Pharmaceutical oil-in-water nano-emulsion
10736842 ยท 2020-08-11
Assignee
Inventors
Cpc classification
A61K31/519
HUMAN NECESSITIES
A61P29/00
HUMAN NECESSITIES
A61K31/167
HUMAN NECESSITIES
A61K31/4178
HUMAN NECESSITIES
A61P25/18
HUMAN NECESSITIES
A61K47/10
HUMAN NECESSITIES
A61K47/22
HUMAN NECESSITIES
A61K9/1075
HUMAN NECESSITIES
A61K47/26
HUMAN NECESSITIES
A61K47/44
HUMAN NECESSITIES
A61K47/14
HUMAN NECESSITIES
International classification
A61K47/10
HUMAN NECESSITIES
A61K31/519
HUMAN NECESSITIES
A61K31/167
HUMAN NECESSITIES
A61K47/22
HUMAN NECESSITIES
A61K47/44
HUMAN NECESSITIES
A61K31/4178
HUMAN NECESSITIES
A61K47/26
HUMAN NECESSITIES
A61K47/14
HUMAN NECESSITIES
Abstract
Accordingly, the present invention provides a pharmaceutical oil-in-water nano-emulsion, with a pharmaceutically active substance. The selected pharmaceutically active substance is encased in monounsaturated fatty acid droplets with the droplets having an average particle size in the range of 60 to 200 nm. The nano-emulsion is also provided with a non-ionic surfactant system, which is a mixture of polyethers, macrogolglycerides and polysaccharides, along with pharmaceutically acceptable adjuvants. The present invention also provides a process for the preparation of pharmaceutical oil-in-water nano-emulsion.
Claims
1. A pharmaceutical oil-in-water nano-emulsion composition, comprising: a pharmaceutically active substance, encased in monounsaturated fatty acid droplets, wherein said monounsaturated fatty acid is present in an amount of about 5-25% w/w based on the weight of the total composition said droplets having an average particle size in the range of 60 to 200 nm; a non-ionic surfactant system comprising a mixture of polyethers, macrogolglycerides and polysaccharides wherein the polyethers are present in an amount ranging from about 2-25% w/w based on the total weight of the composition, wherein the macrogolglycerides are present in an amount ranging from 10-30% w/w based on the total weight of the composition, wherein the polysaccharides are present in an amount ranging from 2-30% w/w based on the total weight of the composition; water present in an amount of between 15 and 50% w/w; and pharmaceutically acceptable adjuvants, wherein the composition is highly stable having a drug loading capacity of the pharmaceutically active substance of up to 100 mg/mL.
2. The composition as claimed in claim 1, wherein said pharmaceutically active substance is lipophilic or partially lipophilic and is selected from a group consisting of antipsychotics, antiemetics, analgesics, antipyretics, anti-inflammatory agents or any lipophilic-based drugs.
3. The composition as claimed in claim 2, wherein said antipsychotics are selected from the group consisting of ziprasidone, fluphenazine, haloperidol, olanzapine, chlorpromazine, risperidone, aripiprazole, molindone, loxapine, and sulpiride and pharmaceutically acceptable salts thereof.
4. The composition as claimed in claim 2, wherein said antiemetics are diphenhydrinate, diphenhydramine, doxylamine, meclizine, ondansetron, promethazine, prochlorperazine, or pharmaceutically acceptable salts thereof.
5. The composition as claimed in claim 2, wherein said analgesics, antipyretics, and anti-inflammatory agents are selected from the group consisting of paracetamol, methadone, diamorphine, fentanyl, buprenorphine, temazepam, piracetam, sufentanil, mefenamic acid, naproxen, piroxicam, indomethacin, valdecoxib, celecoxib, probenecid, nabumetone, ibuprofen, flurbiprofen, isoxicam, meclofenamic acid, fenclozic acid, and phenyl butazone.
6. The composition as claimed in claim 1, wherein said monounsaturated fatty acid is an oleic acid.
7. The composition as claimed in claim 1, wherein said polyether surfactant is a combination of polyethylene glycol and diethylene glycol monoethyl ether.
8. The composition as claimed in claim 1, wherein said polyether surfactant is polyethylene glycol and is present in an amount ranging from about 2.5% to 20% w/w based on the total weight of the composition.
9. The composition as claimed in claim 1, wherein said macrogolglyceride surfactant is caprylocaproyl macrogol-8 glyceride, acconon CC 6, or a combination thereof.
10. The composition as claimed in claim 1, wherein said polysaccharide surfactant is polyoxyethylene sorbitan fatty acid esters.
11. The composition as claimed in claim 1, further comprising a solvent selected from the group consisting of benzyl alcohol, phenyl ethyl alcohol, and chloro butanol.
12. The composition as claimed in claim 1, wherein said adjuvants are selected from the group consisting of stabilizers, antioxidants, preservatives, mucoadhesive agents, buffering agents, absorption enhancers, and pH adjusting agents.
13. The composition according to claim 12, wherein said antioxidant is selected from butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid and tocopherol, or a combination thereof in the range of 0.01% to 0.2% w/w of the total composition.
14. The composition according to claim 12, wherein said absorption enhancers are selected from macrogol-15-hydroxystearate, sodium glycocholate, sodium caprylate, and a combination thereof.
15. The composition as claimed in claim 1, wherein the pharmaceutically active substance is selected from the group consisting of olanzapine, ondansetron, risperidone and pharmaceutically acceptable salts thereof; the mononunsaturated fatty acid is oleic acid; and the non-ionic surfactant system comprises a mixture of polyethylene glycol, caprylocaproyl macrogol-8 glyceride, and polyoxyethylene (20) sorbitan monolaurate.
16. A method for the treatment of migraine, nausea, cluster headache, schizophrenia, bipolar disorder, vomiting, psychosis, or sleep disorders, said method comprising nasal administration of the composition of claim 15.
17. A process for the preparation of an oil-in-water emulsion composition as claimed in claim 1, comprising the steps of i) forming an oil phase in the presence of a monounsaturated fatty acid, a polyether surfactant, a macrogolglyceride surfactant, and a polysaccharide surfactant, under stirring at an ambient temperature; and ii) adding a therapeutic amount of pharmaceutically active substance to said oil phase, under constant stirring and at an ambient temperature, to encase said active substance, in said monounsaturated fatty acid droplets, said droplets with particle size in the range of 60 to 200 nm, to obtain a homogenous oil phase; and iii) adding an aqueous medium to said homogenous oil phase, under stirring to obtain the oil-in-water emulsion.
18. The composition of claim 3, wherein said antipsychotics are olanzapine or risperidone, or pharmaceutically acceptable salts thereof.
19. The composition of claim 10, wherein said polyoxyethylene sorbitan fatty acid ester is selected from the group consisting of polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (80) sorbitan monooleate, sorbitan monooleate, and a combination thereof.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION OF THE INVENTION
(115) A composition for delivery of lipophilic or partially lipophilic based active pharmaceutical substance and a method for preparing the same, is disclosed.
(116) In one embodiment, the present invention relates to an oil-in-water emulsion comprising an oil phase, the average particle size of which is in the range of 60 to 200 nm, a method for preparing the composition and the use of the composition for the delivery of the active pharmaceutical substance. The composition demonstrates favourable dilution properties without being affected by the solubility characteristics of individual components of the composition. Furthermore, the composition exhibits a stable state throughout its shelf life.
(117) The emulsion of the present invention comprises at least an active pharmaceutical substance, a surfactant, or a mixture of surfactants and additives, wherein the average particle size of the emulsion of the composition is less than 200 nm.
(118) In a further embodiment, the invention provides pharmaceutical compositions comprising such compositions and methods of making and using such compositions.
(119) The active pharmaceutical substance referred herein may also be referred to herein as drug, active pharmaceutical ingredient or therapeutic agent. These terms are used interchangeably refer to chemical material or compound which, when administered to a species (human or animal), is generally bioavailable and induces the desired pharmacologic effect.
(120) In one embodiment the invention provides composition comprising of a lipophilic or partially lipophilic based drugs, an oil phase, surfactants, co-surfactants, adjuvants or other excipients comprising of one or more of stabilizers, antioxidants, preservatives, mucoadhesive agents, buffering agents, absorption enhancers and pH adjusting agents;
(121) In an embodiment of the invention, the active pharmaceutical substance is selected from a group of substances that are soluble in oil or partially soluble in water, such as angiotensin-converting enzyme (ACE) inhibitors, antipsychotics, anti-emetics, analgesics and anti-inflammatory drugs including olanzapine, risperidone, ondansetron and paracetamol. The active pharmaceutical substance can be entrapped in the composition and incorporated into the composition to maintain its stability and to increase its bioavailability. Olanzapine, risperidone, ondansetron and paracetamol is preferred.
(122) The term Partially soluble in water referred herein includes sparingly soluble (1 gram drug gets dissolved in 30 to 100 ml solute) slightly soluble (1 gram drug gets dissolved in 100 to 1000 ml solute) and/or very slightly soluble (1 gram drug gets dissolved in 1000 to 10000 ml solute) as provided under European Pharmacopeia definitions and as described in biopharmaceutics classification system under class II and class IV.
(123) The oil phase of the inventive composition comprises one or more fatty acids. Preferably, these are selected from fatty acids having 6 to 22 carbon atoms, more preferably 13 to 21 carbon atoms, more preferably 16 to 20 carbon atoms, most preferably 18 carbon atoms. The fatty acids may be saturated, monounsaturated or polyunsaturated.
