OA17190A - Injectable supersaturated acetaminophen solution for spinal administration. - Google Patents
Injectable supersaturated acetaminophen solution for spinal administration. Download PDFInfo
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- OA17190A OA17190A OA1201400553 OA17190A OA 17190 A OA17190 A OA 17190A OA 1201400553 OA1201400553 OA 1201400553 OA 17190 A OA17190 A OA 17190A
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- Prior art keywords
- acetaminophen
- solution
- supersaturated
- acetamlnophen
- aqueous solution
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Abstract
The present invention relates to an acetaminophen injectable aqueous solution for use in the treatment or in the prevention of pain by spinal 5 administration, wherein said acetaminophen injectable solution is supersaturated. In certain embodiments, the acetaminophen injectable aqueous solution is administered simultaneously, separately or sequentially with a local anaesthetic by spinal administration.
Description
INJECTABLE SUPERSATURATED ACETAMINOPHEN SOLUTION FOR SPINAL ADMINISTRATION
Field of the Invention
The présent Invention relates to an acetamlnophen Injectable solution for spinal administration.
The présent Invention origlnates from the field of drugs In liquid form suitable for spinal administration.
More specifically, the présent Invention relates to an injectable pharmaceutical formulation containlng acetamlnophen as active Ingrédient for the treatment of postsurgical pain by spinal administration.
Prior art
Acetamlnophen (acetyl-p-amlnophenol), commonly known as paracétamol (CAS no: 103-90-2), ls an active Ingrédient possesslng analgésie and antipyretic activlty used widely In medical practice to allevlate acute and chronlc pain and to reduce the body température when this exceeds physîologlcal values.
Paracétamol, conversely to the majority of commonly used analgésie drugs, ls not an NSAID (non-steroldal anti-lnflammatory drug), slnce It ls almost devoid of antiaggregant and anti-lnflammatory activlty. To date, Its mechanism of action remains Utile known, although this molécule was syntheslsed for the first tlme In 1878 and its use in the medical field has been established for more than 100 years.
In the cllnlcal field, acetamlnophen ls used fundamentally as an analgésie in the treatment of mlld and medium pain and as an antipyretic In the treatment of febrile states In adulte and in chlldren.
The most common pharmaceutical form for this active Ingrédient is the solid form. The most typical paracetamol-based pharmaceutical formulations are those In solid tablet form, In granule form or In the form of supposltories. Moreover, formulations containlng acetamlnophen In the form of a solution for intravenous infusion can also be found on the market. These are formulations Indicated for the short-term treatment of pain of medium Intenslty, In particuiar of the type experienced following a surgical Intervention. Intravenous administration ls reserved for cases In which, from a cllnlcal vfewpolnt, there is the need to treat the pain and/or hyperthermla with urgency or In cases In which It Is Impossible to Implement the other administration methods.
Administration of acetamlnophen by means of methods alternative to tradltional methods is still yet to be explored extensively, and essentially no spécifie applications hâve been found In the field of analgésie therapy.
Slnce acetamlnophen Is devold of anaesthetic action, It Is yet to be used In the field of general, local or locorégional anaesthesia, such as spinal anaesthesla. Spinal anaesthesla Is an anaesthesla technique in which an Injectable solution containing an active Ingrédient possesslng local anaesthetic actlvity Is Injected through the dura mater, that Is to say the outer meningeal membrane protectlng the spinal cord, Into the medullary canal thereof. The spinal Injection Is usually carried out by highly quallfied medical personnel between the spinous processes of two vertebrae, usually In the lumbar zone, using spécifie needles, which are long and slender.
The solution containing the active Ingrédient possesslng local anaesthetic actlvity, once Injected In situ, mlxes with the cerebrosplnal fluid, that Is to say the bioiogical fluid that bathes the spinal cord and Is located between the spinal cord and the dura. During the spinal injection, the rlsks of causing neuroioglcal damage are iimlted by the fact that the spinal column Is protected by the pla mater, the Innermost of the meningeal membranes.
During the infusion process, the solution containing the local anaesthetic mlxes with the cerebrosplnal fluid, thus blocklng conduction via the nervous System of Impulses to the brain and causing a réversible loss of sensltivlty, which may be accompanied by motor paralysls. The anaesthesla Is thus implemented both from the anterlor part of the spinal cord, from which the motor nerves origlnate, and from the posterior part, from which the sensory nerves enter. The administration of the solution containing the anaesthetic then causes the absence of sensltivlty of the innervated areas from the nerve roots In question, and at the same time the inhibition of muscular and sensory actlvity.
Generally, spinal anaesthesla 1s used for interventions on organs of the smali pelvls and on the lower llmbs. Typlcal examples where spinal anaesthesla Is used are appendectomy, hemloplasty, caesarean section, arthroscopy, orthopaedic surgery of the lower limbs, etc.
Among the spinal anaesthesla techniques, H has been possible to distingulsh between épidural Injection and Intrathecal (IT) Injection. In the latter case, the solution containing local anaesthetic is injected into what Is known as the subarachnoid space.
Whereas the Intrathecal technique Is more Invasive than the épidural technique since the injection Is performed in a deeper zone of the splne, it lias the advantage of requlring comparably lower doses of local anaesthetic. This aspect generally constltutes an advantage since local anaesthetlcs hâve a certain neurotoxicity.
Depending on the local anaesthetic used, the spinal anaesthesla can last from one to three hours approximately. Once thls action ceases, the patient progressively regains moblllty and sensltivlty; the perception of pain Increases as time passes due to the effects of the surglcal procedure.
The analgésie action of local anaesthetlcs therefore fundamentally remalns limited to the period of the surglcal Intervention, for which reason It is essentlal to estabilsh suitable analgésie therapy in the immédiate post-surglcal period. In the first hours following the surglcal Intervention, the sensation of generalised pain is locaiised In the région of the wound and Is In fact partlculariy Intense, and it Is therefore necessary to establish an effective and prompt analgésie therapy.
In medical practice, It has been observed however that, In order to obtain a suitable post-surglcal analgésie effect, it is necessary to admlnister analgésies In high quantifies or, altematlvely, to resort to the administration of oplold drugs.
Both of these therapeutic approaches not only expose patients to a sériés of possible side effects varylng In accordance with the type and quantity of drug adminlstered, but aiso, in many cases, do not provide a suitable analgésie response.
Currently, there Is therefore a need to provide new analgésie thérapies to be matched with local or locorégional anaesthesla In order to provide an effective analgésie action when the local anaesthetic effect reduces or stops.
One of the objecta of the présent Invention ls therefore to provide pharmaceutfcal formulations for spinal administration that make It possible to obtain an effective analgésie action in cases of acute post-surglcal pain.
Another object of the présent Invention Is to provide an Injectable solution containing an analgésie active Ingrédient suitable for spinal administration in the event of locoregfonal anaesthesla, sald solution havlng an effective and durable analgésie action on the patient when the action of the local anaesthetic runs out.
