Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/12—Aerosols; Foams
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0043—Nose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

• the present invention relates to controlled release transmucosal formulations which mediates abso ⁇ tion and methods of their use. More particularly, the invention relates to compositions comprising a pharmaceutically active ingredient, e.g., morphine, and a chitosan polymer.
• a pharmaceutically active ingredient e.g., morphine
• Sustained release dosage forms are central in the search for improved therapy, both through improved patient compliance and decreased incidences of adverse drug reactions.
• the challenge is to administer a single dose of the drug which is sufficient to maintain the desired concentration over a prolonged period, while eliminating the possibility of overdosing at the outset.
• controlled release has been difficult to impart, because, in contrast to oral dosage forms, it is not feasible to coat or otherwise compound the drug so that the delivery of the drug is retarded in the body after administration. Longer periods of response provide for many therapeutic benefits that are not achieved with corresponding short acting, immediate release preparations.
• therapy may be continued without interrupting the sleep of the patient, which is of special importance, for example, when treating a patient for moderate to severe pain (e.g., a post-surgery patient, a cancer patient, etc.), or for those patients who experience migraine headaches on awakening, as well as for the debilitated patient for whom sleep is essential.
• a further general advantage of longer acting drug preparations is improved patient compliance resulting from the avoidance of missed doses through patient forgetfulness.
• rapid acting drug therapy requires careful administration at frequent intervals to maintain effective steady state blood levels of the drug, and to avoid peaks and valleys in the blood level because of the rapid abso ⁇ tion, and systemic excretion of the compound through metabolic inactivation.
• a controlled release dosage form will ideally provide therapeutic concentration of the drug in blood that is maintained throughout an extended dosing interval with a reduction in the peak/trough concentration ratio.
• Central to the development process are the many variables that influence the in vivo release and subsequent abso ⁇ tion of the active ingredients. Therefore, there remains a need in the art for additional opioid salts capable of use in compositions directed to controlled release administration by transmucosal delivery, particularly for nasal administration.
• transmucosal compositions comprising a highly concentrated pharmaceutically active agent, preferably mo ⁇ hine, and a water soluble polymer, namely chitosan, will mediate abso ⁇ tion of the active agent after administration.
• a highly concentrated pharmaceutically active agent preferably mo ⁇ hine
• a water soluble polymer namely chitosan
• Figure 1 presents mo ⁇ hine plasma concentration (ng/ml) over time (minutes) for a 15 mg mo ⁇ hine composition with chitosan (indicated by triangle) and a 15 mg mo ⁇ hine composition without chitosan (indicated with circle).
• Figure 2 presents the following mean plasma concentration-time profiles of mo ⁇ hine (ng/ml over hours) formulations with chitosan: 10 mg intravenous mo ⁇ hine formulation, intranasal mo ⁇ hine formulations (7.5 mg, 15 mg and 30 mg), and 15 mg oral mo ⁇ hine formulation.
• Figure 3 presents the mean ( ⁇ SD) plasma concentration-time profiles of mo ⁇ hine (ng/ml over hours) following intranasal mo ⁇ hine formulations (7.5 mg, 15 mg and 30 mg) and 10 mg intravenous mo ⁇ hine plus intranasal placebo.
• Figure 4 presents the mean ( ⁇ SD) plasma concentration time profiles of mo ⁇ hine-6-glucuronide (ng/ml over hours) following intranasal mo ⁇ hine formulations (7.5 mg, 15 mg and 30 mg) and 10 mg intravenous mo ⁇ hine plus intranasal placebo.
• Figure 5 presents the mean ( ⁇ SD) plasma concentration time profiles of mo ⁇ hine-3-glucuronide (ng/ml over hours) following intranasal mo ⁇ hine formulations (7.5 mg, 15 mg and 30 mg) and 10 mg intravenous mo ⁇ hine plus intranasal placebo.
• Figure 6 presents the linear relationship between the bioavailability of intranasal mo ⁇ hine (represented as area under the curve in ng/ml/min.) and the administered dose (in mg).
• compositions of the present invention contain a therapeutically effective amount of at least one pharmaceutically acceptable medicament (active ingredient).