(124) Monounsaturated fatty acids are preferred. Preferred fatty acids are myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, and vaccenic acid. Oleic acid is especially preferred. Mixtures of fatty acids are also contemplated, although use of a single fatty acid remains favoured.
(125) The amount of fatty acid present in the inventive emulsions is in the range of 5 to 25% w/w. More preferably, the fatty acid is present in the range of 5 to 15% w/w, and still more preferably in the amount of 7.5 to 10% w/w.
(126) In a further embodiment, the composition further comprises of various surfactants selected from a group of polyether sufactants, macroglyceride surfactants and/or polysaccharide sufactants. Suitable polyethers are paraformaldehyde, polyethylene glycol, polypropylene glycol, Diethylene glycol monoethyl ether (Transcutol) and polytetramethylene glycol. Polyethylene glycol and/or transcutol is preferred. The polyether suitably has a molecular weight in the range of from 50 gmol-1 to 1000 gmol-1, more preferably from 100 gmol-1 to 500 gmol-1, still more preferably from 150 gmol-1 to 400 gmol-1, such as about 200 gmol-1 (PEG 200) and/or 400 gmol-1 (PEG 400). The polyether may optionally be end-capped.
(127) The polyether is present in the emulsion in an amount of from 2.0 to 25% w/w, preferably from 2.5% to 20% w/w, for example about 15 w/w of PEG 200 or 400 and most preferably from 2.5% of Transcutol.
(128) The oil phase further comprises of a macrogolglyceride surfactant. The term macrogolglyceride refers to saturated polyglycolized glycerides such as stearoyl-, lauroyl-, oleoly-, lineoyl-, and caprylocaproyl-macrogol glycerides. A preferred macrogolglyceride is caprylocaproyl macrogol-8 glycerides, commercially available under the trade name Labrasol and Acconon CC6. The macrogolglyceride is present in the emulsion in an amount of from 10 to 30% w/w, preferably from 12 to 25% w/w. most preferably 15% to 22.5% w/w of labrasol and 15% w/w of acconon CC 6.
(129) The oil phase further comprises a polysaccharide surfactant. Preferred polysaccharide surfactants are polyoxyethylene sorbitan fatty acid esters or sorbitan monooleate. Particularly preferred are polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), and polysorbate 80 (polyoxyethylene (20) sorbitan monooleate), with polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate) and polysorbate 80 (polyoxyethylene (80) sorbitan monooleate) being most preferred. Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate) and polysorbate 80 (polyoxyethylene (20) sorbitan monooleate) is commercially available as Tween 20 and Tween 80 and sorbitan monooleate is commercially available as Span 80
(130) The polysaccharide surfactant is present in the emulsion in an amount of from 2 to 30% w/w, preferably from 5 to 25% w/w and most preferably 5% of span 80 and 15% to 22.5% w/w of tween.
(131) In a further embodiment, the composition in accordance with the present invention can contain one or more additives such as stabilisers, antioxidants, preservatives, mucoadhesive agents, in-situ gelling agents, buffering agents, absorption enhancers and pH adjusting agents in order to improve the physical and chemical stability of the composition. These additives are preferably chosen from the group comprising of butylated hydoxytoulene, butylated hydroxyanisole, Kolliphor HS, Benzyl alcohol, tocopherol, EDTA and ascorbic acid to prevent oxidation, and to form a stable composition.
(132) In another embodiment, the said antioxidants are selected from a group comprising of one or more of butylated hydroxytoluene, butylated hydroxyanisole and ascorbic acid. The amount of antioxidants in the composition of the invention can preferably range from 0.01% to 5% by weight and more preferably from 0.01% to 0.2% by weight with respect to the total weight of the composition.
(133) In one embodiment, the said absorption enhancers are also optionally added to this invention to improve the mucous absorption and bioavailability. Preferred absorption enhancers are selected from the group consisting of macrogol fatty acid esters, bile salts, and salts of medium-chain fatty acids. Amongst macrogol fatty acid esters, macrogol-15-hydroxystearate, is commercially available as Kolliphor HS. Amongst bile salts, sodium glycocholate is preferred. Amongst salts of medium-chain fatty acids, sodium caprylate is preferred. The amount of absorption enhancers in the composition of the invention can preferably range from 0.1% to 10% by weight and more preferably from 1% to 5% by weight with respect to the total weight of the composition.
(134) In a further embodiment, to improve the residence time of the dosage form at the site of absorption, mucoadhesive agents may also optionally be added to this invention. Preferred mucoadhesive agents are selected from the group comprising of Synthetic polymers including Cellulose derivatives like hydroxy propyl methylcellulose, sodium carboxy methylcellulose, Poly (vinyl pyrrolidone), Poly (vinyl alcohol); natural polymers like tragacanth, sodium alginate, guar gum, xanthan gum; hydrophilic Polymers: carbomers, chitosan; hydrogels: sodium alginate, guar gum and modified guar gum, etc.
(135) In one embodiment, the different buffering agents that can be used for maintaining the pH are acetate buffer solution, phosphate buffer solution, maleate buffer solution, preferably sodium acetae tryhydarte with glacial acetic acid buffer solution and potassium dihydrogen phosphate with sodium hydroxide buffer solution was used.
(136) The dispersed phase particles and other ingredients of the composition of the invention have an average size of less than 200 nm and preferably ranging from 40 to 170 nm. The composition of the present invention are notable for their low and uniform particle size.
(137) The decrease in the size of the particles makes it possible to promote the penetration of the drug into the target site more effectively and improves the bioavailability. The composition has an excellent stability rate by virtue of the optimum zeta potential, preferably in the range 30 mV to +30 mV, preferably in the range 10 mV to +10 mV most preferably in the range 05 mV to +05 mV.
(138) In an embodiment, the invention provides highly stable composition having drug loading capacity of up to 100 mg/ml, preferably up to 80 mg/ml and leads to quick release of drug to the target site in less than 30 minutes preferably less than 10 minutes.
(139) The composition of the present invention are further notable for their low viscosity, and a desired degree of dispersibility can be obtained to increase the (dispersed) inner phase content to deliver the active ingredient effectively which makes them suitable for administration via e.g. the nasal route. Preferably, the viscosity of the emulsions is less than 250 cP or lower, more preferably less than 150 cP, or lower
(140) In another embodiment of the invention, the composition is a transparent and clear monophasic system with high stability.
(141) In one embodiment, the composition of the invention is substantially free of co-solvents, including monohydric alcohols. However, if required co-solvents may be added in less quantities. The preferred co-solvents are benzyl alcohol, phenyl ethyl alcohol, chlorobutanol. In this context, substantially free or less quantities means less than 1% w/w.
(142) The composition of the present invention is further notable for their high stability.
(143) In one embodiment, the composition of the invention provides an advantage of higher drug loading capability in the range of 10 to 80 mg/ml as evidenced in the examples below. Preferably, the drug loading for olanzapine is in the range of 35 to 45 mg/ml, preferably 40 mg/ml, and most preferably 38.46 mg/ml. The drug loading for ondansetron is in the range of 10 to 15 mg/ml, preferably 12 mg/ml, the drug loading for paracetamol is between 60 to 80 mg/ml, preferably 75 mg/ml; and for resperidone it is between 20 to 30 mg/ml preferably 25 mg/ml. This property of the invention enables improvement of drug bioavailability and reduction of the dosing frequency also suitable for highly potent low-dose drugs. Even with higher drug content, the invention showed stable and favorable physicochemical characteristics. The higher drug loading and the reduction in the particle size indicate the solubility of the lipophilic and partially lipophilic drugs in the instant invention leading to high bioavailability.
(144) The emulsion of the invention comprises an aqueous phase. Preferably, the aqueous phase is present in an amount greater by weight than any other single component. The aqueous phase is present in an amount of between 15 and 50% w/w.
(145) In yet another embodiment, the compositions of the present invention are prepared by conventional methods well known to those skilled in the art. The composition of the composition of the invention can be obtained by a process of subjecting the oleic acid, surfactants and co-surfactants or a mixture thereof to homogenization using magnetic stirrer. The oil and surfactant mixture is then mixed with a solution containing the required drug and the additives are added and subjected to vigorous stirring at controlled room temperature ranging between 20 C. to 25 C. (68 to 77 F.) using any suitable mixing apparatus known to those skilled in the art for about 30 minutes or until the entire amount of drug is dissolved. The homogenized mixture is then subjected to water phase preferably containing ascorbic acid and mixed well to get clear transparent composition, which indicates that the drug has dissolved/incorporated successfully.
(146) In further embodiment, the composition can be used in any pharmaceutical field where this type of composition is useful. While various embodiments herein describe nasal and ocular route of delivery, most preferably nasal delivery of compositions containing the drug, it is further envisaged that the delivery of the drug can be performed by any suitable delivery mechanism that provides therapeutically effective levels of the drug. Accordingly, the system is particularly useful for non-parenteral modes of administration such as buccal, sublingual, rectal, transdermal, topical, nasal, urethral, vaginal, and ocular. When administered by such non-parenteral modes the methods and composition of the present invention can deliver drug both locally and systemically as desired including oral, intramuscular and transcutaneous routes.