SUMMARY OF THE INVENTION
The inventors of the présent patent application hâve now found that by admlnisterlng a supersaturated aqueous solution of acetamlnophen by spinal route, a proionging of the analgésie effect substantially devofd of slde effects, Is surprislngly obtained. ‘
In accordance with a first aspect, the présent invention provides an acetamlnophen supersaturated fnjectable aqueous solution for analgésie use by spinal administration, wherein sald supersaturated Injectable aqueous solution comprises acetaminophen In a concentration ranging from 1.3 to 8% w/v.
The acetamlnophen supersaturated aqueous solutions according to the Invention with a concentration from 1.3 to 8% w/v are unexpectedly stable, even after a period of storage of more than 18 months.
The Inventors hâve discovered that, by means of spinal administration of an acetaminophen supersaturated Injectable aqueous solution, it Is possible to obtain an effective analgésie effect of unexpectedly prolonged duration, typically equal to or greater than 24 hours. In particular, the spinal administration of an acetaminophen supersaturated solution according to the Invention results in effective anaigesla for at least 24 hours in mice and In rats In the case of Infiammatory pain Induced by carrageenan and In post-surgical pain.
The Inventors hâve also found that acetaminophen supersaturated aqueous solutions are compatible with conventlonal solutions of local anaesthetics and can therefore be co-admlnlstered by spinal administration. Co-admlnlstration with local anaesthetics Is made possible or Is fadlitated in any case slnce the solutions according to the Invention hâve a quantity of solvent less than that of unsaturated acetaminophen solutions.
The administration of Injectable solutions by spinal administration generally présents limitations. A first limitation is of the physical type, slnce, In the case of spinal anaesthesia, the drug Is perfused In a defined and confined space in which a Iimited quantity of solution can be Infused. In the case of the acetaminophen hypersaturated solution, this limitation Is overcome slnce a therapeutically effective quantity of active Ingrédient Is dissolved in a volume of solvent that Is reduced .
compared to an unsaturated conventional solution of the same active Ingrédient
The low volume of supersaturated solution needed to obtain an analgésie therapeutic response allows the slmultaneous administration with local anaesthetic solutions. . ' ‘
For example, an acetaminophen supersaturated solution with a volume of 15 approximately 0.5-1.5 ml of water can be added to a solution of equai volume of local anaesthetic In order to obtain a total solution of approximately 1-6 ml that can be adminlstered by means of spinal administration without exceedlng the physlological limlts imposed by the subdural space (Intrathecal).
The acetaminophen supersaturated solution can therefore be added to and/or mlxed with a conventional solution of a local anaesthetic in order to obtain effective analgesla for a perlod of time greater than the period of activity of the anaesthetic, In particular In the case In which the anaesthetic Is a short-actlng or medium-actlng anaesthetic.
In addition, the acetaminophen solutions and the local anaesthetic solutions hâve Increased chemlcal-physical compatibilité which allows these solutions to be used concomltantiyorln mixture.
in accordance with a second aspect of the Invention, an acetaminophen supersaturated aqueous solution Is provided for analgésie use, comprising Its simiütaneous, separate or sequentlal spinal administration with a local anaesthetic.
The slmultaneous, separate or sequentlal spinal administration of an acetaminophen supersaturated aqueous solution with a local anaesthetlc Is also made possible due to the Increased stabllity of the acetaminophen supersaturated aqueous solution as such or In mixture with conventlonal local anaesthetlcs.
In some embodiments, spinal administration of the acetaminophen supersaturated solution Is Implemented before pain Is percelved, typically before a surgical Intervention. The analgésie action determlned by the acetaminophen has a positive additive effect, and not a synergistic effect, with respect to the anaesthesla produced by the local anaesthetlc. The duration of the sensory and motor block remains unchanged. The pharmacoklnetics of .the anaesthetlc thus remalns unchanged, enabling rapid discharge of the patient in the case of joint administration with short-acting anaesthetlcs In clinlcal practice.
In accordance with a third aspect of the invention, a process for preparing an acetaminophen supersaturated aqueous solution, In particular of the type described above, Is provided.
With the process for preparing the acetaminophen supersaturated aqueous solution according to the Invention, the presence of oxygen or of dissolved air In the solvent Is typically eliminated or substantiaily reduced, thus caustng an Increase of the stabiilty of the acetaminophen solution.
In accordance with this aspect of the Invention, a process for preparing an acetaminophen supersaturated solution comprising the dissolution of acetaminophen in a deoxygenated-water-based solvent, for example by degassing with a flow of Inert gas, typically nitrogen and/or an Inert gas, for example argon.
The acetaminophen supersaturated solution obtained with the process according to the invention Is highly stable, has an Increased concentration of i acetaminophen In the solvent, and can be mixed with a solution of a conventional local anaesthetlc In order to obtain a solution with a total volume that Is compatible with the volume Injectable by means of spinal administration in a single administration process.
In accordance with a further aspect of the Invention, a method for treating pain, in particular acute post-surgical pain, comprising spinal infusion of an acetaminophen supersaturated Injectable aqueous solution having a concentration from 1.3 to 8% w/v In a therapeuticaily effective amount Is provided. Spinal administration of acetamlnophen supersaturated solution can be Implemented simultaneously, separately or sequentially with the administration of a local anaesthetic.
In some embodiments, the analgésie treatment method according to the invention comprises the administration of a therapeuticaily effective quantity of acetamlnophen supersaturated solution before pain is percelved, typlcally before the surgical intervention. In these conditions, the analgésie effect achieved has an unexpectedly prolongea duration, for example greater than 24 hours.
BRIEF DESCRIPTION OF THE FIGURES
- figure 1 shows a graph lllustrating the analgésie effect over time of two solutions containing, respectively, 10 and 100 pg of acetamlnophen in hyperalgesia caused by induction of peripheral Inflammation, '
- figure 2 shows a graph lllustrating the development of oedema resulting from peripheral Inflammation measured as an increase In the volume of the paw of laboratory mice,
- figure 3 shows a graph lllustrating the analgésie effect over time of a solution containing 200 pg of acetamlnophen In a model of post-surglcal pain in rats,
- figure 4 shows the effect of co-admlnlstration of acetamlnophen (200 pg) and a solution of 3 % chloroprocalne (20 pL)
DETAILED DESCRIPTION OFTHE INVENTION
In accordance with a first aspect, the invention relates to an acetamlnophen Injectable aqueous solution for analgésie use by spinal administration, wherein sald Injectable solution Is supersaturated and convenientiy comprises acetamlnophen dissolved In water in a concentration ranging from 1.3 to 8% w/v.
in accordance with some embodiments, the acetamlnophen Injectable aqueous solution Is supersaturated and has a concentration ranging from 1.8 to 8.0 w/v of acetamlnophen.
In accordance with some embodiments, the acetamlnophen injectable aqueous solution Is supersaturated and has a concentration ranging from 1.3 to 2.3 % w/v.
The appllcant has found that the use of acetamlnophen supersaturated solutions makes It possible to reduce the volume of solvent to be administered In the intrathecal space, thus enabling the co-administration with Injectable solutions of conventional local anaesthetics.
Solutions of acetamlnophen with concentrations equai to or greater than 1.3 % can be used within the scope of the Invention. These Injectable solutions provide good compliance and manageability of use.