• active ingredient include but are not limited to analgesics, anesthetics, decongestants, hypnotics, sedatives, antiepileptics, awakening agents, psychoneurotropic agents, neuromuscular blocking agents, antispasmodic agents, antihistaminics, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antitussive expectorants, thyroid hormones, sexual hormones, antidiabetics, antitumor agents, antibiotics, chemotherapeutics, and other CNS acting agents.
• the pharmaceutically active ingredient is an opioid.
• opioid means all agonists and antagonists of opioid receptors, such as mu, kappa, and delta opioid receptors and subtypes thereof.
• opioid receptors and subtypes see Goodman and Gilman's The Pharmacological Basis of Therapeutics 9th ed. J. G. Harman and L. E. Limird Eds., McGraw- Hill New York:1996 pp. 521-555, inco ⁇ orated herein by reference.
• Preferred opioids interact with the mu opioid receptor, the kappa opioid receptor, or both.
• the opioid is an opioid-receptor agonist.
• opioids include, but are not limited to, high potency analgesics (where specific salts or esters are mentioned, it should be understood to include other salt, ester, or free acid forms of the drag), such as fentanyl, codeine, or mo ⁇ hine.
• the opioid is mo ⁇ hine.
• the mo ⁇ hine compound may be selected from, but are not limited to, one of the following compounds: mo ⁇ hine base monohydrate, mo ⁇ hine hydrochloride, mo ⁇ hine sulfate, mo ⁇ hine mesylate, mo ⁇ hine citrate, mo ⁇ hine ascorbate and other salts of mo ⁇ hine.
• the mo ⁇ hine is purified mo ⁇ hine base monohydrate (anhydrous base, MW 303.36), C 1 H 19 O 3 N'H 2 O, having the following structural formula:
• Mo ⁇ hine base (purified, monohydrate) is preferred since it binds to the opiate receptors with higher affinity and is a strong agonist.
• the composition will vary, however, the medicament may be present in the composition from about 18.75 mg/ml to about 300 mg/ml, preferably from about 37.5 mg/ml to about 150 mg/ml. Most preferred, the medicament is present in an amount of about 75 mg/ml.
• Various pharmaceutically acceptable salts, ether derivatives, ester derivatives, acid derivatives, and aqueous solubility altering derivatives of the active compound also are encompassed by the present invention.
• the present invention further includes all individual enantiomers, diastereomers, racemates, and other isomer ratios of the compound.
• the invention also includes all polymo ⁇ hs and solvates, such as hydrates and those formed with organic solvents, of this compound.
• polymo ⁇ hs and solvates such as hydrates and those formed with organic solvents, of this compound.
• Such isomers, polymo ⁇ hs, and solvates may be prepared by methods known in the art, such as by regiospecific and/or enantioselective synthesis and resolution, based on the disclosure provided herein.
• Suitable salts of the compound include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt,
• the mo ⁇ hine salt is a mo ⁇ hine mesylate salt.
• the present invention also includes prodrags of the compound of the present invention. Prodrags include, but are not limited to, functional derivatives of the pharmaceutically active agents that are readily convertible in vivo into the target agents.
• the controlled release material acts as a carrier for the active agent.
• the preferred polymer in the present invention is Chitosan ([(l,4)-2-amino-2-desoxy-b-D- glucan]), a commercially available, nontoxic polymer or a salt or derivative thereof.
• Chitosan is a linear polysaccharide derived from the shells of crustaceans.
• the material can further include a bioadhesive or mucoadhesive polymer such as pectins (polygalacturonic acid), mucopolysaccharides (hyaluronic acid, mucin) or non-toxic lectins.
• a bioadhesive or mucoadhesive polymer such as pectins (polygalacturonic acid), mucopolysaccharides (hyaluronic acid, mucin) or non-toxic lectins.
• the polymer itself may be bioadhesive, e.g., polyanhydride or polysaccharides such as chitosan.
• chitosan includes all derivatives of chitin, e.g., poly-N- acetyl-D-glucosamine, including all polyglucosamines and oligomers of glucosamine materials of different molecular weights, in which the greater proportion of the N-acetyl groups have been removed through hydrolysis (deacetylation).