(147) In one embodiment, the invention provides composition for intra nasal delivery or ophthalmic route; preferably composition comprises drops, gel composition or aerosol composition. In an embodiment, the invention provides composition comprising an emulsion as disclosed herein can be administrated preferably as a spray or aerosol or ocular route. By aerosol we refer to an airborne mist of liquid particles. The dispensing system for such a composition may typically be a can or bottle that contains a liquid pressurized by compressed, propellant gas. Similarly, sprays of liquid particles may be produced by devices in which the liquid is pressurized by a hand-operated pump and forced through an atomizer nozzle. A typical nasal spray composition consists of the therapeutic agent suspended or dissolved in an aqueous medium, which is filled into a bottle with a metered spray pump. Pump actuation by the patient delivers the drug in fine droplets into the nasal cavity. Furthermore, the composition of ocular suspension consists of the therapeutic agent suspended or dissolved in aqueous medium, which is filled in a bottle for use as eye drops.
(148) In still a further embodiment of the invention, the aforesaid composition confers a synergistic therapeutic effect of high bioavailability compared to the therapeutic effect when a pharmaceutical substance is administered separately or in partial combination of the said ingredients of the said composition.
(149) In further embodiment of the invention, the synergistic effect as defined above has been adapted to increase the bioavailability by almost 1.3 times to 12 times relative to the therapeutic effect when pharmaceutical substance is administered separately and/or in partial combination of the said ingredients of the said composition administered through various routes, preferably intra nasal and ocular route. Increasing the bioavailability plays a very important role in the toxicity of the drugs. The composition can help in reduction in the dosage or the frequency of the dosages in the patients due to its higher bioavailability while reducing side effect of the drugs. In an object, the bioavailability of the pharmaceutically active substances is enhanced by at least 1.3 times to 12 times. In another object, the active pharmaceutical substance such as olanzapine when administered to the nasal cavity of a subject establishes a high bioavailability by at least 5 to 6 times in therapeutic plasma concentration within 5 to 10 minutes and bioavailability of 10 to 12 times in brain with in 10 to 30 minutes. The table shows drug efficiency of olanzapine through intra nasal route by almost 1.3 times or by 25% in reaching the brain concentration in 5 to 10 minutes and 1.78 times or 45% in attaining the plasma concentration within minutes when compared to intramuscular route of administration. Similarly, when compared to standard oral route of administration using the same drug olanzapine with the current invention through nasal route, the brain concentration was 5.31 times or 80% better and plasma concentration was almost 10.69 times or 91% higher in.
(150) In a further embodiment, the composition with ondansetron also showed higher bioavailability of therapeutic plasma concentration by at least 8 to 10 times within a mean duration of about less than one hour. As shown in table the plasma concentration was almost 8.29 times or 87% higher than oral route of delivery.
(151) In a further embodiment, as seen in the examples listed below and in table the composition has a drug loading capability of between about 10 mg/ml and about 80 mg/ml, preferably between 12 mg/ml to 75 mg/ml.
(152) Bioavailability of a drug in this context means the mount of dose that reaches the site of action (brain and eye in the instant case) in an unchanged form (and usually active) at a particular time. The area under the time versus plasma and brain concentration curve provided in the results below is reflective of the amount of drug that has been absorbed in the brain and plasma using the compositions of the composition provided herein.
(153) In another embodiment, the invention relates to a nasal spray for treatment of pain associated with migraine, headache, cluster headache, psychosis, nausea and vomiting or chemotherapy induced nausea and vomiting, autonomic cephalgia, agitation, sleep disorder, disturbance of mental state and ocular solution for reduction in ocular pressure.
(154) In one embodiment, the method relates to a method of treatment of a mammal suffering from or susceptible to pain associated with migraine, comprising administering an effective amount of a composition according to the invention, wherein the pharmaceutically active ingredient is, or comprises, olanzapine or a pharmaceutically acceptable salt thereof. Preferably, the method involves administration of the composition nasally. Dosing may be once per day (for example, at the onset of symptoms), or may be several times per day as per the requirements. Preferably, the amount is from 0.01 to 20 mg depending upon the severity of symptoms.
(155) In one embodiment, the method relates to a method of treatment of a mammal suffering from or susceptible to pain associated with migraine, comprising administering an effective amount of a composition according to the invention, wherein the pharmaceutically active ingredient is, or comprises, olanzapine or a pharmaceutically acceptable salt thereof. Preferably, the method involves administration of the composition nasally. Dosing may be once per day (for example, at the onset of symptoms), or may be several times per day as per the requirements. Preferably, the amount is from 0.01 to 20 mg depending upon the severity of symptoms.
(156) In one embodiment, the method relates to a method of treatment of a mammal suffering from antipsychotic related symptoms including schizophrenia and bipolar disorders, comprising administering an effective amount of a composition according to the invention, wherein the pharmaceutically active ingredient is, or comprises, respiridone or a pharmaceutically acceptable salt thereof. Preferably, the method involves administration of the composition nasally. Dosing may be once per day (for example, at the onset of symptoms), or may be several times per day as per the requirements. Preferably, the amount is from 0.01 to 16 mg depending upon the severity of symptoms.
(157) In one embodiment, the method relates to a method of treatment of a mammal suffering from nausea and vomiting that may be caused by surgery or by medicine, comprising administering an effective amount of a composition according to the invention, wherein the pharmaceutically active ingredient is, or comprises, ondansetron or a pharmaceutically acceptable salt thereof. Preferably, the method involves administration of the composition nasally. Dosing may be once per day (for example, at the onset of symptoms), or may be several times per day as per the requirements. Preferably, the amount is from 0.01 to 24 mg depending upon the severity of symptoms.
(158) In one aspect, the method relates to a method of treatment of a mammal suffering from high intraocular pressure, comprising administering an effective amount of a composition according to the invention, wherein the pharmaceutically active ingredient is, or comprises, paracetamol or a pharmaceutically acceptable salt thereof. Preferably, the method involves administrating of the composition through ophthalmic route. Dosing may be once per day (for example, at the onset of symptoms), or may be several times per day.
(159) Preferably, the method of treatment involves delivery of a predetermined amount of therapeutic agent (e.g. olanzapine, ondansetron, respirodone) by means of a metered actuation. Preferably, the method involves administration of from 0.01 to 100 mg of active agent, most preferably 0.1 to 20 mg per metered actuation.
(160) The methods of the invention in some embodiments involve a second therapeutic agent of known efficacy in the treatment of migraine, for simultaneous, separate or sequential administration with the compositions described (particularly those of olanzapine). Preferred second therapeutic agents are selected from the group of almotriptan, eletriptan, flovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan, ergotamine, dihydroergotamine, bosentan and lanepitant.
(161) Accordingly the present invention provides a pharmaceutical oil-in-water nano-emulsion, comprising: a pharmaceutically active substance, encased in monounsaturated fatty acid droplets, the droplets having an average particle size in the range of 60 to 200 nm; a non-ionic surfactant system comprising a mixture of polyethers, macrogolglycerides and polysaccharides; and pharmaceutically acceptable adjuvants.
(162) The present invention also provides a process for the preparation of an oil-in-water emulsion composition, by initially forming an oil phase in the presence of a monounsaturated fatty acid, a polyether surfactant, a macrogolglyceride surfactant and a polysaccharide surfactant, under stirring at an ambient temperature; and adding a therapeutically amount pharmaceutically active substance to the oil phase, under constant stirring and at an ambient temperature, to encase said active substance, in the monounsaturated fatty acid droplets, the droplets with particle size in the range of 60 to 200 nm, to obtain a homogenous oil phase; and adding an aqueous medium to the homogenous oil phase, under stirring to obtain the oil-in-water emulsion.
(163) The preferred embodiments of the present invention are now described by the following examples. These examples are illustrative in nature and will make it possible to understand the invention better and shall not be considered as limiting the scope of the invention.
EXAMPLES
Preparation of the Micro-Emulsion of the Composition Using Olanzapine
Example 1: Composition 1
(164) To 7.5% (w/w) of oleic acid, 2.5% (w/w) of transcutol, 22.5% (w/w) of Labrasol along with 22.5% (w/w) of tween 80 and 15% (w/w) PEG 400 were added sequentially under constant stirring. To this 5% (w/w) Kolliphor HS 15. followed by 3.846% (w/w) of Olanzapine was added and mixed slowly into the above oil-surfactant mixture under constant stirring at 600-1000 rpm using a magnetic stirrer or overhead stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved. Subsequently, 0.1% BHT along with 0.05% (w/w) EDTA and 0.1% (w/w) tochopherol were added consecutively under constant stirring at around 600-1000 rpm using a magnetic stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(165) Sufficient quantity of 4.5 pH buffered water was slowly added under stirring (600-1000 rpm on magnetic stirrer or any suitable stirrer at room temperature) to the above drug solution to get 100% product weight.
Example 2: Composition 2
(166) To 7.5% (w/w) of oleic acid, 2.5% (w/w) of transcutol, 22.5% (w/w) of Labrasol along with 22.5% (w/w) of tween 80 and 15% (w/w) PEG 400 were added sequentially under constant stirring. To this 5% (w/w) Kolliphor HS 15 followed by 3.846% (w/w) of Olanzapine was added and mixed slowly into the above oil-surfactant mixture under constant stirring at 600-1000 rpm using a magnetic stirrer or overhead stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved. Subsequently, 0.1% BHT along with 0.05% (w/w) EDTA and 0.05% (w/w) tochopherol were added consecutively under constant stirring at around 600-1000 rpm using a magnetic stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(167) Sufficient quantity of water was slowly added under stirring (600-1000 rpm on magnetic stirrer or any suitable stirrer at room temperature) to the above drug solution to get 100% product weight.