In certain embodiments, the acetamlnophen supersaturated solution has a concentration of 1.3 to 8% w/v, from 1.8 to 8% w/v, from 1.8 to 3% w/v, from 1.3 to 2.3 % w/v.
In certain embodiments, the acetamlnophen supersaturated solutions of the invention hâve a concentration of or greater than 1.8 % w/v.
Within the scope of the invention, the acetamlnophen solution Is Implemented so as to administer a therapeuticaiiy active quantity of active Ingrédient
The term therapeuticaiiy active means a dose that causes a significant analgésie response in the subject to whom the acetamlnophen supersaturated solution Is administered. This dose varies according to the conditions, âge and welght of the patient
In accordance with some embodiments, the analgésie effect caused by acetamlnophen has a positive additive action, and not a synergistic action, with respect to the anaesthesla produced by the local anaesthetic. The duration of the sensory and motor block remalns unchanged. The pharmacoklnetics of the anaesthetic thus remains unchanged, enabling a rapid discharge of the patient In the case of Joint administration with short-acting anaesthetics In human clinical practice.
Within the scope of the invention, the term saturated solution means a solution that has dissolved therein the maximum quantity of soluté possible at a spécifie température, typically set at 20 ’C.
The term supersaturated solution means a solution that has a concentration of soluté greater than the one that couid be dissolved In water, in particular distilied water for pharmaceutical use, at a température of 20 *C.
Typlcaliy, In the supersaturated solution according to the Invention, acetamlnophen représents the soluté In excess that does not separate spontaneously by crystalllsation. This Is a hystérésis phenomenon widely recognised in physlcs and caused by a ’confllct' between contrasting factors, some of which attempt to draw the phenomenon In one direction (for example thermodynamics, which wouid promote crystalllsation of the soluté In excess), and others of which are Instead obstructive (for example the vlscoslty of the solution and above ali the absence of énucléation centres that enable crystalllsation, these ail belng factors that delay the crystalllsation process). .
Speciflcally, within the scope of the Invention, the term acetamlnophen supersaturated solution’ means solutions with a concentration of acetamlnophen equal to or greater than approximately 13 mg/ml or 1.3 % w/v In water, at a température of 20 ’C. '
The term acetamlnophen dose' means a quantity of acetamlnophen and/or salts or dérivatives thereof that can effectively cause centrai locorégional anaesthesla followlng perfusion via spinal administration.
The acetamlnophen supersaturated solution may hâve a concentration of acetamlnophen no greater than 100 mg/ml, corresponding to 10% w/v, beyond which recrystaiiisation of the active ingrédient may occur.
Typlcaliy, the acetamlnophen supersaturated solutions according to the Invention hâve an acetamlnophen concentration ranging from 1.3 to 2.3 %.
In the acetamlnophen supersaturated solution according to the Invention, the solvent phase is water-based, typically stérile and apyrogenlc.
In accordance with some embodiments, the acetamlnophen supersaturated solution is substantially free of preservatives, and/or additives and/or co-solvents.
In accordance with some embodiments, the supersaturated solution according to the Invention has a pH ranging from 4.5 to 6.5. In some embodiments, this pH range is regulated by addlng a bufferlng agent in suitable quantifies.
In accordance with some embodiments, the acetamlnophen solution according to the invention has a pH substantially equal to 5.5.
In accordance with some embodiments of the invention, the acetaminophen supersaturated solution according to the Invention comprises one or more buffering agents.
In order to regulate the pH of the solution according to the invention In a predetermined range, it is possible to use any buffering agent used In the formulation of solutions Injectable by spinal administration. By way of example, suitable buffering agents comprise carboxylic acids, such as citric acid, or alkaline or earth alkaline phosphates or biphosphates, such as sodium dihydrogen phosphate (Na2HPO4).
In accordance with some embodiments, the acetaminophen solution according to the Invention has an osmolality ranging between 80 and 310 mOsm/kg. In order to modlfy the osmolality of the solution Itself, it is possible to use Isoosmotic agents.
In some embodiments, the acetaminophen solution according to the invention has a relative density at 20 *C ranging between 1.003 and 1.075 g/g.
Typically, the acetaminophen supersaturated aqueous solution according to the invention is used in the treatment and/or in the prévention of pain and In particular In post-surgical analgésie treatment. By way of example, the acetaminophen supersaturated solution Is used In the post-surgical analgésie therapy of surgical Interventions such as appendectomy, hemioplasty, caesarean section, arthroscopy, orthopaedic surgery of the lower limbs, etc.
In some embodiments. In order to obtain an effective analgésie effect, a quantlty of acetaminophen ranging from 6 to 60 mg, typically from 8 to 40 mg, is Injected by spinal administration.
By way of exampie, It is possible to admlnlster an amount of supersaturated solution ranging from 0.5 to 1.3 mi containing acetaminophen at 1.8% w/v In order to obtaln these therapeutic doses.
The therapeutic effect achieved as a resuit of spinal administration of quantifies of acetaminophen conslderably less than those required by other administration methods in order to obtain an equal response représenta one of the advantages of the présent invention.
By way of example, the effective dose of acetaminophen adminîstered by spinal administration In the form of a supersaturated solution according to the invention Is approximateiy 1/100 of the dose of acetamlnophen administered orally necessary to obtain the same analgésie response. In fact, In humans, the maximum oral dose permitted within 24 hours Is equal to 4 g. The maximum spinal dose envlsaged for human dlnlcal practice Is equal to 40 mg, thls belng a dose that can also be used In patients with hepatic pathologies.
Thls drastic réduction of the dosage of active ingrédient necessary to obtain an analgésie response comprises a sériés of advantages In terms of réduction of systemlc toxlclty of the drug and of side effects. In particular, the low dosages of acetamlnophen necessary to obtain an analgésie effect by spinal administration of the formulation according to the Invention conslderably reduce the risks of hepatotoxlcity associated with the administration of acetamlnophen.
In addition, the low volume of acetaminophen supersaturated solution neèded to obtain a suitable therapeutic response allows saîd solution to be mlxed or administered slmultaneously with other active Ingrédients In the form of a solution that can be Injected by spinal administration, since the post-injection Increase in volume of the cerebrosplnal fluid retums to within physlologlcaî limlts.
In accordance with some embodiments, the acetaminophen supersaturated solution Is administered Intrathecaîly.
In some embodiments, the acetaminophen supersaturated solution according to the Invention has a content of air or oxygen dîssolved In the water solvent of less than 200 ppb.
The considérable absence of oxygen Increases the stablllty of the acetamlnophen solution according to the Invention, making it possible to store It for long perlods of time, up to more than 18 months. The stablllty has also been confirmed at low and high températures by carrying out studies at 4 °C, 40 °C and 60 C, and the solutions demonstrated themselves to be stable for at least 3, 6 and 3 months respectively. ·
In some embodiments, the acetamlnophen supersaturated solution contalns deoxygenated water as solvent.
In accordance with a second aspect of the Invention, a process for producing an acetamlnophen supersaturated solution, comprising the solubilisation of acetamlnophén In an amount greater than or equal to 13 mg/ml (1.3 % w/v) In deoxygenated water by means of nitrogen flushlng Is provided.
