abandoned
- 2007-10-17 WO PCT/GB2007/050639 patent/WO2008047163A1/en active Application Filing
- 2007-10-17 EP EP07824851A patent/EP2081574A1/en not_active Withdrawn
- 2007-10-17 CN CNA2007800387417A patent/CN101573116A/en active Pending
-
2009
- 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
Also Published As
| Publication number | Publication date |
|---|---|
| AU2007311621A1 (en) | 2008-04-24 |
| IL197908A0 (en) | 2009-12-24 |
| ZA200902123B (en) | 2010-04-28 |
| GB0905120D0 (en) | 2009-05-06 |
| GB2456434A (en) | 2009-07-22 |
| WO2008047163A1 (en) | 2008-04-24 |
| CA2666581A1 (en) | 2008-04-24 |
| GB0620661D0 (en) | 2006-11-29 |
| EP2081574A1 (en) | 2009-07-29 |
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