Example 3: Composition 3
(168) To 7.5% (w/w) of oleic acid, 1% (w/w) of benzyl alcohol was added followed by 3.846% (w/w) of Olanzapine and mixed slowly into the above oil-surfactant mixture under constant stirring at 600-1000 rpm using a magnetic stirrer or any suitable stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved. Thereafter, to this, 10% (w/w) of transcutol, and 22.5% (w/w) of Labrasol along with 15% (w/w) of tween 80, 15% (w/w) PEG 400, 5% (w/w) Kolliphor HS 15 and 5% (w/w) SPAN 80 were added sequentially under constant stirring. Subsequently, 0.1% BHT along with 0.05% (w/w) EDTA and 0.05% (w/w) tochopherol were added one after the other consecutively under constant stirring at around 600-1000 rpm using a magnetic stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(169) Sufficient quantity of 7 pH buffered water was slowly added under stirring (600-1000 rpm on magnetic stirrer or any suitable stirrer at room temperature) to the above drug solution to get 100% product weight.
Example 4: Composition 4
(170) To 7.5% (w/w) of oleic acid, 2.5% (w/w) of transcutol, 22.5% (w/w) of Labrasol along with 22.5% (w/w) of tween 80, 15% (w/w) PEG 400 were added sequentially under constant stirring. To this 5% (w/w) Kolliphor HS 15 followed by 3.846% (w/w) of Olanzapine was added and mixed slowly into the above oil-surfactant mixture under constant stirring at 600-1000 rpm using a magnetic stirrer or any suitable stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved. Subsequently, 0.1% BHT along with 0.05% (w/w) EDTA and 0.1% (w/w) tochopherol were added consecutively under constant stirring at around 600-1000 rpm using a magnetic stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(171) Sufficient quantity of water was slowly added under stirring (600-1000 rpm on magnetic stirrer or any suitable stirrer at room temperature) to the above drug solution to get 100% product weight.
Example 5: Composition 5
(172) To 7.5% (w/w) of oleic acid, 2.5% (w/w) of transcutol, 22.5% (w/w) of Labrasol along with 22.5% (w/w) of tween 80, 15% (w/w) PEG 400 were added sequentially under constant stirring. To this 5% (w/w) Kolliphor HS 15 followed by 3.846% (w/w) of Olanzapine was added and mixed slowly into the above oil-surfactant mixture under constant stirring at 600-1000 rpm using a magnetic stirrer or any suitable stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved. Subsequently, 0.1% BHT along with 0.05% (w/w) EDTA, 0.1% (w/w) tochopherol and 0.1% (w/w) ascorbic acid were added consecutively under constant stirring at around 600-1000 rpm using a magnetic stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(173) Sufficient quantity of water was slowly added under stirring (600-1000 rpm on magnetic stirrer or any suitable stirrer at room temperature) to the above drug solution to get 100% product weight.
Example 6: Composition 6
(174) To 7.5% (w/w) of oleic acid, 2.5% (w/w) of transcutol, 22.5% (w/w) of Labrasol along with 22.5% (w/w) of tween 80, 15% (w/w) PEG 400 were added sequentially under constant stirring. To this 5% (w/w) Kolliphor HS 15 followed by 3.846% (w/w) of Olanzapine was added and mixed slowly into the above oil-surfactant mixture under constant stirring at 600-1000 rpm using a magnetic stirrer or any suitable stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved. Subsequently, 0.1% BHT along with 0.05% (w/w) EDTA, 0.1% (w/w) tochopherol and 0.15% (w/w) ascorbic acid were added consecutively under constant stirring at around 600-1000 rpm using a magnetic stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(175) Sufficient quantity of water was slowly added under stirring (600-1000 rpm on magnetic stirrer or any suitable stirrer at room temperature) to the above drug solution to get 100% product weight.
Example 7: Composition 7
(176) To 7.5% (w/w) of oleic acid, 15% (w/w) of Labrasol along with 15% (w/w) of tween 80 and 15% (w/w) PEG 400 were added sequentially under constant stirring. To this 5% (w/w) Kolliphor HS 15 followed by 3.846% (w/w) of Olanzapine was added and mixed slowly into the above oil-surfactant mixture under constant stirring at 600-1000 rpm using a magnetic stirrer or any suitable stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved. Subsequently, 0.05% (w/w) of EDTA and 0.1% (w/w) of tochopherol was after the other consecutively under constant stirring at around 600-1000 rpm using a magnetic stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(177) Sufficient quantity of water was slowly added under stirring (600-1000 rpm on magnetic stirrer or any suitable stirrer at room temperature) to the above drug solution to get 100% product weight.
Example 8: Composition 8
(178) To 10% (w/w) of oleic acid, 22.5% (w/w) of Labrasol along with 22.5% (w/w) of tween 20 and 15% (w/w) PEG 200 was added. To this 0.01% (w/w) each of BHA and BHT along with 0.1% (w/w) ascorbic acid was added one after another under constant stirring at around 600-1000 rpm on magnetic stirrer or any suitable stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(179) 38.46 mg olanzapine per gram of emulsion was mixed slowly into the above oil-surfactant mixture under constant stirring at 600-1000 rpm on magnetic stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved.
(180) Sufficient quantity of water was slowly added under stirring (600-1000 rpm) on magnetic stirrer at room temperature) to the above drug solution to get 100% product weight.
Example 9: Composition 9
(181) To 10% (w/w) of oleic acid, 22.5% (w/w) of Labrasol along with 22.5% (w/w) of tween 20 and 15% (w/w) PEG 200 were added. To this, 5% (w/w) Kolliphor HS, 0.01% (w/w) each of BHA and BHT along with 0.1% (w/w) ascorbic acid were added sequentially under constant stirring at around 600-1000 rpm on magnetic stirrer or any suitable stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(182) 38.46 mg of olanzapine per gram of emulsion was mixed slowly into the above oil-surfactant mixture under constant stirring at 600-800 rpm using magnetic stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved.
(183) Sufficient quantity of water was slowly added under stirring (600-1000 rpm) using a magnetic stirrer at room temperature) to the above drug solution to get 100% product weight.
Example 10: Composition 10
(184) To 10% (w/w) of oleic acid, 22.5% (w/w) of Labrasol along with 22.5% (w/w) of tween 20 and 15% (w/w) PEG 200 were added. To this 1% (w/w) sodium glycocholate, 0.01% (w/w) each of BHA and BHT along with 0.1% (w/w) ascorbic acid were added sequentially under constant stirring at around 600-1000 rpm on magnetic stirrer or any suitable stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(185) 38.46 mg of olanzapine per gram of emulsion was mixed slowly into the above oil-surfactant mixture under constant stirring at 600-1000 rpm using a magnetic stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved.
(186) Sufficient quantity of water was slowly added under stirring (600-800 rpm on magnetic stirrer at room temperature) to the above drug solution to get 100% product weight.
Example 11: Composition 11
(187) To 10% (w/w) of oleic acid, 22.5% (w/w) of Labrasol along with 22.5% (w/w) of tween 20 and 15% (w/w) PEG 200 were added. To this 1% (w/w) sodium caprylate, 0.01% (w/w) each of BHA and BHT along with 0.1% ascorbic acid were added sequentially under constant stirring at around 600-1000 rpm on magnetic stirrer or any suitable stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(188) 38.46 mg of olanzapine per gram of emulsion was mixed slowly into the above oil-surfactant mixture under constant stirring at 600-1000 rpm using a magnetic stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved.
(189) Sufficient quantity of water was slowly added under stirring (600-1000 rpm on magnetic stirrer at room temperature) to the above drug solution to get 100% product weight.
Example 12: Composition 12
(190) To 10% (w/w) of oleic acid, 22.5% (w/w) of Labrasol along with 22.5% (w/w) of tween 20 and 15% (w/w) Acconon CC 6 were added. To this 0.01% (w/w) each of BHA and BHT along with 0.1% (w/w) ascorbic acid was added one after another under constant stirring at around 600-1000 rpm on magnetic stirrer or any suitable stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(191) 38.46 mg olanzapine per gram of emulsion was mixed slowly into the above oil-surfactant mixture under constant stirring at 600-1000 rpm on magnetic stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved.
(192) Sufficient quantity of water was slowly added under stirring (600-1000 rpm) on magnetic stirrer at room temperature) to the above drug solution to get 100% product weight.
(193) Preparation of the Micro-Emulsion of the Composition Using Paracetamol
Example 13: Composition 13
(194) To 10% (w/w) of oleic acid, 22.5% (w/w) of Labrasol along with 22.5% (w/w) of tween 20 and 15% (w/w) PEG 200 was added. The ingredients were added sequentially under constant stirring at around 600-800 rpm using a magnetic stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(195) 7.5% (w/w) of paracetamol was mixed slowly into the above oil-surfactant mixture followed by addition of 0.5% (w/w) sodium citrate under constant stirring at 600-1000 rpm using a magnetic stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved.
(196) Sufficient quantity of water was slowly added under stirring (600-1000 rpm) on magnetic or any other suitable stirrer at room temperature to the above drug solution to get 100% product weight.
Example 14: Composition 14
(197) To 10% (w/w) of oleic acid, 22.5% (w/w) of Labrasol along with 22.5% (w/w) of tween 20, 15% (w/w) PEG 200 and 1% (w/w) sodium glycoholate was added. The ingredients were added sequentially under constant stirring at around 600-1000 rpm using a magnetic or any other suitable stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(198) 7.5% of paracetamol was mixed slowly into the above oil-surfactant mixture followed by addition of 0.5% (w/w) sodium citrate under constant stirring at 600-1000 rpm using a magnetic or any other suitable stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved.