In some embodiments, the process for preparing the solution according to the Invention comprises the mixing of water by Injection and acetamlnophen In a nitrogen atmosphère or In the presence of a nitrogen stream, In which the acetamlnophen is provided In an amount so as to give an acetamlnophen supersaturated medlcated solution. .
In accordance with certain embodiments, the process for preparing an acetamlnophen solution of the invention comprises an élimination step of the oxygen or a degasslng step of the solvent, which typlcally Is water.
In some embodiments, the élimination of oxygen or the degasslng of the water comprises a step of treatment of water with an Inert gas, typlcally nitrogen and/or a noble gas, for example argon. In accordance with some embodiments, the process for producing the acetamlnophen supersaturated solution comprises the following steps:
a) dissolution of acetamlnophen In deoxygenated or degassed water convenlently by the passage of a nitrogen flow,
b) filtration of the acetamlnophen solution obtained In nitrogen stream,
c) distribution of the solution In nitrogen stream,
d) stérilisation of the solution.
In some embodiments, step a) is carried out at a hlgher température than room température, for example ranging from 55 to 70'C to produce the supersaturated solution of acetamlnophen.
In accordance with some embodiments of the process, In the Initial step of dissolution of acetamlnophen In water, one or more buffering agents, typlcally cltric acid and/or sodium dihydrogen phosphate, are added In order to regulate the pH of said aqueous solution, for example in the range from 4.5 to 6.5.
In accordance with some embodiments, step b) of filtration of the acetaminophen solution Is carried out by means of sterillsing filter. Step b) can be carried out at a higher température than the amblent température, for example ranglng from 70 to 80’C.
In some embodiments, step c) of distribution Is performed at a température greater than room température, for example ranglng from 55 to 75*C.
In accordance with some embodiments, the step d) of stérilisation of the acetaminophen solution is carried out by means of heating, typically to températures greater than 100 °C for a period of time suitable for stérilisation, for example equai to or greater than 15 minutes
In accordance some embodiments, the acetaminophen supersaturated solution of the Invention is obtained with a process that comprises the foliowing steps:
a) Dissolution of acetaminophen in deoxygenated water, for exampie by degassing In a nitrogen stream at a hlgher température' than room température, convenientiy ranging from 55 to 70eC
b) Filtration of the solution in a nitrogen stream at a hlgher température than room température, for example ranging from 70 to 80*C
c) Distribution of the solution in a nitrogen stream at a hlgher température than room température, for exampie ranging from 55 to 75eC.
In accordance with some embodiments, the acetaminophen supersaturated solution is packaged In suitable stérile vlals In the presence of inert gas, typically nitrogen, In order to prevent oxidative phenomena, which could compromise the stability of the solution.
In accordance with a third aspect of the présent Invention, an acetaminophen supersaturated aqueous solution for analgésie use comprising slmultaneous, separate or sequential spinal administration with a local anaesthetic is provided.
In accordance with another aspect, the présent invention provides an analgésie treatment method comprising the spinal administration of an acetaminophen supersaturated solution according to any one of the previously described embodiments.
The results of the experiments on animal models conducted by the applicant hâve demonstrated that the spinal administration of an aqueous solution of paracétamol, of the type previously described, détermines an anti-hyperalgesic effect and antl-allodynlc effect of the paracétamol In pain models such as post-operative and acute inflammatory pain resulting from the Intraplantar administration of carrageenan.
Experimental data shows that in Inflammatory or post-operative pain models, the administration of a paracétamol solution of the invention exerts a effective and prolonged analgésie and anti-allodynlc action that Is not predlctable from the literature data. . .
In particular, under the experimental conditions In which the acetaminophen solution of the invention was tested, the activation of a neuronal firing Is provoked In the affected area, whera the paracétamol Is effective In controlling the Intensity of the ‘ ascending stimulus, decreasing the awareness and sensltlvity of the aigeslc threshold thus determinlng an unexpectedly prolonged analgésie effect in some embodiments, the acetaminophen supersaturated solution Is administered simuitaneously with the administration of a local anaesthetlc.
In some embodiments, the slmuitaneous administration requires the mixing of the acetaminophen solution with a solution of a local anaesthetic.
One of the advantages of the acetaminophen supersaturated solution is provided by the possiblilty of having an elevated content of active Ingrédient In a reduced volume of solvent. The acetaminophen solutions according to the Invention typically contain from 1.3 to 2.3 mg per ml of solvent, typically water for Injection.
These solutions can be mlxed with the solutions of conventional local anaesthetlcs, which typically hâve a volume ranging between 1 and 2.5 ml, to obtaln a final mixture for Infusion with a total volume convenlently ranging from 2 to 4 ml.
The simultaneous spinal administration of local anaesthetic and acetaminophen supersaturated solution makes it possible to obtaln a combined anaesthetic and analgésie effect by carrylng out a single spinal Injection, thus limltlng the risks of injury to the spinal cord of the patient and increasing the compliance with the combined anaesthetic-analgeslc treatment
In accordance with a further aspect, the présent Invention provides a method of combined anaesthetic-analgeslc treatment, which comprises the slmultaneous, separate or sequentiai administration of an acetaminophen supersaturated solution and a solution of local anaesthetlc.
A further advantage of the acetaminophen solution according to the Invention lies In Its compatiblllty with conventional local anaesthetics.
Within the scope of the présent Invention, It ls possible however to use any anaesthetlc that can be administered by spinal administration, independently of its period of action.
For example, short-acting local anaesthetics such as lldocaine, articalne, oxybuprocaine, chloroprocalne, or a medlum-acting local anaesthetic selected from prilocalne, meplvacalne, etldocaine, or a long-acting local anaesthetic selected from ropivacaine, bupivacalne, clnchocainé, levobupivacaine, proxymetacalne and tetracajne are used within the scope of the invention.
The présent Invention daims the prlority of Italian patent application MI2012A001154 of 29 June 2012, the content of which ls fulîy Incorporated herein by référencé.
The présent Invention will now be described with reference to the following examples, which are provided purely for Illustrative purposes and are not to be understood to IImit the présent Invention.
EXAMPLE 1.
Acetaminophen supersaturated solution injectable by spinal administration having the following formulation:
acetaminophen15 mg
Injectable stérile water1 ml
The solution had a pH of 5.7
EXAMPLE 2
Acetaminophen supersaturated buffered solution Injectable by spinal administration having the following formulation:
acetaminophen 20 mg
Injectable stérile water 1 ml cltric acid 0.45 mg sodium dihydrogen phosphate 0.91 mg
The pH of the solution was approximately 5.5
EXAMPLE 3
Buffered acetaminophen supersaturated solution injectable by spinal administration having the following formulation:
acetaminophen60 mg injectable stérile water1 ml citric acid 0.45mg sodium dihydrogen phosphate 0.91mg
The pH of the solution was approximately 5.5
EXAMPLE 4 ’'
Comblned anaesthetic-analgeslc formulation Injectable by spinal administration, having the following formulation:
acetaminophen20 mg chloroprocaine10mg
Injectable stérile water5 ml
EXAMPLE 5 acetaminophen solutions having different concentrations were studied: un saturated solution containing 10 mg/ml (1.0%) of acetaminophen, supersaturated solution containing 15 mg/ml (1.5%) of acetaminophen supersaturated solution containing 20 mg/ml (2.0%) of acetaminophen hypersaturated solution containing 25 mg/ml (2.5%) and two formulations: acetaminophen in water and acetaminophen In water + citrate buffer.
