WO2014077787A1 - Combinations including abeta2 agonist and glycopyrrolate - Google Patents

Combinations including abeta2 agonist and glycopyrrolate Download PDF

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Publication number
WO2014077787A1
WO2014077787A1 PCT/TR2013/000314 TR2013000314W WO2014077787A1 WO 2014077787 A1 WO2014077787 A1 WO 2014077787A1 TR 2013000314 W TR2013000314 W TR 2013000314W WO 2014077787 A1 WO2014077787 A1 WO 2014077787A1
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Prior art keywords
glycopyrrolate
carmoterol
pharmaceutical composition
formoterol
containing combination
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French (fr)
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Mahmut Bilgic
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators

Definitions

  • glycopyrrolate is 3-(alpha-cyclopentylmendeloyloxy)-l, l-dimethylpyrrolidinium and it was first described in US Patent No. 2956062. This document describes that glycopyrrolate is a acetyl choline antagonist and it is effective for inhibiting gastrointestinal motility.
  • glycopyrrolate Commercial preparations include solution for injection 0.2 mg/ml, oral solution 1 mg/5 ml and oral tablet forms 1, 1.5 and 2 mg.
  • a pharmaceutical composition comprising or combined or simultaneous use of glycopyrrolate and a p 2 -agonist, has substantially higher therapeutic benefit in comparison with monotherapies.
  • glycopyrrolate and a P2-agonist ensures that therapeutic effect is exerted within shorter time and the effect is more stronger in comparison with that of monotherapies.
  • those favorable effects are not only obtained with combination therapy comprising of two active substance, but they can be also obtained when two active substances are concurrently administered in a single dosage form or when they are administered simultaneously in two independent dosage forms. Higher therapeutic effect can be also manifested longer action time.
  • compositions containing glycopyrrolate and a p 2 -agonist which can be administered sequentially in different dosage forms or simultaneously administered in different dosage forms or concurrently administered in same dosage form.
  • current invention provides with a method which treats asthma and chronic obstructive pulmonary disease (COPD) by administering therapeutic doses of glycopyrrolate and a ⁇ 2- agonist.
  • COPD chronic obstructive pulmonary disease
  • current invention is related with pharmaceutical compositions, which include therapeutic amount of glycopyrrolate and a p2-agonist and at least one pharmaceutically acceptable substance.
  • Said pharmaceutical compositions can be found in combination in a single formulation, which includes glycopyrrolate and a p2-agonist and at least one pharmaceutically acceptable excipient, but they can be also formulated with different preparations of glycopyrrolate and ⁇ 2 -agonist with at least one pharmaceutically acceptable excipient.
  • Resultant different formulations can be further processed into a single dosage form or they can be prepared as independent dosage forms. If formulations are prepared in independent dosage forms, said dosage forms can be similar or different.
  • Current invention is related with use of glycopyrrolate and a p2-agonist in accordance with the invention in order to prepare a drug, which can be sequentially, simultaneously or independently administered in a combination therapy, which aims to treat asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • glycopyrrolate included in pharmaceutical compositions of current invention, can be pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers or diasteromers an/or any one of polymorphic forms, such as amorphous substance and crystal or combinations thereof.
  • Glycopyrrolate is preferably in the form of R,R-glycopyrrolate.
  • P2-agonist of current invention can be selected from a group comprising of albuterol, terbutaline, formoterol, tolobuterol, salmeterol or carmoterol.
  • p2-agonist of current invention is preferably formoterol and carmoterol or more preferably carmoterol.
  • the formoterol included in pharmaceutical compositions of current invention, can be pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers or diasteromers an or any one of polymorphic forms, such as amorphous substance and crystal or combinations thereof. Accordingly, formoterol has R or S form, and preferably, R-formoterol is used. Moreover, formoterol can be in the form of various organic and inorganic salts, such as hydrochloride, hydrobromide, tartarate, maleate and citrate, or a salt form containing their optically active forms.
  • Carmoterol included in pharmaceutical compositions of current invention, can be pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers or diasteromers an/or any one of polymorphic forms, such as amorphous substance and crystal or combinations thereof. Accordingly, carmoterol has R,R, S,R, S,S or R,S form, but preferably, R,R carmoterol is used. Moreover, carmoterol can be in the form of various organic and inorganic salts, such as hydrochloride, hydrobromide, tartarate, maleate and citrate, and preferably, it has form of hydrochloride salt.
  • compositions of current invention containing R,R-glycopyrrolate and carmoterol or formoterol, can be prepared in any one of dosage forms, including but not limited to tablet, effervescent tablet, effervescent granule, effervescent dry power, film coated tablet, enteric coated tablet, dry powder, granule, capsule, extended release tablet, modified release tablet, delayed release tablet, orodispersible tablet, chewing tablet, inhalation solution, aerosol or dry powder for inhalation.