(199) Sufficient quantity of water was slowly added under stirring (600-1000 rpm) on magnetic or any other suitable stirrer at room temperature to the above drug solution to get 100% product weight.
(200) Preparation of the Micro-Emulsion of the Composition Using Risperidone
Example 15: Composition 15
(201) To 10% (w/w) of oleic acid, 22.5% (w/w) of Labrasol along with 22.5% (w/w) of tween 20 and 15% (w/w) PEG 200 was added. To this 5% (w/w) Kolliphor HS 15 and 0.01% (w/w) each of BHA and BHT were added sequentially under constant stirring at around 600-800 rpm using a magnetic stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(202) 2.5% (w/w) of Resperidone was mixed slowly into the above oil-surfactant mixture followed by addition of 0.1% (w/w) ascorbic acid dissolved in water under constant stirring at 600-1000 rpm using a magnetic stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved.
(203) Sufficient quantity of water was slowly added under stirring (600-800 rpm on magnetic stirrer at room temperature) to the above drug solution to get 100% product weight.
Example 16: Composition 16
(204) To 10% (w/w) of oleic acid, 22.5% (w/w) of Labrasol along with 22.5% (w/w) of tween 20 and 15% (w/w) Acconon CC6 were added. To this 0.01% (w/w) each of BHA and BHT were added sequentially under constant stirring at around 600-800 rpm using a magnetic stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(205) 2.5% (w/w) of Resperidone was mixed slowly into the above oil-surfactant mixture followed by addition of 0.1% (w/w) ascorbic acid dissolved in water under constant stirring at 600-1000 rpm using a magnetic stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved.
(206) Sufficient quantity of water was slowly added under stirring (600-1000 rpm) on magnetic stirrer at room temperature to the above drug solution to get 100% product weight.
(207) Preparation of the Micro-Emulsion of the Composition Using Ondansetron
Example 17: Composition 17
(208) To 10% (w/w) of oleic acid, 0.01% (w/w) each of BHA and BHT were added, followed by 1.2% (w/w) of Ondansetron sequentially under constant stirring. To this 22.5% (w/w) of Labrasol along with 22.5% (w/w) of tween 20 and 15% (w/w) of PEG 200 were added and was mixed slowly into the above oil-surfactant mixture under constant stirring at 600-1000 rpm using a magnetic stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved. Subsequently, 0.1% (w/w) of ascorbic acid and 0.5% of sodium citrate were added sequentially under constant stirring at around 600-800 rpm using a magnetic stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(209) Sufficient quantity of water was slowly added under stirring (600-1000 rpm on magnetic stirrer at room temperature) to the above drug solution to get 100% product weight.
Example 18: Composition 18
(210) To 10% (w/w) of oleic acid, 0.01% (w/w) each of BHA and BHT were added, followed by 1.2% (w/w) of Ondansetron sequentially under constant stirring. To this 22.5% (w/w) of Labrasol along with 22.5% (w/w) of tween 20 and 15% (w/w) of PEG 200 were added and was mixed slowly into the above oil-surfactant mixture under constant stirring at 600-1000 rpm using a magnetic stirrer at room temperature (20 to 25 C.) for about 30 minutes or until the entire amount of drug was dissolved. Subsequently, 1% sodium glycocholate, 0.1% (w/w) of ascorbic acid and 0.5% of sodium citrate were added sequentially under constant stirring at around 600-800 rpm using a magnetic stirrer at room temperature (20 to 25 C.) until a homogeneous phase was formed.
(211) Sufficient quantity of water was slowly added under stirring (600-1000 rpm on magnetic stirrer at room temperature) to the above drug solution to get 100% product weight.
(212) Physiochemical Characterisation of the Micro Emulsion
(213) In another embodiment of the present invention, physiochemical properties such as Particle size distribution and the droplet size of all the emulsions along with polydispersity and Zeta potential was measured and assessed by dynamic light scattering also referred to as photon correlation spectroscopy using a particle size analyser. In an embodiment, 1 mL of the diluted composition sample was placed in a clear disposable zeta cuvette. The zeta potential analysis at 25 C. in Malvern Zetasizer instrument was performed. The zeta potential and polydispersity indices were calculated using the inbuilt software. The primary feature of the nano or micro emulsions is the droplet size, which must be in the nanometer range and is a crucial factor indicating their performance because it determines the rate and extent of drug release as well as drug absorption. Therefore, in the advantageous composition of the present invention, the average droplet size of emulsion was found to be around 150 nm. Polydispersity index (PDI) indicates uniformity of droplet size within the composition and its stability. The value of PDI was found to be less than 0.3. Low value of PDI indicated uniform distribution of nano droplets within the composition, leading to more rapid absorption and improved bioavailability of the drug.
(214) In a further embodiment,
(215) Determination of Emulsion Stability
(216) In a further embodiment, different test samples of the composition containing olanzapine, Paracetomol, Risperidone, Ondansetron were prepared according to the examples above, and the emulsion was used to determine the stability of the composition and to check any phase separation or turbidity. The compositions were stored and maintained at two different temperatures. The amount of drug degraded and remaining in the compositions were determined by withdrawing samples at regular intervals and analysing for drug content by analytical HPLC methods at 0 day and 30 day time interval. The results are as described in the table below.
(217) Long term (room temperature) 25 C.2 C./60% RH5% RH; (Intermediate conditions) 30 C.2 C./65% RH5% RH; 30 C.2 C./75% RH5% RH; (accelerated conditions) 40 C.2 C./75% RH5% RH
(218) Long term (refrigerator) 5 C.3 C.
(219) RH indicates relative humidity
(220) TABLE-US-00001 Table 1 for Olanzipine compositions at 0 day and 30 day time period period Initial 25 C./ 30 C./ 30 C./ 40 C./ Batch No Test (RT) 2-8 C. 60% RH 65% RH 75% RH 75% RH Composition 1 % Assay: 108.8 102.7 94.9 88.4 97.7 76.9 pH: 7.291 7.378 7.318 7.278 7.324 7.346 Particle 66.36 82.76 83.37 92.7 75.02 81.41 size (nm) PDI 0.408 0.286 0.289 0.285 0.313 0.29 Zeta 0.0793 0.152 0.0278 0.0657 0.0999 0.00659 potential (mV): Viscosity 141.5 185.6 194 95.6 197.8 168.7 (cP): Composition 2 % Assay: 105.5 107.6 101.4 95.5 92.9 85.7 pH: 7.488 7.594 7.291 7.466 7.337 7.426 Particle 64.32 64.57 82.5 80.25 68.05 49.78 size (nm) PDI 0.372 0.28 0.284 0.438 0.294 0.224 Zeta 0.0981 0.301 0.0702 0.171 0.0437 0.0591 potential (mV): Viscosity 139.6 160.3 186.5 190.3 209 191.2 (cP): Composition 3 % Assay: 107.2 103.2 100.2 98.2 99.6 84.3 pH: 7.48 7.457 7.452 7.406 7.484 7.432 Particle 164.4 164.6 162 165.3 169.5 147.3 size (nm) PDI 0.418 0.375 0.286 0.289 0.293 0.252 Zeta 0.0991 0.0743 0.0841 0.127 0.211 0.209 potential (mV): Viscosity 128.4 147.1 110.6 129.3 106.8 65.6 (cP): Composition 4 % Assay: 106.9 108.5 94.1 95.8 86.8 77.3 pH: 7.324 7.525 7.411 7.304 7.36 7.481 Particle 73.55 71.1 84.47 97.15 77.79 80.43 size (nm) PDI 0.304 0.322 0.283 0.276 0.289 0.293 Zeta 0.4 0.175 0.0954 0.0148 0.129 0.0134 potential (mV): Viscosity 102.1 187.5 159.3 180 172.5 150.9 (cP): Composition 7 % Assay: 104 101.5 93.1 92.9 91.8 66.6 pH: 7.095 6.936 6.988 7.034 6.998 7.223 Particle 143.5 144.9 158.6 163.8 170.4 156.5 size (nm) PDI 0.266 0.255 0.276 0.276 0.306 0.282 Zeta 0.0327 0.0155 0.0863 0.28 0.495 0.0123 potential (mV):