The acetaminophen solutions were prepared using water deoxygenated by means of nitrogen flushing (oxygen residue < 200 ppb); In the case of the solutions of acetaminophen atone, Initial pH values around 6.0 were obtained Independently of the concentration of the acetaminophen itself, In any case ranging between 4.5 and
6.5.
The active Ingrédient was solubiiised In heated water In defined conditions (approxlmately 50 *C). The solution thus obtalned can be stored In the long term withln a wide range of températures without reprecipitation and/or chemical alteration of the acetamlnophen.
The solublllty of the acetamlnophen at 20 *C was approxlmately 13 mg/ml (1.3 % 5w/v).
The acetamlnophen solutions were obtalned by means of a process requlring the following schematlc steps:.
a) dissolution In water deoxygenated by means of degassing In nitrogen flow of the active Ingrédient and of the excipients for the formulations where présent
b) filtration of the solution In nitrogen stream
c) distribution of the solution In nitrogen stream'
d) stérilisation of the vlals at 121 ’C for 15 minutes.
The following Injectable solutions were obtalned:
mg/ml | RD029 naturai PH | RD029 buffered PH | RD028 naturel PH | RD028 buffered PH | RD026 naturai PH | RD026 buffered PH |
Acetamlnophen | 10 | 10 | 15 | 15 | 20 | 20 |
Cltrlc acid | - | 0.45 | - | 0.45 | - | 0.45 |
Disodium phosphate | « | 0.91 | - | 0.91 | - | 0.91 |
WFI | 990 | 988.64 | 985 | 983.64 | 980 | 978.64 |
Once charged Into the dissolver, the water for Injection was degassed by means of boiling and was then oooled to 60 ’C. Acetamlnophen and, for the buffered solutions, cltrlc acid and disodium phosphate was/were added. The solution was left under stirring, maintaining a constant Influx of nitrogen, for 25 minutes.
The pH value measured at this point of the préparation process revealed the following results:
RD029 naturel PH | RD029 buffered PH | RD028 naturel pH | RD028 buffered PH | RD026 naturel pH | RD026 buffered PH | |
PH | 5.39 | 5.72 | 5.42 | 5.76 | 4.89 | 5.82 |
After 25 minutes from the addition of active Ingrédient and excipients and reachlng 40 ’C, the solution was then fîltered under nitrogen pressure and was coilected in flasks previousiy purged with Inert gas (Nî). The solution was distributed into vials In nitrogen stream, and the vials were subjected to final stérilisation In autoclave In 5 overkill conditions (121 ’C for 15 minutes).
The analyses carried out on the vials after stérilisation provided the following results:
RD029 naturel PH | RD029 buffered PH | RD028 naturel pH | RD028 buffered PH | RD026 naturel PH | RD026 buffered PH | |
Colour and transparency | compila nce | compliance | compliance | compliance | compliance | compliance |
pH ofthe solution | 5.9 | 5.8 | 5.9 | 5.8 | 6.0 | 5.8 |
Acetamlnophe n titre (HPLC) | 100.5 | 100.9 | 101.4 % | 101.0% | 100.2 % | 100.6 % |
4anmlnophenol (HPLC) | not observe d | not observed | not observed | not observed | not observed | not observed |
Dlacetaminoph en titre (HPLC) | not observe d | not observed | not observed | not observed | not observed | not observed |
Titre of other tmpurittes | not observe | not observed | not observed | not observed | not observed | not observed |
(HPLC) | et · | |||||
Particulate contamination | z 10 pm 5.20 2 25 pm 0.33 | 2 10 pm 12.57 . 2 25 pm 0.33 | 2l0pm 7.87 2 25 pm 0.67 | 210 pm; 7.47 2 25 pm 0.13 | 2 10pm; 8.74 2 25 pm 0.21 | 2 10 pm 9.41 2 25 pm; 0.32 |
Stability of the acetamlnophen solutions studled
Stability*. 3 batches with respective acetamlnophen concentration of 1 %, 1.5 % and 2 % w/v were placed at 4 C, 25 ’C, 30 ’C, 40 ’C and 60 ’C.
Chemlcal-physlcal analyses were not conducted on the samples at 4 *C. The objective of the storage at low températures was to confirm any recrystailisation of the active Ingrédient To thls end, the samples were subjected to weekiy Visual analyses. After 3 months, the presence of preclpitate was not found In any of the tested solutions.
After 9 months at 25 and 30 *0, 6 months at 40 ’C, and 3 months at 60 ’C, the solutions were unchanged from a chemlcal-physlcal viewpolnt.
The pH of the unbuffered solutions demonstrates a rising trend, starting from values from approximately 6.0 and reaching 6.5 under the condition of maximum stress (60 'C).
The acetamlnophen titre remalns unchanged. The product of oxidation, 4amlnophenol, always remalns below the détection llmlt of the HPLC method used for the analyses. The concentration of the dimer always remains less than 0.10 %. No other Impurities are observed.
EXAMPLE 6 solutions of acetamlnophen with different concentrations were analyzed supersaturated solution with acetamlnophen content of 20 mg/ml (2.0%), 5ml vials filled to 3ml supersaturated solution with acetamlnophen content of 25 mg/ml (2.5%), 5ml vials filled to 3ml .
supersaturated solution with acetamlnophen content of 30 mg/ml (3.0%), 5ml vials filled to 3ml supersaturated solution with acetaminophen content of 50 mg/ml (5.0%), 5ml vlals filled to 3ml supersaturated solution with acetaminophen content of 80 mg/ml (8.0%), 5ml vlals 5 filled to 3ml
The acetaminophen solutions were prepared using water deoxygenated by nitration (resldual oxygen < 200 ppb). Initial pH values of around 5.5 were obtained, regardless of the concentration of the acetaminophen itself, in each case of between 4.5 and 6.5. The solublllzation of the active Ingrédient took place In water for Injection malntalned 10 at a température of between 55 and 70'C. The solution thus obtained can be stored at length under these température conditions without précipitation and/or chemical alteration of the acetaminophen.
The acetaminophen solutions were obtained with a process that provided for the following schematic steps:
a) Dissolution In deoxygenated water by degasslng of the active ingrédient In a nltrogen flow at a température range from 55 and 70'C.
b) Filtration of the solution In a nltrogen stream at a température range from 70 to 80 -C
c) Distribution of the solution In a nitrogen stream at a température range from 55 to
75 ’C. .
d) Sterilizatlon of the vlals at 121 *C for 15 minutes.
The following Injectable solutions were produced:
mg/ml | RD036 | RD037 | RD039 | RD040 | RD042 |
Acetaminophen | 20 | 25 | 30 | 50 | 80 |
WFI | 980 | 975 | 970 | 950 | 920 |
After loading In the dlssolver, the water for Injections was degassed by bolling and then cooled to 70 °C. Acetaminophen was added. The solution was left under 25 stirring, whîle malntainlng a constant Influx of nltrogen and the température above 55 ’C for 25 minutes.
