Classifications

• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
• • 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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • 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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5015—Organic compounds, e.g. fats, sugars
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents

Definitions

• This disclosure relates to a method and compositions for alleviating keratoconjunctivitis sicca, a dry eye condition.
• keratoconjunctivitis sicca or dry eye may affect as many as 9 million Americans over 50 years of age. Discomfort from dry eye ranges from a mild burning to a persistent sense of scratching under the lids. Dry eye is not just painful, but the condition can predispose to eye infections and also produce blurred vision. Dry eye is thought to be due to either an inability to produce sufficient tears or inflammation in the external eye.
• capsaicinoid nasal solutions which, when administered intranasally, cause substantially less or no nasal irritation than the composition previously described or utilized and are well tolerated by patients.
• a second unanticipated advantage of these formulations is that they release the capsaicinoid compound over a longer duration and in increased amounts over a 24-hour period.
• these formulations proved to be highly effective at increasing tear production and were well tolerated.
• the present disclosure involves a very novel approach.
• Dry eye syndromes are diseases in which the quantity and composition of tears are altered, and these parameters are affected by defects in the neural activity of cranial nerves V (trigeminal) and VII (facial) which innervate the lacrimal gland. Terminal branches of the trigeminal and facial nerves are present in the nasal mucosa. Consequently, utilizing a nasal route of administration for compounds (capsaicinoids) known to affect the conductive functions of these nerves, readily and conveniently accesses the terminal branches of these nerves in the nasal mucosa.
• the methods and formulations described herein provide a vastly improved method of increasing tear production without producing the adverse ocular effects (e.g. eye irritation, blurred or reduced vision) frequently produced by the installation of cyclosporine or lifitegrast drops into the eyes, as well as improves over the prior nasal treatment formulation as described above. Furthermore, by affecting the neural regulation of lacrimal gland secretion, this method produced more prompt improvement in patient's eyes then the slower anti-inflammatory actions of the current therapies.
• adverse ocular effects e.g. eye irritation, blurred or reduced vision
• An improved method and compositions for increasing tear production comprises intranasally administering a therapeutically effective amount of a capsaicinoid compound embedded in multiple layers of solid lamellar crystals of monoglycerides, to patients with deficient tear production. It was surprising and unexpected to use a nasal route of administration to successfully treat an ocular condition. To the inventor's knowledge, no nasal preparations have been reported to successfully treat disorders of the eyes while minimizing ocular irritation.
• a method of treating keratoconjunctivitis sicca includes administration of an effective amount of a composition containing lipoidal microencapsulated capsaicinoid compounds to the nasal mucosa with a resulting significant increase in production of ocular tearing without the localized ocular burning, stinging, blurring of vision and other adverse symptoms and signs attendant to the use of current treatments for dry eye.
• the capsaicinoid compound may be embedded or encapsulated in lamellar crystals of a monoglyceride and in a vehicle suitable for intranasal administration, and further include pharmaceutically acceptable excipients.
• a method of making a composition for treating keratoconjunctivitis sicca comprises the steps of: adding a capsaicinoid compound and a monoglyceride to water to form a mixture; mixing and heating the mixture at least to the melting point of the monoglyceride; cooling the mixture to cause crystallization of the monoglyceride and encapsulation of the capsaicinoid compound in monoglyceride crystals.
• a suitable capsaicinoid compound for example, includes capsaicin, civamide, acetylated derivatives of capsaicin and civamide, or salts of all of the aforementioned capsaicinoids.
• compositions disclosed herein are, for example, comprised of the above referenced capsaicinoid compounds in concentrations of about 0.001 to about 5.0% by weight microencapsulated within solid crystals of monoglycerides and incorporated into vehicles suitable for nasal administration. Use of such compositions results in markedly diminished nasal irritation as compared to compositions cited in U.S. Application 11/868,286, and also provide for a more prolonged and quantitatively greater release of the active capsaicinoid over a 24-hour period.
• the topical formulations suitable for application to skin or mucous membranes are comprised of the monoglyceride encapsulated capsaicinoids incorporated into a vehicle suitable for administration to the nasal mucosa such as solutions, suspensions, creams, ointments, gels or foams.
• the inventor has surprisingly discovered an improved method of producing increased tear production (lacrimation) without the adverse intraocular side effects noted with the eye drops currently utilized to treat patients with dry eye and without the undesirable nasal irritation elicited by the compositions disclosed in U.S. Application 11/868,286.