(221) TABLE-US-00002 Table 2 for Olanzapine compositions at 0 day and 30 day time period 25 C./ 40 C./ Batch No Test Initial 2-8 C. 60% RH 75% RH Composition % Assay: 99.92 96.43 92.6 64.59 8 pH: 6.84 6.62 6.5 6.74 Particle 98.72 97.17 109.4 107.2 size (nm) PDI 0.243 0.31 0.412 0.438 Zeta 0.101 0.526 0.376 0.298 potential (mV): Viscosity 62.35 79.93 75.45 70.26 (cP): Composition % Assay: 100.63 97.53 92.22 64.59 9 pH: 6.94 6.6 6.55 6.74 Particle 96.11 87.26 74.91 91.65 size (nm) PDI 0.245 0.306 0.284 0.388 Zeta 0.00741 0.0881 0.432 0.0307 potential (mV): Viscosity 96.74 92.83 86.66 70.26 (cP): Composition % Assay: 100.63 99.19 92.7 66.59 10 pH: 7.02 6.75 6.86 7 Particle 79.6 84.8 55.79 88.8 size (nm) PDI 0.279 0.292 0.241 0.315 Zeta 0.161 0.00795 0.2 0.00409 potential (mV): Viscosity 60.5 96.56 89.84 84.54 (cP): Composition % Assay: 100.23 95.21 92.36 70.09 11 pH: 7.4 7.15 7.19 7.25 Particle 87.53 87.68 85.85 87.61 size (nm) PDI 0.242 0.295 0.298 0.395 Zeta 0.176 0.0151 0.506 0.112 potential (mV): Viscosity 58.51 109.9 103.5 97.6 (cP): Composition % Assay: 100.85 97.87 92.52 68.88 12 pH: 6.73 6.39 6.5 6.57 Particle 92.01 56.99 63.26 70.92 size (nm) PDI Zeta 0.162 0.152 0.335 0.254 potential (mV): Viscosity 94.44 70.9 66.03 64.36 (cP):
(222) TABLE-US-00003 Table 3 for Olanzapine compositions at 30 day time period 25 C./ 30 C./ 40 C./ Batch No Test 2-8 C. 60% RH 75% RH 75% RH Composition 5 % Assay: 98.1 93.6 91.7 87.5 Particle 98.77 87.18 84.34 size (nm) PDI 0.408 0.31 0.349 Zeta 0.198 0.24 0.0726 potential (mV): Composition 6 % Assay: 106 96.2 96 84 Particle 79.66 87.65 86.37 size (nm) PDI 0.418 0.311 0.351 Zeta 0.111 0.0981 0.0412 potential (mV):
(223) TABLE-US-00004 Table 4 for Paracetamol 25 C./ 40 C./ Batch No Test Initial 2-8 C. 60% RH 75% RH Composition % Assay: 99.35 100.28 101.66 99.84 13 pH: 6.12 6.29 6.07 6.16 Particle size 121.5 135.3 146.3 136.8 (nm) PDI 0.252 0.431 0.407 0.287 Zeta potential 0.592 0.583 0.309 0.361 (mV): Viscosity 60.81 61.57 62.65 60.45 (cP): Composition % Assay: 100.64 101.05 99.1 99.91 14 pH: 6.17 6.27 6.27 6.14 Particle size 125.3 123.6 127.7 130.2 (nm) PDI 0.311 0.387 0.317 0.319 Zeta potential 0.341 0.219 0.00259 0.364 (mV): Viscosity 58.97 60.65 59.86 60.27 (cP):
(224) TABLE-US-00005 Table 5 for Risperidone emulsions 25 C./ 40 C./ Batch No Test Initial 2-8 C. 60% RH 75% RH Composition % Assay: 99.78 100.44 98.02 97.77 15 pH: 6.14 5.58 5.72 5.46 Particle size 117.5 161 148.3 158.3 (nm) PDI 0.274 0.488 0.446 0.514 Zeta 0.588 0.0531 0.115 0.157 potential (mV): Viscosity 56.2 67.95 65.19 65.24 (cP): Composition % Assay: 99.38 99.99 98.14 97.19 16 pH: 5.66 5.98 5.87 5.78 Particle size 103.5 107 100.6 107.5 (nm) PDI 0.194 0.251 0.233 0.228 Zeta 0.139 0.139 0.00712 0.973 potential (mV): Viscosity 63.57 66.57 64.71 64.21 (cP):
(225) TABLE-US-00006 Table 6 for Ondansetron emulsions 25 C./ 40 C./ Batch No Test Initial 2-8 C. 60% RH 75% RH Composition 17 % Assay: 101.51 100.7 100.57 100.11 pH: 5.86 5.4 5.78 5.35 Particle 146.6 166.7 151.5 154.3 size (nm) PDI 0.332 0.522 0.462 0.318 Zeta 0.254 0.175 0.233 0.0449 potential (mV): Viscosity 66.69 70.02 67.98 69.1 (cP): Composition 18 % Assay: 100.77 98.71 98.67 100.8 pH: 6.08 5.9 5.9 5.85 Particle 142.5 146.7 131.4 144.9 size (nm) PDI 0.449 0.405 0.447 0.331 Zeta 0.248 0.389 0.361 0.229 potential (mV): Viscosity 65.48 65.95 65.98 67.68 (cP):
(226) As can been seen from the results in Table 1 to 4, the emulsions showed high stability, observed during a 1 month stability study. The zeta potential was estimated using Zetasizer instrument from Malvern and the percentage drug content was determined using HPLC.
(227) In a further embodiment, the pH of the emulsions according to the invention is an important determinant of how well they are tolerated or favourable when administered into the nasal cavity, ophthalmic or any other preferred route. The emulsion may cause irritation and stinging if the pH is too high or low. Therefore, the pH of the aqueous phase of an emulsion according to the invention is preferably in the range pH 4.5 to 8.0, more preferably 5 to 7.5. The pH of the aqueous phase of the emulsions according to the invention may be adjusted and controlled by means well known to those skilled in the art, such as buffer salts, acids and bases selected from various organic acids or/and alkali metal salts thereof.
(228) Thermodynamic Stability and Phase Separation Tests
(229) In a further embodiment, temperature cycling, centrifugation and freeze-thaw cycle stress tests were performed to evaluate the thermodynamic stability of all the drug loaded compositions. Heating-cooling cycle of three cycles between refrigerator temperature 5 C. and 40 C. with storage at each temperature of not less than 48 h was studied. The values of the particle size, zeta potential and the pH did not vary significantly after the end of the heating-cooling cycle from the initial as per the results in table 8 below, which showed the stability of the compositions. Furthermore, since all the compositions were stable at these temperatures, they were further subjected to centrifugation test to check for any phase separation or turbidity.
(230) In a further embodiment, the compositions were centrifuged at 5000 rpm for 30 min. After centrifugation, no phase separation or precipitation of the drug was observed which further confirmed the stability of the emulsion. Subsequently, the compositions were further subjected to freeze thaw stress test. Three freeze thaw cycles between 20 C. and 15 C. with storage at each temperature between 24 h and 48 h was conducted for the compositions. The values of the particle size, zeta potential and the pH did not vary significantly after the end of the freeze thaw cycle from the initial as per the results in table 7 below, which shows the stability of the composition. Further, the positive results indicated that all the compositions are thermodynamically stable systems and are formed at a particular concentration of oil, surfactant and cosurfactant, with no phase separation, creaming or cracking.
(231) TABLE-US-00007 TABLE 7 Freeze-Thaw Study Results Particle Zeta Viscosity Size Polydispersity Potential (cps at Batch No (d .Math. nm) Index (PdI) (mV) 200 rpm) pH Composition 1 70.69 0.306 0.234 213.7 7.518 Composition 2 94.31 0.280 0.535 205.3 7.450 Composition 3 239.2 0.485 0.107 138.7 7.167 Composition 4 91.33 0.307 0.186 143.4 7.388 Composition 5 77.47 0.291 0.006 180.0 7.365 Composition 6 90.76 0.290 0.358 190.3 7.318 Zeta Particle Polydispersity Potential Batch No Size (d .Math. nm) Index (PdI) (mV) pH Composition 8 92.71 0.390 0.0462 6.75 Composition 9 82.68 0.239 0.0868 6.72 Composition 10 74.27 0.363 0.106 7.02 Composition 11 77.41 0.281 0.0777 6.98
(232) TABLE-US-00008 TABLE 8 Heat Cool Cycle Study Results Particle Zeta Viscosity Size Polydispersity Potential (cps at Batch No (d .Math. nm) Index (PdI) (mV) 200 rpm) pH Composition 1 59.78 0.415 0.180 196.8 7.468 Composition 2 75.25 0.367 0.286 212.8 7.401 Composition 3 215.4 0.474 +0.141 142.5 7.103 Composition 4 77.02 0.410 0.184 182.8 7.476 Composition 5 61.73 0.410 0.169 209 7.200 Composition 6 78.76 0.461 0.158 216.5 7.223
(233) TABLE-US-00009 TABLE 8 Heat Cool Cycle Study Results Zeta Particle Polydispersity Potential Batch No Size (d .Math. nm) Index (PdI) (mV) pH Composition 8 86.24 0.400 0.136 6.79 Composition 9 93.43 0.368 0.175 6.87 Composition 10 70.13 0.298 0.0311 6.98 Composition 11 78.52 0.268 0.0101 6.92
Determination of Solubility of Olanzipine
(234) In yet another embodiment, the components used in the delivery system should have high solubilisation capacity for the drug in order to ensure its solubilisation in the resultant dispersion. As an example, the solubility of the drug olanzapine was studied using different unsaturated fatty acids. The results of the solubility studies have been provided below.
(235) It is also observed that the solubility of olanzapine in other unsaturated fatty acids was also studied. An accurately weighed quantity of olanzapine (40 mg) was added in 1 mL of oil and vortex mixed for 2 hrs. at 37 C. and observed visually for solubilisation. In case solubilisation was observed with the 40 mg of olanzapine in that particular oil, then subsequently 10 mg quantities of olanzapine were added to determine the exact solubility of the drug in that oil until the drug remained in its insolubilized form. Olanzapine has its maximum solubility in oleic acid. Olanzapine has solubility of less than 40 mg/mL in Labrafil(tradename), Capryol 90(tradename), Acconon CC6(tradename) and Kolliphor HS(tradename). Acconon CC6 and Kolliphor HS are miscible with water and hence were not used as oil in the development of the micro-emulsions. Olanzapine has a solubility of 60 mg/ml in Capryol 90 but it is lower than oleic acid. The solubility of olanzapine in oleic acid is 200 mg/ml.