The pH value measured around 55 ’C and at thls point of the préparation gave the following results:
RD036 | RD037 | RD039 | RD040 | RD042 | |
pH | 5.49 | 5.48 | 5.40 | 5.25 | 5.10 |
minutes after adding the active ingrédient, the solution was brought to 80 ’C, 5 fïltered under nitrogen pressure and collected In flasks !n previously purged with an inert gas (N 2)· The distribution Into vlals took place in a nitrogen stream and the vials were subjected to terminal sterillzation In an autoclave under over-klll conditions (121 ’C for 15 minutes).
The analysis carrled out on the vlals following sterillzation gave the following results:
RD036 | RD037 | RD039 | RD040 | RD042 | |
Colour and transparency | Compilant | Compilant | Compilant | Compilant | Compilant |
pH of the solution | 6.2 | 6.2 | 6.0 | 5.8 | 5.8 |
Acetamlnophen dire (HPLC) | 100.5% | 101.4% | 101.3% | 101.8% | 100.9% |
4-amlnophenol titre (HPLC) | Not detected | Not detected | Not detected | Not detected | Not detected |
Dlacetamlnophen titre (HPLC) | Not detected | Not detected | Not detected | Not detected | Not detected |
Titre of other impurities (HPLC) | < 0.05%* | < 0.05%* | < 0.05%* | < 0.05%* | < 0.05%* |
Partlculate | i 10 μπι: | 2 10 pm: | s 10 pm: | s 10 pm: | i 10 pm: |
RD036 | RD037 | RD039 | RD040 | RD042 | |
contamination | 733.40 2 25 pm: 9.80 | 32.20 2 25 pm: 11.80 | 311.20 2 25 pm: 196.20 | 3.80 2 25 pm: 0.20 | 20.10 2 25 pm: 5.80 |
‘dlsregarded limlt
Stabllltv of the acetaminophen solutions studled
Stabillty. 5 batches with acetaminophen concentration of 2.0%, 2.5%, 3%, 5% and 8% w/v respectively were placed at 4 ’C, 25 ’C and 40 ’C;
Physicochemlcal analyses were not conducted on the samples at 4 ’C. The purpose of storage at low températures was to check any recrystallizatlon of the active ingrédient. For thls purpose, the samples were subjected to weekly Visual analysis. After 2 months, there was ho evfdence of the presence of precipltate In the tésted solutions.
After 2 months at 25, 40 and 4 ’C, the solutions are unchanged from a physicochemlcal perspective.
The pH of the solutions show an Increasing trend starting from values of about 5.5 and reaching 6.0 in the condition of maximum stress (40 ’C).
The titre of the acetaminophen remalns unchanged. They 4-aminophenol impurity always remains below the détection iimit of the HPLC method used for the analysis. The concentration of the dimer is always less than 0.1 %. No other impurities were detected.
EXAMPLE 7
Chemlcai-Dhvslcal stabllitv of the mixtures of acetaminophen and local anaesthetics for spinal use,
The solutions with a concentration of acetaminophen of 1.5 % and 2 % w/v of example 5 were mixed with various anaesthetics for spinal use (from the classes of amides and esters, for example bupivacalne HCl, lidocalne HCl, prilocaine HCl, chloroprocalne HCl, mepivacalne HCl, roplvacalne HCl) in various proportions so as to cover the entire known dosage range of each of these anaesthetics and a dosage range of acetamlnophen from 10 mg to 60 mg.
Such mixtures were prepared using equlpment and méthodologies commonly used by anaesthetlsts (syringes, needies and orders of addition of the components).
The tests carried out involved the following anaesthetics for spinal use:
- chloroprocaine 1 %: minimum dosage: 4 ml; maximum dosage 5 ml
- chloroprocaine 3 %: minimum dosage: 1.3 ml; maximum dosage 1.7 ml
- hyperbaric priiocaine 2 %: minimum dosage: 2 ml; maximum dosage 3 ml
- priiocaine 2 %: minimum dosage: 2.5 ml; maximum dosage 4 ml ‘
- ropivacalne 5 mg/ml: minimum dosage: 3 ml; maximum dosage 5 ml
- ropivacalne 10 mg/ml: minimum dosage: 1.5 ml; maximum dosage 2.5 ml
- hyperbaric buplvacaine 0.5 %: minimum dosage: 1.5 ml; maximum dosage 4 ml
- meplvacaine 2 %: minimum dosage: 1 ml; maximum dosage 3 ml
- meplvacaine 4 %: minimum dosage: 0.5 ml; maximum dosage 1.5 ml
- ildocalne 0.5 %: minimum dosage: 8 ml; maximum dosage 16 mi
- Ildocalne 2 %: minimum dosage: 2 ml; maximum dosage 4 ml
Mixtures with the solutions of acetamlnophen 1.5 % and 2 % with dosages from 10 mg to 60 mg were prepared for each dosage, both minimum and maximum, of each anaesthetic for spinal use:
- acetamlnophen 1.5 %: minimum dosage: 0.7 ml; maximum dosage 4 mi
- acetaminophen 2 %: minimum dosage: 0.5 ml; maximum dosage 3 ml
The two products (anaesthetic and acetaminophen) were mlxed In accordance with the operative procedures commonly used in the fïeld of anaesthesla. The solutions were drawn using the same stérile syrlnge through a needle of 18G diameter and by dispenslng the mixture thus created Into a glass vlal using a needle for spinal anaesthesla (the dlameters used were 24G, 25G, and 27G).
The order in which the solutions were drawn (first anaesthetic and ’ then acetamlnophen and vice versa) was varied a number of fîmes In order to assess both the records and the résultant mixtures, which were monltored for 10 days In order to assess the absence of preclpltate.
None of the prepared solutions demonstrated the presence of preclpitate up to 10 days from préparation.
The mixture with minimum dosage of hyperbaric buplvacalne 0.5 % (1.5 ml) and maximum dosage of acetamlnophen 2 % (3 ml) was prepared 3 times. The first time In accordance with the usual operative procedures, the second time leaving the mixture In the syringe and placing It at a température of 4 °C for 10 days, and the third time preparing the mixture at a température of 15 *C. In none of these cases was the presence of crystals and/or preclpitate observed.
Two tests without addition of anaesthetic, but only with drawing of acetarplnophen 2 % were also carried out. In the first test, the acetamlnophen was drawn via syringe through an 18G needle and was dispensed Into a glass vial through a 27G needle. One hour after dlspenslng of the solution, there was no slgn of the presence of crystals arid/or preclpitate; 19 hours after préparation, the presence of needle-shaped crystals was observed.
In the second test, acetamlnophen 2 % was drawn via syringe through an 18G needle and was left in the syringe. The formation of crystals within the solution was observed after 30 minutes.
Ali of the mixtures thus produced were analysed from a chemical view point both with regard to the acetamlnophen and with regard to the active Ingrédient of the anaesthetic. No slgnlficant Instances of dégradation were observed in any case within 24 hours.