• This method consists of the intranasal administration of a class of chemicals called capsaicinoids encapsulated in lipoidal microcapsules, resulting in increased tear production without significant irritation to the eyes and intranasal cavities themselves.
• Suitable capsaicinoid compounds for the formulation described herein include, for example, capsaicin, civamide, acetylated derivatives of capsaicin and civamide, or salts of all of the aforementioned capsaicinoids.
• civamide cis-8-methyl-N-vanillyle-nonenamide
• U.S. Pat. Nos. 5,063,060 and 7,244,446 incorporated here by reference.
• intranasal capsaicinoids for treatment of headache and neuralgia pain, as well as nasal stuffiness, it was discovered surprisingly that intranasally administered capsaicinoids produce increased ocular tear production without undesirable effects on the eyes.
• U.S. Application No. 11/868,286 provided for incorporation into the compositions of either a local anesthetic or topically effective corticosteroid.
• the inventor nevertheless discovered after filing 11/868,286 that while incorporation of a local anesthetic or topical steroid might minimally ameliorate the adverse effects of the capsaicinoid on the nasal mucosa, the resulting formulations were still too irritating for most subjects to tolerate.
• the active compound is encapsulated in a solid crystal of a monoglyceride.
• Monoglycerides are a class of glycerides including a molecule of glycerol linked with an ester bonded to a fatty acid.
• a fatty acid has a 4 to 28 carbon atom chain, such as 6 to 21, or 10 to 15 carbon atoms. The carbon atom chain may be straight or branched and saturated or unsaturated.
• 1-glyceryl monolaurate and 1-glyceryl monomyristate are the preferred monoglycerides for the composition disclosed herein.
• the fatty acid is attached to a primary alcohol
• the resultant compound is a 1-monoglyceride and when attached to a secondary alcohol, the compound is designated a 2-monoglyceride.
• the monoglyceride has a melting point of about 25°C to about 65°C, such as about 30°C to about 45°C, or about 32°C to about 35°C.
• two or more monoglycerides are used in the composition.
• the monoglyceride is a polar lipid that is in a lamellar, crystalline phase.
• Monoglycerides are widely used in foods as emulsifiers to prevent mixtures of oils and water from separating. They are also incorporated in some cosmetics to enhance skin hydration and barrier function. However, by heating a batch of certain active pharmaceutical ingredients (APIs), e.g., the capsaicinoid compounds described herein with a monoglyceride and water until the monoglyceride is dissolved (e.g., to about 60°C to about 100°C, or about 65°C to about 80°C), stirring for about 15 to about 20 minutes under an inert nitrogen atmosphere (“nitrogen blanket"), then cooling the mixture to cause crystallization of the monoglyceride, individual molecules of the API can be coated with an envelope of monoglyceride particles. These particulate monoglyceride shells can be hydrolyzed in the skin or mucosa membranes to release glycerin and fatty acids and in doing such, also release the API.
• APIs active pharmaceutical ingredients
• the monoglycerides may be added in an amount of about 10 to about 50% by weight, such as about 15% to about 35%, or about 25% to about 30% by weight. Water may be present in an amount of 50% to 90%, such as about 60% to about 80%, or about 65% to about 75%.
• the APIs and other inactive ingredients may be added in an amount of about 0.001% to about 10%, such as about 0.1% to about 7%, or about 1% to about 5%.
• the monoglyceride may be in a weight ratio with the capsaicinoid compound of about 10,000:1 to about 30:1, such as, for example, about 5000:1 to about 100:1, or about 3000:1 to about 300:1.
• capsaicin, civamide, acetylated derivatives or salts of capsaicin and civamide are embedded in multiple layers of solid lamellar crystals of monoglycerides from 40-100 A thick, such as 50 to 90A, or 60 to 80 A, and incorporated into formulations such as solutions, suspensions, lotions, creams, gels, ointments and foams and then introduced into the nasal passages.
• the formulation can, for example, be introduced into the nasal passages by a drop or spray of a solution or suspension of the capsaicinoid compound.
• the patients generally administer the formulation utilized into the left, right or both nasal passages once or twice daily.
• Other pharmaceutically acceptable excipient components suitable for an intranasally delivered formulation for mammals may be added to the composition. These may include, for example, preservatives and emulsifiers, for example, polyoxyethylene(20) oleyl ether (BRIJ-98) and polyethylene glycol stearate (Myrj 59).
• compositions and method produces effective stimulus of increased tear production without untoward ocular side effects such as stinging or blurred vision in the eyes and intranasal irritation.
• compositions described herein reduce the frequency and/or severity of intranasal side effects by incorporating the capsaicinoid compound into lipoidal microspheres which provide a prolonged and more substantial release of the capsaicinoid on the nasal mucosa.
• the comparative API (civamide) release at 2, 6 and 24 hours is provided in Table 2 below.
• the monoglyceride encapsulated formulation released more than 4 times the amount of civamide over 24 hours than did the non-encapsulated formulation.

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• 2018
  • 2018-08-23 CN CN201880095418.1A patent/CN112384208A/zh active Pending
  • 2018-08-23 JP JP2021502828A patent/JP2021534081A/ja active Pending
  • 2018-08-23 WO PCT/US2018/047700 patent/WO2020040769A1/en active Application Filing
  • 2018-08-23 KR KR1020217000930A patent/KR20210021017A/ko not_active Application Discontinuation

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