• the chitosan is produced from chitin by deacetylation to a degree of greater than 40%, preferably about 50% to 98%, and more preferably about 70% to 90%.
• Chitosan derivatives or salts of chitosan may also be used instead of chitosan.
• chitosan derivatives includes ester, ether or other derivatives formed by bonding of acyl and/or alkyl groups with OH groups, but not the NH 2 groups, of chitosan. Examples include O-alkyl ethers of chitosan and O-acyl esters of chitosan. Modified chitosans, particularly those conjugated to polyethylene glycol, are included in this definition.
• Low and medium viscosity chitosans may be obtained from various sources, including Pronova Biopolymer (Drammen, Norway); Seigagaku America Inc., (MD, USA); Meron Pvt, Ltd. (India); Vanson Ltd, (VA, USA); and AMS Biotechnology Ltd., (UK). Suitable derivatives include those which are disclosed in Roberts, Chitin Chemistry, (MacMillan Press Ltd., London (1992)).
• the chitosan, chitosan derivative or salt, of the present invention preferably has a molecular weight of about 4,000 Daltons or more, preferably in the range of about 25,000 to about 2,000,000 Daltons, and most preferably in the range of about 250,000 to about 600,000 Daltons.
• Chitosans of different low molecular weights can be prepared by enzymatic degradation of chitosan using chitosanase or by the addition of nitrous acid. Both procedures are known to those skilled in the art.
• the chitosan compound is water-soluble.
• Particularly preferred chitosan compounds, which may be mentioned, include the UPG210 and UPG 213 chitosan available from FMC Co ⁇ oration (Philadelphia, PA).
• UPG210 and UPG 213 chitosan are high molecular weight range materials that are highly purified thereby allowing for controlled release or more regularized bioavailability and are therefore more appropriate for the consistency of delivery of a pharmaceutical grade material.
• the ratio of the pharmaceutically active ingredient to the chitosan polymer must be within a specific range to obtain the controlled release properties of the chitosan polymer.
• the ratio will vary depending on the molecular weight of the compounds used, for example, depending on the specific chitosan used. Therefore, in the present invention, the ratio is preferably calculated on the basis of a molecule to molecule ratio.
• the molecule to molecule ratio of the active ingredient to the chitosan may be from about 1:1 to about 100,000:1, preferably, from about 5,000:1 to about 80,000:1.
• the ratio of the chitosan and active ingredient may be expressed on weight to weight or weight to volume basis.
• purified mo ⁇ hine base monohydrate mo ⁇ hine base monohydrate (molecular weight 303.4) is combined with the preferred chitosan (having a molecular weight of approximately 420,000).
• the applicable ratio of mo ⁇ hine to the chitosan described above is from about 5:1 to about 60:1.
• the ratio is from about 7.5:1 to about 30:1.
• the chitosan polymer may be present in ranges of about 2 mg/ml to about 7 mg/ml, preferably about 4mg/ml to about 6 mg/ml. The most preferred amount in the composition is about 5 mg/ml.
• the formulations of the present invention are designed to produce a controlled increase in therapeutic plasma levels of the pharmaceutically active ingredient during the abso ⁇ tion phase after nasal administration. This mediated abso ⁇ tion of the medicament is followed by a period of controlled dissolution of the medicament to maintain therapeutic plasma levels. Without the controlled release during the abso ⁇ tion phase, there is a risk of too rapid abso ⁇ tion when applying the dosage necessary to maintain a therapeutic level of the medicament over a prolonged period.
• the chitosan formulation of the present invention has demonstrated regularized and mediated abso ⁇ tion by first order rate kinetics during the abso ⁇ tion phase of the product when delivered to the nasal mucosa.
• abso ⁇ tion of mo ⁇ hine formulated without chitosan is non-linear during the uptake phase; however, the same formulation with chitosan demonstrates linear uptake.
• the compositions of the present invention may also contain one or more pharmaceutically acceptable antioxidants.
• Non-limiting examples include methanesulfonic acid, citric acid, sodium citrate, ascorbic acid, and sodium ascorbate.