EXAMPLE 8
The efficacy of the acetamlnophen supersaturated solution administered by spinal administration (IT) was tested by means of explorative experlments in a mode! of Inflammatory pain in mlce, Induced by means of Intraplantar injection (Injection In the rear left paw, referred to herelnafter as the site of inflammation*) of carrageenan (50 pl 1 %).
The pain threshold following mechanical stimulation (expressed in grams) was measured after 2, 4, 6 and 24 hours after Induction of the inflammation. This threshold Is to be consldered an indlcator of inflammatory pain.
The development of oedema at the site of Inflammation was measured and expressed as an Increase of volume (mL) of the site of Inflammation.
Spinal administration in the mouse was carried out as described by Fairbanks (2003).
Experimental groups:
N=5 mlce received spinal vehicle (IT; to be understood as a placebo) and intraplantar administration of carrageenan
N=7 mlce received acetamlnophen IT (10 pg) and intraplantar administration of carrageenan
N=7 mlce received acetamlnophen IT (100 pg) and intraplantar administration of carrageenan
Results ’ IT acetamlnophen In the dose of 100 pg per mouse was effective In reducing In fl a mm a tory pain In the mouse. The mlce to which IT acetamlnophen was administered In the dose of 100 pg had a slgnlflcantly hlgher pain threshold following mechanical stimulation of the site of Inflammation (figure 1).
IT acetamlnophen In the dose of 100 pg per mouse produced only a slight réduction (approximately 20 %) of the development of oedema at the site of inflammation during the first two hours following Induction (figure 2).
IT acetamlnophen In the dose of 10 pg per mouse was not effective In reducing the Inflammatory pain inslgnlficantly compared to the group of control mlce (figure 1).
At ail tested doses, IT acetamlnophen did not produce any clear slgn of toxlclty or clear behavioural and motor changes.
The accompanylng figure 1 shows the pain threshold following mechanical stimulation at the site of Inflammation after IT administration of placebo, 10 pg of acetamlnophen and 100 pg of acetamlnophen.
Figure 2 shows the development of oedema at the site of Inflammation during the first two hours after induction after IT administration of placebo, 10 pg of acetamlnophen and 100 pg of acetamlnophen. The raw data and the relative stati stical analysis of example 6 will be presented hereinafter.
Threshold of mechanicai hyperalgesia (values expressed In grams)
basal | 42.5 | 32.5 | 47.5 | 37.5 | 32.5 | ||
2 hours | 13 | 14 | 9 | 9 | 8 | ||
4 hours | 12 | - 13 | 85 | 9 | 9 | ||
8 hours | 11.5 | 10 | 9.5 | 11 | 9 | ||
24 hours | 12 | 10.5 | 8 | 8.5 | 7.5 |
I.Æ' :Μί | Λ II·'' | 'Æ*· | 3¾¾ | ||||
basal | 32,5 | 4Z.5 | 32,5 | 32,5 | 22.5 | 30.0 | 25.0 |
2hours | 8.0 | 90 | 11.5 | 8.0 | 8.0 | 9.0 | 10.0 |
4 hours | 13.0 | 72 | 72 | 130 | 90 | 7Λ | 8.5 |
8 hours | 11.5 | 13.0 | 9.0 | 11.0 | 10.0 | 7Λ | 10.0 |
24 hours | 13.0 | 11.5 | 12.0 | 13.0 | 12.0 | 9.5 | 11.5 |
jKfllffiSkd | |||||||
basai | 27.5 | 35 | 20 | 372 | 32.5 | 30 | 30 |
2 hours | 23.5 | 12.5 | 23 | 17 | 13.5 | 14 | 11.5 |
4 hours | iô | 17.5 | 20 | 16 | 20 | 17.5 | 15 |
8 hours | 20 | 15 | 21.5 | 15.5 | 16 | 17 | 18 |
24 hours | 19 | 14.5 | 19 | 212 | 162 | 18 | 17 |
Paw volume (oedema) (value» expressed In mL)
Λ. & | |||||||
basal | 025 | 025 | 0J3 | ÛJ | 024 | ||
2 hours | 0.4 | 0.41 | 0.39 | 0.35 | 0.39 | ||
4 hours | 0.42 | 0.42 | 0.39 | 0.39 | 0.37 | ||
Bhours | 0.41 | 0.44 | 0.4 | 0.39 | 0.37 | ||
24 hours | 0.48 | 0.44 | 0.43 | 0.38 | 0.4 |
basal | 0.29 | 0.24 | 02 | 021 | 026 | 0.22 | 029 |
2 hours | 0.43 | 0.36 | 0.38 | 0.37 | 0.44 | 0.36 | 0.37 |
4 hours | 0.39 | 0.36 | 0.34 | 0.38 | 0.44 | 0.41 | 0.44 |
6 hours | 0.44 | 0.36 | 0.33 | 0.37 | 0.45 | 0.33 | 0.36 |
24 hours | 0.47 | 0.4 | 0.48 | 027 | 0.5 | 0.42 | 0.42 |
basal | 0.27 | 0.28 | 029 | 0.24 | 026 | 025 | 0.18 |
2 hours | 0.32 | 0.34 | 0.33 | 0.33 | 0.37 | 0.38 | 0.33 |
4 hours | 0.35 | 0.37 | 0.38 | 0.38 | . 0.38 | 0.35 | 0.34 |
6 hours | 0.38 | 0.4 | 0.39 | 0.38 | 0.43 | 04 | 0.35 |
24 hours | 033 | 041 | 042 | 0.44 | 047 | 045 | 046 |
each column représenta a different experimental subject EXAMPLE 9
The effîcacy of the acetamlnophen supersaturated solution admlnlstered by spinal administration (IT) was tested with explôrative experlments In a model of post-surglcal pain in rats. The post-surglcal pain was induced by means of incision and subséquent suture of the subplantar région of the rear left paw, as described by Timothy J. Brennan (1996). .
The pain threshold following mechanical stimulation (expressed In grams) was measured after 2,4,6 and 24 hours after the Incision. This threshold Is considered to be an Indicator of pain and hyperalgesia of the zone affected by surgical Intervention.
Experimental groups
N=5 rats received spinal vehicle (IT; to be understood as placebo) Immediately before the surgical procedure. ‘
N=5 rats received acetaminophen IT (200 pg) Immediately before the surgical procedure. '
Results
IT acetaminophen In the dose of 200 pg per rat was effective In reducing postsurglcal pain, as shown in figure 3. The rats to which IT acetaminophen was admlnlstered In the dose of 200 pg had a significantly higher pain threshold following mechanical stimulation of the site of Incision (figure 3). IT acetamlnophen in the dose of 200 pg produced significant cumulative analgesla over 24 hours.
IT acetaminophen did not produce any clear slgn of toxicity or ciear behavloural or motor changes. The raw data and the relative statistlcal analysis according to the présent example will be presented herelnafter.