  • dosage forms including but not limited to tablet, effervescent tablet, effervescent granule, effervescent dry power, film coated tablet, enteric coated tablet, dry powder, granule, capsule, extended release tablet, modified release tablet, delayed release tablet, orodispersible tablet, chewing tablet, inhalation solution, aerosol or dry powder for inhalation.
  • compositions containing R,R-glycopyrrolate and carmoterol or formoterol can be preparaed in any one of those dosage forms, but said formulation can be also prepared in any one of those dosage forms if R,R-glycopyrrolate and carmoterol or formoterol are stored in independent dosage forms.
  • compositions containing combination of invention can be found in different packages, comprising of any one of above mentioned dosage forms or combinations thereof, or a treatment package comprising of this combination.
  • compositions containing R,R-glycopyrrolate and carmoterol or formoterol can also contain at least one excipient in addition to active substances R,R-glycopyrrolate and carmoterol or formoterol.
  • Pharmaceutical compositions containing R,R-glycopyrrolate and carmoterol or formoterol, in accordance with the invention can also contain at least one excipient which selected from a group comprising of dispersant, diluent, lubricant, glidant, binder, effervescent pair comprising of at least one acidic agent and at least one basic agent, coloring agent, pH regulating agent, surfactant, sweetener and/or flavoring agent and aroma agent.
  • Physiologically non-hazardous excipients which can be found in inhalation formulations of the invention, can be selected from monosaccharides (glucose, arabinose etc.), disaccharides (lactose, saccharose, maltose etc.), oligo- and poly-saccharides (dextran ext.), poly-alcohols (sorbide, mannite, xylite), salts (sodium chloride, calcium carbonate etc) or a group comprising of mixtures of those excipients.
  • small- and large-sized excipients can be comprised of same or different chemical substances.
  • all excipients are preferably comprised of same chemical substance in inhalation formulations.
  • the invention provides a dry powder formulation which is comprised of only large-sized excipients or only small-sized excipients or both large- and small-sized excipients, such that the formulation has two different average particle sizes. If excipient particles are found in two fractions, active substances of formulation and small particulate excipients are carried during inhalation by binding to active zone of large particulate excipients. Large excipient particles are entrapped in upper respiratory tract of the patient. Active substances care carried by large excipient particles during inhalation and thanks to small particulate excipients, which bind to same active zone, active substances disintegrate from large particulate excipients and they reach lung when patient breaths.
  • small excipient particles ensures that active substance is entrapped in upper respiratory tract and not released to systemic circulation before it reaches lungs.
  • two different particule size of excipients in dry powder formulation offers a therapeutic advantage.
  • the term "large particulate excipient” implies an excipient with mean particle size of 10 ⁇ to 90 ⁇ , whereas the term “small particulate excipient” implies an excipient with mean particle size below 10 ⁇ .
  • ratio of small-sized excipient particles, which are contained in the excipient that has two different particle size, to large-sized excipient particles ranges from 1 : 1 to 1 :30, preferably from 1 : 1 to 1 : 15 and more preferably 1 : 1 to 1 :8.
  • quantity of active substance in dry powder formulation is ranging from 1 ⁇ g to 750 ⁇ g or in other words, in the range of 1 ⁇ g, 5 ⁇ g, 10 ⁇ g, 25 ⁇ g, 30 ⁇ g, 40 ⁇ g, 50 ⁇ g or 75 ⁇ g to 100 ⁇ & 600 ⁇ , 650 ⁇ g, 700 ⁇ g or 750 ⁇ , preferably in the range of 1 ⁇ g to 500 ⁇ g , or in other words, in the range of 1 ⁇ 5 ⁇ & 15 ⁇ g, 25 ⁇ g, 50 g ya da 75 ⁇ g or 100 ⁇ g to 125 ⁇ & 150 ⁇ 175 ⁇ & 250 ⁇ 3 ⁇ 4 300 ⁇ g, 350 g, 400 ⁇ g, 450 ⁇ & 475 ⁇ g or 500 ⁇ g and preferably in the range of 1 ⁇ g to 400 ⁇ g.
  • aerodynamic particle diameter of active substances contained in said formulation will be in the range of 0,05- 25 ⁇ , preferably in the range of 0, 1 - 20 ⁇ and more preferably in the range of 0,5- 10 ⁇ .
  • Dispersant used in pharmaceutical compositions of the invention can be selected from the group comprising of carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, micro-crystallized cellulose, methyl cellulose, chitosan, starch, sodium starch and glycolate.
  • Diluent used in pharmaceutical compositions of the invention can be selected from the group comprising of calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, micro-crystallized cellulose, dextrose, fructose, lactylol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc and xylitol.
  • Lubricant used in pharmaceutical compositions of the invention can be selected from the group comprising of calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc powder, stearic acid and zinc stearate.
  • Glidants used in pharmaceutical compositions of the invention can be selected from the group comprising of tribasic calcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate and talc.
  • Binder used in pharmaceutical compositions of the invention can be selected from the group comprising of carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone and starch.