• the total amount of antioxidants present in the composition is from about 20 to 50 mg per ml for the citric acid/sodium citrate formulations and a range of about 20 to about 40 mg per ml to be used as particularly suitable.
• citric acid may be present in an amount ranging from about 10 to about 20 mg/ml
• the sodium citrate may be present in an amount ranging from about 5 to about 20 mg/ml.
• the amount of antioxidants present in the composition is from about 40 to about 70 mg per ml and a particularly suitable range from about 50 to about 65 mg per ml.
• ascorbic acid may be present in an amount ranging from about 40 to about 50 mg per ml
• sodium ascorbate may be present from about 10 to about 15 mg/ml.
• the antioxidant is present in the composition from about 10 to about 60 mg per ml, and a particularly suitable range from about 13 to about 50 mg per ml.
• the antioxidants of the present invention have a buffering effect and are used in amounts sufficient to adjust and maintain the pH of the compositions of the present invention in the range of about 3.0 to about 7.0, preferably about 4.0 to about 5.0.
• suitable buffers include, but are not limited to, citrates, ascorbates, phosphates and glycines.
• compositions of the present invention also contain at least one antimicrobial preservative in the range of 0.0005% to about 0.5% by weight/volume of the composition, preferably in the range of 0.005% to 0.5% by weight/volume to accommodate the combination of excipients that can be constraed as antimicrobials by weight/volume of the composition.
• Typical suitable antimicrobial agents include benzalkonium chloride (BAK), benzethoniurn chloride, disodium EDTA, and sodium benzoate.
• BAK benzalkonium chloride
• benzethoniurn chloride benzethoniurn chloride
• disodium EDTA sodium benzoate.
• the range of amounts of antimicrobials used in the present invention are dependent upon the particular components used. For example, a preferred amount of BAK is about 0.15mg/mL (0.015%). A preferred amount of disodium EDTA is about l.Omg/mL (0.1%). A preferred amount of sodium benzoate is about 0.2mg/mL (0.02%).
• the initial amounts of ascorbic acid or citric acid is used to insure solubility of the mo ⁇ hine.
• transmucosal refers to the mode of administration of the formulation.
• the transmucosal modes of administration include, but are not limited to, nasal, buccal, rectal, vaginal, and occular modes of administration.
• the formulation is administered nasally.
• amount refers to quantity or to concentration as appropriate to the context.
• the amount of a drug that constitutes a therapeutically effective amount varies according to factors such as the potency of the particular drag, the route of administration of the formulation, and the mechanical system used to administer the formulation.
• a therapeutically effective amount of a particular drag can be selected by those of ordinary skill in the art with due consideration of such factors.
• pharmaceutically acceptable refers to molecular entities and compositions that are "generally regarded as safe", e.g., that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as dizziness and the like, when administered to a human.
• the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S.
• carrier refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered.
• Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin (Mack Publishing Company, Easton, Pa., USA 1985).
• compositions of the present invention are manufactured in a conventional manner such as by mixing the ingredients under nitrogen gas at ambient or elevated temperatures to achieve solubility of ingredients where appropriate.
• the solution may be prepared as follows. To any appropriate reaction container, the active agent and the acid solution are mixed together. The polymer and antimicrobial agent are mixed together. The two mixtures are combined and chelating agents are mixed together. Each ingredient is mixed until the solution appears homogenous. The antioxidants and buffers are added to the mixture to adjust the pH of the solution. The final batch volume is adjusted with any suitable liquid, e.g., water. The solution is further mixed until uniform and filtered with a pre-sterilized filter using conventional filtration equipment. Preferably, a pre-sterilized 0.22 micron filter is used.
• the solution yields an osmolality of about 200 mOsm to about 900 mOsm.
• the solution yields an osmolality of about 400 to about 600 mOsm.
• the solution yields an osmolality of about 500 mOsm.
• the viscosity of the solution is from about 1 to about 50 centipoise. It is preferable to have a low viscosity as spray droplet size is small with a lower viscosity product optimizing surface area exposure and more regularized (reliable) delivery of product.
• the composition yields about 18.75 to about 300 microgram of pharmaceutically effective agent per 100 microliter nasal spray.