VI | aiJCLE | ACETAMHOPHEN200 | ||||||||
0 | 48.25 | 46.75 | 393 | 4445 | 4545 | 451 451 41 | 4245 | 41.5 | ||
2 | J84S | 243 | 20.75 | 25 | 2745 | 27 23.5( 27.75 | 27 | 25 | ||
4 | 2045 | 17 | 28.75 | 17.75 | 2745 | 22451 233| 24 | 28 | 38.75 | ||
24 | 11« | 18.5 | 703 | Ü.S | ili | 29-ïs| lè.2$| 29 | ~14.5 | UE | ||
48 | 174S | 24.75 | 18.5 | 23.25 | 17 | 224$ 1 2θ| 2645 | 19.76 | 24.75 | ||
i i ... | ||||||||||
i | > 1 Absotite réduction ofthapatithrêshokf ί | |||||||||
THE | ||||||||||
2 | *30 | •22.25 | -18.75 | •19.25 | -18 | •18 | •213 | -13.25 | •IS4S | •163 |
4 | -28 | -29.75 | •1045 | •263 | •18 | -2245 | 213 | -17 | -144$ | •Z 7 5 |
24 | -22.45 | •28.25 | •19 | •21.7$ | -23.75 | •15.75 | '26.7$ | •12 | -17.7$ | -6.75 |
48 | -31 | •22 | -21 | -21 | -28.25 | •22-75 | -16 | -14.75 | •22 49 | -16.75 |
. 1 | ................. ’ « | |||||||||
i - Radu | Æon ol the pa· threshold fi 56 - | |||||||||
τυέ | ||||||||||
2 | 37.82 | 5231 | $233 | 56.50 | 6042 | 60.00 | 5242 | 67.68 | 63.91 | 6044 |
4 | 41.07 | 36.36 | »•>8 | 40.11 | 6042 | .... $036 | 5242 | 5834 | 6647 | 93.37 |
i< | 5337 | 39.57 | 51.90 | 5035 | 4731 | 65.00 | 40-56 | “ 70.73 | 57.99 | 8343 |
48 | ïsTs | 52.94 | 46.84 | 5234 | 3737 | 4934 | 6434 | 64.02 | 4647 | 59.64 |
κ> œ
EXAMPLE 10
The efficacy of the acetaminophen supersaturated solution adminîstered by spinal administration (IT) was tested with explorative experiments In a model of post-surgical pain In rats In combination with a solution of chloroprocalne 3 %.
The post-surgical pain was Induced by means of incision and subséquent suture of the subplantar région of the rear left paw, as described by Timothy J. Brennan (1996).
The pain threshold following mechanical stimulation (expressed In grams) was measured 4 hours after the Incision. Complété réduction of the anaesthetic effect of the spinal chloroprocalne Is expected within this period of time. The réduction of the pain threshold Is considered to be an Indicator of pain and hyperalgesla of the zone affected by surgical intervention.
Experimental croups '
N=5 rats recelved spinal vehlcle (IT; to be understood as placebo) Immedlately before the surgical procedure .
N=5 rats recelved acetaminophen IT (200 pg) Immedlately before the surgical procedure
N=4 rats recelved chloroprocalne IT (3 %, 20 pL) Immedlately before the surgical procedure
N=4 rats recelved acetaminophen IT (200 pg) + chloroprocalne IT (3 %, 20 pL) Immedlately before the surgical procedure.
Results
IT acetaminophen In the dose of 200 pg per rat was effective in reduclng postsurgical pain, as shown In figure 4. The rats to which IT acetaminophen was adminîstered in the dose of 200 pg had a significantiy hlgher pain threshold following mechanical stimulation of the site of incision (figure 4).
IT chloroprocalne (3 %, 20 pL) for rats did not change the pain threshold following mechanical stimulation of the site of incision, Indicating a termlnation of the anaesthetic effect.
IT acetaminophen In the dose of 200 pg for rats in co-admlnlstration with chloroprocaine (3 %, 20 pL) produced a significant rise of the pain threshold following mechanical stimulation of the site of incision with a trend suggestive of an additlonal analgésie effect.
IT acetaminophen In the dose of 200 pg per rat in co-administration with 5 chloroprocaine (3 %, 20 pL) did not produce any clear sign of toxlcity or clear behavloural or motor changes. The rats that received chloroprocaine (3 %, 20 pL) had, after 4 hours, a complété recovery In terms of walking and tension of the rear ilmbs.
.The raw data In accordance with the présent example will be presented 10 hereinafter.
Rat no. | VehJde | Chlore pro ce he | Acetamlnophen | Acetaminophen * Chloroprocaine |
1 | 20,25 | . 23.60 | 22.75 | 37.00 |
2 | 17.00 | 22.75 | 24.90 | 28.75 |
3 | 28.75 | 19.75 | 24Ό0 | 37.00 |
4 | 17.75 | 24.25 | 28.00 | 23.50 |
5 | 27.25 | 38-75 |
I 31
Claims (11)
- I CLAIMS CLEAN1. A stable acetaminophen supersaturated Injectable aqueous solution for analgésie use by spinal administration wherein said supersaturated Injectable aqueous solution s comprises a solvent which Is degassed or substantlally oxygen or air free and comprises acetaminophen In a concentration greater than 1.8 w/v.
- 2. An acetaminophen supersaturated injectable aqueous solution for use as clalmed in clalm 1 wherein the acetaminophen concentration Is ranglng from 1.8 to 8.0 % w/v.
- 3. An acetaminophen supersaturated Injectable aqueous solution for use as clalmed 10 In clalm 1 or 2 wherein said Injectable aqueous solution is substantlally free of preservatives, and/or additives and/or co-solvents.
- 4. An acetaminophen supersaturated Injectable aqueous solution for use according to clalm 1, obtained by degasslng water by a fiow of an inert gas and by dissolving acetaminophen thereln In an amount to give a supersaturated solution.15
- 5. An acetaminophen supersaturated aqueous solution for use as clalmed In anyone of clalms 1-4 in the treatment of post-surgical pain.
- 6. An acetaminophen supersaturated aqueous solution for use as clalmed in anyone of clalms 1-4 comprising the slmultaneous, separate or sequentlal spinal administration with a local anaesthetic.20
- 7. An acetaminophen supersaturated aqueous solution for use as clalmed In clalm 6 wherein the acetaminophen solution is added to or mixed with a solution of a local anaesthetic for spinal administration.
- 8. An acetaminophen supersaturated aqueous solution for use as clalmed In claim 6 or 7 wherein said local anaesthetic is a short-actlng local anaesthetic selected from25 lldocalne, articalne, oxybuprocalne, chloroprocalne or a medium-acting local anaesthetic selected from priiocalne, mepivacalne, etldocaine or a long-actlng local anaesthetic selected from roplvacaine, bupivacalne, cinchocaine, levobupivacaine, proxymetacalne, tetracaine.
- 9. An acetaminophen supersaturated aqueous solution for use as clalmed in cialm 630 for the comblned analgeslc-anaesthetic treatment.
- 10. An acetamlnophen supersaturated aqueous solution for use as clalmed In claim 6 wherein the analgésie effect of acetamlnophen has a longer duration than the analgésie effect of the local anaesthetlc.
- 11. An acetamlnophen supersaturated aqueous solution for use as clalmed in claim s 6 wherein the local anaesthetlc and acetamlnophen exert an analgésie effect even after the end of the anaesthetlc effect caused by the local anaesthetlc.
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ITMI2012A001154 | 2012-06-29 |
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