(236) As seen from the above results, oleic acid showed highest solubilisation capacity as compared to other unsaturated fatty acids.
(237) Pharmacokinetics of Microemulsions
(238) Animal Studies: Olanzapine
(239) Experiments were performed on male Sprague-Dawley (S.D.) rats weighing 270-330 g, which fasted overnight before dosing. The emulsions were administered intra-nasally and intramuscularly at dose of 2.0 and 6.0 mg/kg olanzapine, respectively. Blood and brain samples were collected for analysis. The following pharmacokinetic parameters were evaluated and the results were captured.
(240) Micro-emulsions were formulated and their in vivo pharmacokinetic performance was evaluated upon intranasal delivery in comparison to oral delivery. Further, the micro-emulsions were explored for relative bioavailability compared with intramuscular administration. Higher drug concentrations were observed in the target organ which is the brain. Direct nose to brain transport indicated more effective and best brain targeting of the micro-emulsions (Drug delivery system). The percentage of relative bioavailability indicated the amount of drug available in the systemic circulation for re-uptake by the brain for prolonged effect. Pharmacokinetic studies conclusively demonstrated rapid brain uptake of drug when compared with intramuscular and oral solutions. The results indicated that, the developed micro-emulsion compositions were effective for target organ delivery.
(241) Derived pharmacokinetic parameters of olanzapine micro-emulsions following intranasal administration were compared with oral and intramuscular administration. The results are tabulated and provided in the following Table 9
(242) TABLE-US-00010 TABLE 9 Comparison of pharmacokinetic parameters of olanzapine following intranasal administration of olanzapine micro-emulsions with control group of oral and intramuscular administration in male Sprague Dawley rats. % Relative AUC bio- tissues Route/ availability ratio in Composition Tmax Cmax AUClast AUCinf T T/P in relation relation (Dose) Matrix (h) (ng/ml) (ng .Math. h/ml) (ng .Math. h/ml) (h) ratio to IM to IM IN/Composition 8 Plasma 0.08 780.00 866.00 867.00 3.03 5.00 71.00 NA (2 mg/kg) Brain 0.50 2024.00 4217.00 4336.00 1.57 NA 0.61 IN/Composition 9 Plasma 0.16 678.00 691.00 745.00 2.67 5.59 57.00 NA (2 mg/kg) Brain 0.25 1926.00 3863.00 4193.00 2.60 NA 0.55 IN/Composition Plasma 0.08 566.00 573.00 597.00 1.88 5.43 47.00 NA 10 (2 mg/kg) Brain 0.16 2495.00 3113.00 3252.00 1.98 NA 0.44 IN/Composition Plasma 0.08 596.00 637.00 649.00 1.30 5.05 52.00 NA 11 (2 mg/kg) Brain 0.25 1785.00 3217.00 3283.00 1.47 NA 0.46 IM Composition Plasma 0.50 1319.00 3645.00 3650.00 2.78 5.81 NA NA (6 mg/kg) Brain 1.00 5615.00 21172.00 21236.00 3.19 NA NA PO Composition Plasma 1.00 218.91 1177.88 1178.57 2.12 5.93 32.00 NA (6 mg/kg) Brain 1.00 1408.36 6983.72 6988.47 2.19 NA 0.33 INintranasal; IMintramuscular; POper-oral, NAnot applicable. IM & Oral compositions are control group taken for comparison of pK parameters.
Results:
Intranasal Administration (2 mg/kg) Composition 1
(243) Following the intranasal administration of olanzapine emulsion to rats at 2 mg/kg, mean time to reach peak plasma concentration (T.sub.max) for olanzapine was found to be 0.08 h. The mean exposure (C.sub.max and AUC.sub.last) of olanzapine was found to be 780 ng/ml and 866 ng.Math.h/ml, respectively. Olanzapine was eliminated with mean elimination half-life of 3.03 h.
(244) Brain (Including Olfactory Tubercle):
(245) Following intranasal administration of olanzapine emulsion to rats at 2 mg/kg, the mean exposure C.sub.max and AUC.sub.last of olanzapine was found to be 2024 ng/ml and 4217 ng.Math.h/ml for brain tissue. Olanzapine was eliminated with mean brain elimination half-life of 1.57 h for brain tissue.
(246) The relative bioavailability of intra nasal olanzapine composition in plasma was found to be 71%.
(247) AUC is the area under the plasma concentration versus time curve from time 0 to time x after nasal route. The relative bioavailability was determined by comparing the AUC of nasal administration and oral and intramuscular administration.
(248) Intranasal Administration (2 mg/kg) Composition 2
(249) Plasma:
(250) Following intranasal administration of olanzapine emulsion to rats at 2 mg/kg, mean time to reach peak plasma concentration (T.sub.max) for olanzapine was found to be 0.16 h. The mean exposure C.sub.max and AUC.sub.last of olanzapine was found to be 678 ng/ml and 691 ng.Math.h/ml, respectively. Olanzapine was eliminated with mean elimination half-life of 2.67 h.
(251) Brain (Including Olfactory Tubercle):
(252) Following intranasal administration of olanzapine emulsion to rats at 2 mg/kg, the mean exposure C.sub.max and AUC.sub.last of olanzapine was found to be 1926 ng/ml and 3863 ng.Math.h/ml for brain tissue. Olanzapine was eliminated with mean elimination half-life of 2.60 h for brain tissue.
(253) The relative bioavailability of IN G7 olanzapine composition in plasma was found to be 57%.
(254) Intranasal Administration (2 mg/kg) Composition 3
(255) Plasma:
(256) Following intranasal administration of olanzapine emulsion to rats at 2 mg/kg, mean time to reach peak plasma concentration (T.sub.max) for olanzapine was found to be 0.08 h. The mean exposure (C.sub.max and AUC.sub.last) of olanzapine was found to be 566 ng/ml and 573 ng.Math.h/ml, respectively. Olanzapine was eliminated with mean elimination half-life of 1.88 h.
(257) Brain (Including Olfactory Tubercle):
(258) Following intranasal administration of olanzapine emulsion to rats at 2 mg/kg, the mean exposure C.sub.max and AUC.sub.last of olanzapine was found to be 2495 ng/ml and 3113 ng.Math.h/ml for brain tissue. Olanzapine was eliminated with mean elimination half-life of 1.98 h for brain tissue.
(259) The relative bioavailability of olanzapine composition in plasma was found to be 47%.
(260) Intranasal Administration (2 mg/kg) Composition 4
(261) Plasma:
(262) Following intranasal administration of olanzapine emulsion to rats at 2 mg/kg, mean time to reach peak plasma concentration (T.sub.max) for olanzapine was found to be 0.08 h. The mean exposure (C.sub.max and AUC.sub.last) of olanzapine was found to be 596 ng/ml and 637 ng.Math.h/mL, respectively. Olanzapine was eliminated with mean elimination half-life of 1.30 h.
(263) Brain (Including Olfactory Tubercle):
(264) Following intranasal administration of olanzapine emulsion to rats at 2 mg/kg, the mean exposure (C.sub.max and AUC.sub.last) of olanzapine was found to be 1785 ng/ml and 3217 ng.Math.h/ml for brain tissue. Olanzapine was eliminated with mean elimination half-life of 1.47 h for brain tissue.
(265) The relative bioavailability of Olanzapine composition in plasma was found to be 52%.
(266) Additionally, from the table above it can be observed that the Cmax in the brain when given through the IN route was 2495 ng/g with a dose administration of 2 mg/kg, but with respect to IM and oral administered dose of 6 mg/kg, it was 5615 ng/g and 1408.36 ng/g respectively. Therefore, in order to achieve the same concentrations reaching the brain one can reduce the dose of administration through the nasal route by 25% vis a vis IM and 80% vis a vis oral. Furthermore, the Tmax i.e., the time taken to reach the maximum concentration in brain by the nasal composition was attained within 10 mins when compared to 60 mins through the conventional routes of administration. Similarly, the time taken to reach the maximum concentration in plasma, via the nasal composition was 5 mins when compared to 30 mins and 60 mins through the intra muscular and oral routes of administration respectively.
(267) Ondansetron
(268) Comparative pharmacokinetics evaluation of three different compositions of ondansetron following intranasal, intramuscular and oral administration in sprague dawley rats. The objective of this study was to to evaluate and compare the plasma pharmacokinetic profile of Ondansetron Composition with marketed standards in Sprague Dawley rats following single Intranasal and per oral administration.
(269) Sprague Dawley rat were randomly allotted to different groups. The Ondansetron Composition with marketed standards was administered. Approximately 0.5 mL of blood was collected from the retroorbital plexus of each rat into pre-labeled tubes containing K.sub.2EDTA at 0, 10 mins, 20 mins, 0.5, 1, 2 and 4 hr post dosing. Blood samples was centrifuged at approximately 5000 rpm for 10 min in refrigerated centrifuge at 4 C. and plasma samples was harvested and stored in deep freezer (80 C.) until the analysis. At the end of experimental sample collection, plasma samples were transferred in to analytical department for analysis.
(270) The results are provided in table 10 below.
(271) Comparison of pharmacokinetic parameters of olanzapine following intranasal administration of Ondansetron micro-emulsions with control group of oral and intramuscular administration in male Sprague Dawley rats.