• the dosage forms used may be administered alone or in combination with other active agents.
• the active agents can be administered concurrently, or they each can be administered at separately staggered times.
• the dosage may be adjusted when combined with other active agents as described above to achieve desired effects.
• unit dosage forms of these various active agents may be independently optimized.
• EXAMPLE 1 Morphine Nasal Spray Formulation
• An aqueous nasal spray composition is prepared from the following components: Ingredients Weight/ml Mo ⁇ hine, anhydrous base 75.0 mg Methanesulfonic acid 25.3 mg B enzalkonium chloride (BAK) 0.15 mg Edatate Disodium, USP 1.0 mg Chitosan 5 mg WFI Water OS to 1ml
• the active agent and the methanesulfonic acid solution are mixed together.
• the polymer and antimicrobial agent are mixed together.
• the two mixtures are combined and chelating agents are mixed together. Each ingredient is mixed until the solution appears homogenous.
• the antioxidants and buffers are added to the mixture to adjust the pH of the solution.
• the final batch volume is adjusted with any suitable liquid, e.g., water.
• the solution is further mixed until uniform, with a pH value ranging between 3.0-5.0, and filtered with a pre-sterilized filter using conventional filtration equipment. Preferably, a pre-sterilized 0.22 micron filter is used.
• the solution yields an osmolality of about 500 mOsm. Viscosity of the solution measures less than 50 centipoise.
• the resulting formulation yields a 7.5 milligram mo ⁇ hine per 100 micro liter spray.
• EXAMPLE 2 Morphine Nasal Spray Formulation An aqueous nasal spray composition is prepared from the following components: Ingredients Weight/ml Mo ⁇ hine base (MW 303.4) 75.0 mg
• the active agent and the citric acid solution are mixed together.
• the polymer and antimicrobial agent are mixed together.
• benzalkonium chloride may be used in an amount of 0.15 mg.
• the two mixtures are combined and chelating agents are mixed together. Each ingredient is mixed until the solution appears homogenous.
• the antioxidants and buffers are added to the mixture to adjust the pH of the solution.
• the final batch volume is adjusted with any suitable liquid, e.g., water.
• aqueous nasal spray composition is prepared from the following components: Ingredients Weight/ml
• the solution is prepared as follows. To any appropriate reaction container, the active agent and the ascorbic acid solution are mixed together. The polymer and antimicrobial agent are mixed together. The two mixtures are combined and chelating agents are mixed together. Each ingredient is mixed until the solution appears homogenous. The antioxidants and buffers are added to the mixture to adjust the pH of the solution. The final batch volume is adjusted with any suitable liquid, e.g., water.
• the solution is further mixed until uniform and filtered with a pre-sterilized filter using conventional filtration equipment.
• a pre-sterilized 0.22 micron filter is used.
• the solution yields an osmolality of about 500 mOsm. Viscosity of the solution measures less than 50 centipoise.
• the resulting formulation yields a 7.5 milligram mo ⁇ hine per 100 microliter spray.
• EXAMPLE 4 Process Description of Morphine Formulations The following exemplifies a method of preparation of the 1 liter batch size for the mo ⁇ hine and chitosan formulation: The process begins by making stock solutions of citric acid (20 gm in a 200 ml volumetric flask) and sodium citrate (10 gm in a 100 ml volumetric flask) in purified water, USP in slight excess of the amount needed for formulating the batch. In the case of the ascorbic acid formulation, a similar process of making the stock solutions beforehand will be performed. A stock solution of BAK is also made and assayed prior to manufacture to enable an accurate amount of this ingredient to be added to the batch.
• 600 ml of purified water is added to a mixing vessel and stirred using nitrogen to remove dissolved oxygen.
• 2ml of citric acid solution is added to the 600 ml while stirring.
• 5 gm of chitosan is slowly added to the mixing vessel under constant nitrogen and mixing.
• 159 ml of the citric acid stock solution is added to a second mixing vessel under constant nitrogen sparging.
• 79.8 gm of purified mo ⁇ hine base monohydrate is added to the mixing vessel while mixing to dissolve the mo ⁇ hine. 79.8 gm is equivalent to 75 gm of the anhydrous base.
• the chitosan solution is quantitatively added to the mo ⁇ hine citrate solution and mixed, still using the nitrogen sparge.
• the equivalent of 0.15 gm of BAK is added from the stock solution with constant mixing.
• the 1 gm of disodium edetate is added and mixed until the solution is clear.
• 75 ml of the sodium citrate is added under constant mixing.
• the batch is adjusted to a pH of 4.1 using the citric acid or the sodium citrate solutions.
• the batch is filtered through a Millipore Durapore 0.22 micron filter and collected in a collection vessel under a nitrogen stream. In process tests including pH, Osmolality, mo ⁇ hine assay and BAK assay are performed. Pre and post filtration bioburden testing is performed for reference.
• the batch is filled using a peristaltic pump into the packaging containers that are continuously sparged with nitrogen.
• the package containers are sealed, inspected, labeled and packaged as required.
• the finished product is tested to include appearance, identification, pH, mo ⁇ hine assay, related substances, spray weight delivery, spray assay delivery, droplet size, spray shape and size, BAK assay, net contents, microbial testing, and others based on final package configuration.
• EXAMPLE 5 Bioavailability of Intranasal Morphine Formulations To demonstrate the tolerability and pharmacokinetic profile of a novel controlled release nasal mo ⁇ hine solution containing chitosan the solution was administered to healthy volunteers. The example shows "controlled" release ability of the present invention as demonstrated by regularized abso ⁇ tion of the product through the nasal mucosa, and the first order rate kinetics during the abso ⁇ tion phase of the product when delivered to the nasal mucosa.
• the study was a randomized, six-way complete crossover trial of single-dose administration of mo ⁇ hine via intranasal, oral and intravenous routes. Each two consecutive treatments were separated by a washout period of at least 3 days. Intranasal formulations were administered double-blind with respect to dose, with oral and intravenous formulations administered in an open label manner. In addition to the test drugs, each limb of the study was performed under a naltrexone block. The opioid antagonist was administered before each study treatment to prevent the centrally mediated effects of mo ⁇ hine and unpleasant effects of opiate administration in na ⁇ ve subjects.
• An aqueous nasal spray composition was prepared from the following components: Formula concentration: Cone.1 Conc.2 Cone.3 Ingredients Weight/ml Weight/ml Weight/ml Mo ⁇ hine, anhydrous base 37.5 mg 75.0 mg 150 mg Methanesulfonic acid 12.7 mg 25.3 mg 50.6 mg Benzalkonium chloride (BAK) 0.15 mg 0.15 mg 0.15 mg Edetate Disodium, USP 1.0 mg 1.0 mg l.Omg Chitosan 5.0 mg 5.0 mg 5.0 mg 5.0 mg WFI Water QS to 1ml QS to 1ml QS to 1ml Molecule Ratio of Morphine:Chitosan - 11.500:1 -23.000:1 -46,000:1
• the six treatment limbs were as follows: 1. Intranasal mo ⁇ hine base formulation 7.5 mg (3.75 mg per nostril) 2. Intranasal mo ⁇ hine base formulation 15 mg (7.5 mg per nostril) 3. Intranasal mo ⁇ hine base formulation 30 mg (15 mg per nostril) 4. Intranasal mo ⁇ hine base 15 mg (7.5 mg per nostril, contains no chitosan) 5. Oral mo ⁇ hine sulphate (15mg Oramo ⁇ h ® solution) plus intranasal placebo 6. Intravenous mo ⁇ hine sulphate 10 mg over 30 minutes plus intranasal placebo.
• Nasal placebo was administered to volunteers concomitant with intravenous or oral dosages. Intravenous and oral dosage arms were open label.
• the pharmacodynamic effects of mo ⁇ hine were avoided with naltrexone pre-treatment.
• Thirteen subjects (6 male and 7 female) were randomized into the study, of which five males and seven females successfully completed the study.