(272) TABLE-US-00011 TABLE 10 Route/ Composition Tmax Cmax AUCinf T/P (Dose) Matrix (h) (ng/ml) (ng .Math. h/ml) T (h) ratio IN/Composition Plasma 0.50 15.59 20.63 2.22 0.90 (0.82 mg/kg) Brain 0.17 19.63 18.61 0.43 PO Composition Plasma 1.00 1.88 6.97 2.30 0.00 (0.82 mg/kg) Brain 0.00 0.00 0.00 0.00 INintranasal; IMintramuscular; POper-oral, NAnot applicable. IM & Oral compositions are control group taken for comparison of pK parameters.
Results:
Intranasal Administration (0.82 mg/kg) Composition Developed
Plasma:
(273) Following the intranasal administration of Ondansetron emulsion to rats at 0.82 mg/kg, mean time to reach peak plasma concentration (T.sub.max) for Ondansetron was found to be 0.50 h. The mean exposure (C.sub.max and AUC.sub.last) of Ondansetron was found to be 15.59 ng/ml and 20.63 ng.Math.h/ml, respectively. Ondansetron was eliminated with mean elimination half-life of 2.22 h.
(274) Brain:
(275) Following intranasal administration of Ondansetron emulsion to rats at 0.82 mg/kg, the mean exposure C.sub.max and AUC.sub.last of Ondansetron was found to be 19.63 ng/ml and 18.61 ng.Math.h/ml for brain tissue. Ondansetron was eliminated with mean brain elimination half-life of 0.43 h for brain tissue.
(276) The results in the table above shows that with the intra nasal route of administration of the sample composition there is a marked decrease in the Tmax and a prolongation in half-life when compared with other conventional routes using the marketed salt form of the drug. i.e. for the intra nasal the maximum concentration in plasma was observed within 30 mins when compared with the oral route which took 60 mins for the same. No significant brain concentration was detected in case of oral route of administration whereas for the intra nasal route a concentration of 19.63 ng/ml was observed. With respect to the plasma concentrations achieved, the intranasal administration is comparable with that of the intra muscular route of administration.
(277) Paracetamol
(278) Intraocular pressure lowering activity of paracetamol composition 2% and paracetamol solution 2% with pilocar 2% in New Zealand white rabbits was performed.
(279) Healthy male New Zealand White Rabbits were randomly allotted in to four groups after intraocular pressure (TOP) measurement in both the eyes. On experimental day, before and after treatment basal intraocular pressure was measured using a Tonometer (Make: HS Climent Clarke International, Model: MK2) and recorded for all the animals of the 4 groups.
(280) Ophthalmological examination by indirect method was performed once during the acclimatization period and 24 hr post instillation of test item. All animals were observed once daily for clinical signs of toxicity and twice daily for mortality and morbidity during experimental period.
(281) Based on the results obtained from the experiment, there were no significant treatment related changes in intraocular pressure up to 24 hrs on single dose administration with Paracetamol solution 2%, Paracetamol composition 2% and Pilocarpine 2% in New Zealand White Rabbits. However, a statistical significant (ie 0.05 level) decrease in intraocular pressure from 12.0 to 9.3 mm Hg was observed for the Paracetamol composition 2% treated group at 2 hr time point. However, the same was not observed with Pilocarpine 2% or the Paracetamol solution treated groups.
(282) Ex Vivo Corneal Permeation of Paracetamol Solution 2% on Bovine Corneas Using the Franz Diffusion Instrument
(283) The bovine corneas, free of defects were used for the conduct of ex-vivo corneal permeation study. Permeation studies of Paracetamol composition 2% and Paracetamol solution 2% on bovine corneas was done by using the Franz diffusion instrument. 1 mL of each test item composition was added to the separate donor chamber in which the corneas are mounted. 1 mL of placebo was added to one donor chamber in which the cornea was mounted and was served as control. After the start of treatment of each test item and control, 500 L of receptor fluid was collected at 0, 0.25, 0.5, 1, 2 and 4 hours (5 minutes) and the same amount of receptor fluid was replaced at each time point. The collected samples were analyzed immediately for the content of Paracetamol by the HPLC method., the results are provided in table 11 below
(284) The analysis of Paracetamol composition 2% and Paracetamol solution 2% was calculated at the 4.sup.th hour sample collection for the calculation of permeated amount (mg) and % permeation of Paracetamol content. At the end of the experiment each cornea (freed from adhering sclera) washed with receptor fluid and homogenized with 5 mL of receptor fluid and the contents were analyzed by the analytical method.
(285) TABLE-US-00012 TABLE 11 Intraocular pressure in mm Hg Time Points Treatment Basal IOP 0.5 h 1 h 2 h 4 h 8 h 12 h 24 h Left Right Left Right Left Right Left Right Left Right Left Right Left Right Left Right Left Right Eye Eye Eye Eye Eye Eye Eye Eye Eye Eye Eye Eye Eye Eye Eye Eye Eye Eye 50 L 50 L Mean 12.2 12.4 11.3 10.9 11.2 10.9 12.4 11.3 12.2 11.8 12.7 2.2 11.1 11.1 11.1 11.1 of of SD 2 2.7 1.8 2.1 2.7 2.1 1.5 2.4 0.8 0.8 0.7 1.4 1 1 1 1 Placebo Para- cetamol solution 2% 50 L 50 l Mean 11.8 12 10.4 10.4 10.4 10.4 9.8 9.3* 10 10 9.8 9.8 10.9 10.4 10.9 10.4 of of Para- SD 1.5 1.8 1.9 0.8 1.9 0.8 1.4 1.8 1.2 1.2 0.8 0.4 0.4 0.4 0.4 0.4 Placebo cetamol formul- ation 2% 50 L 50 L Mean 11.1 10.9 11.1 9.8 11.3 9.8 11.6 10.7 10.7 10.4 11.6 10.9 11.8 11.8 11.8 11.8 of of SD 1 1 1 1.7 1.2 1.7 1.4 1.2 1.2 1.4 1 1.5 1.5 1.5 1.5 1.5 sterile Pilocar water 2% 50 L 50 L Mean 11.8 11.8 12 11.1 11.6 11.1 11.8 10.7 12.4 12 12 11.8 12.7 11.8 12.7 11.8 of of Para- SD 1.7 1.5 2 0.4 1 0.4 1.7 2 0.4 1.8 0.7 1 0.7 0.8 0.7 0.8 sterile cetamol water formul- ation 2% *The mean difference is significant at the 0.05 level. Note: The statistical analysis was performed Basal IOP vs 0.5 hr, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr and 24 hr IOP of each eye of each group
(286) TABLE-US-00013 TABLE 12 Corneal penetration studies Amount Permeated (mg) Amount Permeated (mg) Time (h) for Composition 2% for Simple solution 2% 0 0 0 0.25 0 0 0.5 0.006 0.006 1 0.060 0.083 2 0.409 0.455 4 1.164 2.134
(287) TABLE-US-00014 TABLE 13 Corneal membrane homogenization Composition Average in mg Composition 2% 0.621 Simple solution 2% 1.318
CONCLUSION
(288) From the sample analysis it is observed that the permeation observed in Paracetamol composition 2% was 1.164 mg and Paracetamol solution 2% was 2.134 mg at 4 hour as per the results in table 12 above
(289) The results obtained from the corneal homogenized sample for Paracetamol composition 2% was found to be 0.621 mg and Paracetamol solution 2% was 1.318 mg as per the results in table 13 above.
(290) The permeation study shows that the simple solution is able to permeate the drug much more than composition but fails in lowering the IOP significantly. This might be because of the synergistic effect of the composition of the composition that makes the effect.
ADVANTAGES OF THE INVENTION
(291) The competitive advantage of the invention described lies in its enhanced drug delivery mechanism, ease of use, enhanced access, reduced dosage of administration leading to reduced side effects and high drug loading, which leads to better patient acceptance and compliance and increased bioavailability.
(292) In particular, the composition of this invention helps in solubilizing higher amounts of drug. This invention also provides increased absorption of pharmaceutical agents through endothelial or epithelial membranes. Furthermore, the invention with nano-sized oil droplets and the drug dissolved in it, surrounded by surfactant layer aids the lipophilic compounds to be stable in aqueous environment. The invention presents a stable composition by preventing oxidation and hydrolysis. This invention also improves the mucous absorption and bioavailability.
(293) This invention offers clinical advantages over competitor products in a large market of considerable unmet need. The drug delivery system is able to enhance the rapid onset of action for lipophilic drugs than the conventional or existing delivery systems. Furthermore, the nasal route not only improves the bioavailability by preventing extensive first-pass metabolism but also targets the receptor site and passes through the blood-brain barrier (BBB). Direct transport of drugs to the brain circumventing the brain barriers following intranasal administration provides a unique feature and better option to target the site of action and to reduce the side effects.
(294) This invention also offers the advantages of the drug being administered simply, non-invasively, cost-effectively, and conveniently. One such example showing the ease of treatment is demonstrated by easy sprayability and ease of self-administration with reduced side effects. The composition demonstrates improved bioavailability, rapid drug absorption via highly vascularized mucosa, thus demonstrating a superior mode of delivery to the existing treatment options.
(295) This invention is superior in at least one of the criteria from the similar compositions described in the literature i.e., higher drug loading, better in vivo performance, rapid onset of action etc. Even at this higher drug content, the developed systems show suitable physicochemical characteristics. A benefit of the invention is to prepare a composition of higher drug concentration for lipophilic and moderately lipophilic compounds, at concentrations of around 10-80 mg/ml.