• Standard model independent pharmacokinetic methods were used to calculate Cmax, tmax, AUC, Fabs and Frel on the basis of plasma mo ⁇ hine, M-3-G and M-6-G levels. Intra-formulation and dose proportionality were also assessed. Prior to statistical analysis the parameters AUC, AUCt and Cmax were normalized to a 30 mg dose and log transformed. An initial analysis of variance was performed, which included the factors, subject, period, treatment and first order carry-over in the model. As first order carry-over was found not to be statistically significant it was subsequently dropped from the model.
• the formulation bioavailability based on statistical analysis for each dose when compared to mo ⁇ hine alone (contains no chitosan) was found to be 139.8%, 95% CI [105.1, 185.9], 127.1%, 95% CI [97.1, 166.5] and 102.5%, 95% CI [78.1, 134.6] for doses of 7.5 mg, 15 mg and 30 mg of the formulation, respectively.
• Bioavailability was inversely related to dose indiating the greatest effect of the chitosan enhancer to be at lower doses. All intranasal treatments were found to have approximately twice the bioavailability of oral mo ⁇ hine sulphate.
• AUC M-6-G / AUC Morphine Based on the 95% CI criteria dose proportionality could not be concluded for mo ⁇ hine-6-glucuronide using C max , AUC t and AUC for the mo ⁇ hine formulation.
• Mean half-life estimations were quite similar between treatments, ranging between 2.01 h and 4.36 h.
• M-3-G the formation of M-3-G from mo ⁇ hine was greatest following oral mo ⁇ hine sulphate due to first pass metabolism and least after intravenous infusion of mo ⁇ hine sulphate.
• the metabolic ratios following the intranasal formulations were comparable ranging between 24.8 and 30.0, again somewhere between the two values for oral and intravenous infusion.
• the metabolic ratio for M-3-G was greater than that for M-6-G regardless of the route of administration.
• the metabolic profile of intranasal mo ⁇ hine is similar to that of mo ⁇ hine delivered by intravenous infusion as indicated in Figures 4 (M-6-G) and 5 (M-3-G).
• analgesic levels of mo ⁇ hine can be attained within five minutes following nasal administration.
• Absolute bioavailability of mo ⁇ hine from the mo ⁇ hine formulation relative to intravenous dosing was found to be 82.3%, 74.9% and 60.4% for doses of 7.5 mg, 15 mg and 30 mg, respectively.
• Mo ⁇ hine bioavailability after the mo ⁇ hine formulation compared to mo ⁇ hine alone (no chitosan) treatments was found to be 139.8%, 127.1% and 102.5% for doses of 7.5 mg, 15 mg and 30 mg, respectively.
• Relative bioavailability of mo ⁇ hine after the mo ⁇ hine formulation relative to oral mo ⁇ hine sulphate based on AUC values was found to be 218.2%, 198.5% and 160.1% for the 3 dose levels, respectively.
• EXAMPLE 6 Safety, Tolerability, and Pharmacokinetic Profile of Intranasal Morphine Formulations This example presents a double-blind, single- and multiple-dose study to assess the safety, tolerability, and pharmacokinetic profile of three ascending dose levels of an intranasal controlled release mo ⁇ hine and chitosan solution in healthy subjects.
• the objectives of this study were to examine and compare the single- and multiple-dose safety and tolerability of three dose levels of the mo ⁇ hine formulation with respect to intranasal placebo (saline solution) and to determine and compare the single- and multiple-dose pharmacokinetic profiles of three dose levels of formulation. Thirty-six healthy male and female subjects were planned to be enrolled into the study.
• aqueous nasal spray composition is prepared from the following components: Formula concentration: Conc.l Conc.2 Cone.3 Ingredients Weight/ml Weight/ml Weight/ml Mo ⁇ hine, anhydrous base 37.5 mg 75.0 mg 150 mg
• Methanesulfonic acid 12.7 mg 25.3 mg 50.6 mg Benzalkonium chloride (BAK) 0.15 mg 0.15 mg 0.15 mg Edatate Disodium, USP 1.0 mg 1.0 mg l.Omg Chitosan 5.0 mg 5.0 mg 5.0 mg WFI Water QS to 1ml QS to 1ml QS to 1ml Molecule Ratio of Morphine: Chitosan - 11,500:1 -23,000:1 -46,000:1
• test product dose and mode of administration, and duration of treatment were as follows:
• 7.5 mg dose level 3.75 mg of mo ⁇ hine in 100 ⁇ L of vehicle, one spray per nostril.
• 15 mg dose level 7.5 mg of mo ⁇ hine in 100 ⁇ L of vehicle, one spray per nostril.
• Tolerability was measured by nasal examinations (measuring severity of rhinorrhea, mucosal erythema, bleeding, and residue) performed on Days 1, 2, 3, 5, and 7, and nasal symptom scores recorded using a 100 mm visual analog scale on Days 1, 2, 3, 5, and 7.
• Safety Safety variables included adverse events, vital signs, and laboratory assessments. Plasma levels of mo ⁇ hine and its metabolites were tabulated and summarized for individual subjects.
• pharmacokinetic parameters were calculated for single and multiple dose regimens of mo ⁇ hine using a validated pharmacokinetic analysis program: C max , T max , V, AUC, and dose proportionality. Additional analyses for mo ⁇ hine and/or its metabolites were performed as the data allowed. Continuous variables were presented using summary statistics including number of non-missing observations, mean, standard deviation, median, maximum, and minimum. Categorical variables were summarized using frequency counts and percentages. All collected data was presented in subject listings. No formal statistical tests were performed on the clinical and safety assessments.
• Results of the nasal examination for rhinorrhea, mucosal erythema, bleeding, and residue were converted to a numerical ordinal scale and summarized using the number of non-missing observations, mean, standard deviation, and median.
• the nasal symptom scores (using a 100 mm visual analog scale) were summarized using the number of non-missing observations, mean, standard deviation, and median.
• Vital signs were summarized using the number of non-missing observations, mean, standard deviation, and median.
• Clinical laboratory evaluations for which the results were continuous were summarized using the number of non-missing observations, mean, standard deviation, median, minimum, and maximum. All adverse events were tabulated by COSTART body system, COSTART preferred term, and treatment.
• Mean values for AUC ⁇ on Day 1 were similar to those for AUCss on Day 7, implying linearity in the pharmacokinetics of mo ⁇ hine within a given dose.
• Mean half-lives (XVi) ranged from 2 hours to 11 hours on Day 1 and from 9 to 10 hours on Day 7.
• the pharmacokinetics of mo ⁇ hine-6-glucuronide (M6G) and mo ⁇ hine-3- glucuronide (M3G) were consistent with those of mo ⁇ hine.
• Mean plasma concentrations increased proportionally to the increase in dose on Day 1 and Day 7 and were -2-fold higher on Day 7 than on Day 1 for all 3 doses.
• Mean values for AUC ⁇ on Day 1 were comparable to those for AUCss on Day 7, suggesting linearity in the pharmacokinetics of both glucuronide metabolites.
• Mean t'/ ⁇ s for M6G ranged from 2 hours to 9 hours on Day 1 and from 10 to 11 hours on Day 7 and those for M3G from 7.6 hours to 9.5 hours on Day 1 and from 8.7 to 11 hours on Day 7.
• the most common treatment-emergent AEs were rhinitis (56% of 30 mg subjects, 78% of 15 mg subjects, 56% of 7.5 mg subjects, and 17% of placebo subjects), taste perverse (44% of 30 mg subjects, 67% of 15 mg subjects, 11% of 7.5 mg subjects, and 0% of placebo subjects), pharyngitis (56% of 30 mg subjects, 44% of 15 mg subjects, 0% of 7.5 mg subjects, and 0% of placebo subjects), headache (11% of 30 mg subjects, 44% of 15 mg subjects, 22% of 7.5 mg subjects, and 17% of placebo subjects), and nausea (11% of 30 mg subjects, 33% of 15 mg subjects, 22% of 7.5 mg subjects, and 25% of placebo subjects).
• the most common abnormal screening physical examination findings were in the skin system (40 occurrences; 89%o of subjects in the 30 mg and 15 mg groups, 78% of the 7.5 mg group, and 75% of the placebo group) and in the mouth/throat/neck system (23 occurrences; 67% of the 30 mg group, 44%o of the 15 mg group, 56% of the 7.5 mg group, and 33% of the placebo group).

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