  • the acidic agent can be selected from a group of organic acids such as malic acid, citric acid, tartaric acid and fumaric acid
  • basic agent can be selected from a group comprising of sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate.
  • pH regulating agent used in pharmaceutical compositions of the invention can be selected among citrate, phosphate, carbonate, tartarate, fumarate, acetate and amino acid salts.
  • Surfactant used in pharmaceutical compositions of the invention can be selected among sodium lauryl sulphate, polysorbate, polyoxyethylene, polypropylene glycol, oleic acid and similar agents. Oleic acid is preferably used in inhalation formulations.
  • Stabilizer used in pharmaceutical compositions of the invention can be selected from a group comprising of tocopherol, tetrasodium edetate, nicotinamide and cyclodextrin.
  • Sweetener and/or flavoring agent used in pharmaceutical compositions of the invention can be selected from a group comprising of acesulfame, aspartam, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol and sodium chloride.
  • Aroma agent used in pharmaceutical compositions of the invention can be selected among menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar aromas.
  • compositions of the invention contains R-R glycopyrrolate at rate of 0.1-99 % by weight, preferably at rate of 1-98 % by weight and more preferably at rate of 5-95 % by weight.
  • compositions of the invention contains carmoterol or formoterol at rate of 0.1-99 % by weight, preferably at rate of 1-98 % by weight and more preferably at rate of 5-95 % by weight.
  • agonist contained in pharmaceutical compositions of the invention is preferably carmoterol or formoterol or their pharmaceutically acceptable salt and quantity of active substances ranges from 1 ⁇ g to 100 ⁇ g , preferably from 1.5 ⁇ g to 50 ⁇ g and more preferably from 2 ⁇ g to 30 ⁇ g in pharmaceutical composition.
  • Amount of glycopyrrolate or pharmaceutically acceptable salt, for example glycopyrrolate bromide, used in pharmaceutical compositions of the invention can be in the range of 0.01 mg to 10 mg, preferably in the range of 0.02 mg to 5 mg and more preferably in the range of 0.1 mg to 3 mg.
  • Pharmaceutical compositions of the invention, containing R,R-glycopyrrolate and carmoterol or formoterol, can also contain a third active substance in addition to active substances R,R- glycopyrrolate and carmoterol.
  • Third active substance can be selected among antacid, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, anti-diarrheal, anti-obesity, antithrombotic, antifmrino lytic, anti-anemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, anti-acne, anti-bacterial, antimicotic, antiviral, antineoplastic, anti-arrhythmic, anti-adrenergic, anti-epileptic, anti-parkinson, antiprotozoal, antihelminthic, antiinflammatory, diurective, laxative, sulphonamide, imidazol, corticosteroid, tiozolydyndion, biguanide, immuno- stimulant, immunosuppressive, muscle relaxant, analgesic, psychoepileptic, psychoanaleptic, peripheral vasodilator, beta blocker,
  • ACE. ⁇ inhibitors, multivitamin and minerals, Vita 'm ' IinS.' , A, Vitamin D and analogues, Vitamin B l, Vitamin C, Vitamin E, Vitamin B6, Vitamin B2, Vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride and selenium.
  • R,R glycpyrrolate is preferably used in pharmaceutical compositions of the invention.
  • a pharmaceutical composition of the invention can be obtained using one of below specified methods: ⁇
  • the active substance, R,R glycopyrrolate and carmoterol or formoterol, is homogeneously blended and if required, minimum one of above written excipients is added, or
  • the active substance, R,R glycopyrrolate and carmoterol or formoterol is granulated with granulation solution, which contains minimum one of above written excipients, and next, it is homogeneously blended with other excipients, or
  • the active substance, R,R glycopyrrolate and carmoterol or formoterol is blended with minimum one of above written excipients and the blend is granulated with granulation solution, and next, it is homogeneously blended with other excipients, or
  • the active substance, R,R glycopyrrolate and carmoterol or formoterol is blended with minimum one of above written excipients and the blend is granulated with granulation solution, which contains minimum one of above mentioned excipients, and next, it is homogeneously blended with other excipients, or
  • R,R-glycopyrrolate and carmoterol or formoterol are prepared in two independent formulations, any one of active substance compositions, mentioned in above written methods, is separately used and resultant formulations are combined or stored in different dosage forms. Resultant pharmaceutical composition or compositions can be converted into any one of above specified dosage forms. If it is a tablet form, tablets can be treated with film coating agents, for example sugar-based coating agents, water-soluble film coating agents, enteric coating agents, delayed release coating agents or other coating compositions, which contain any combination thereof.
  • film coating agents for example sugar-based coating agents, water-soluble film coating agents, enteric coating agents, delayed release coating agents or other coating compositions, which contain any combination thereof.
  • saccharose can be used alone or optionally with talc, calcium, carbonate, calcium phosphate, calcium sulphate, gelatin, arabic gum, polyvinylpyrrolidone and pullulan or any combination thereof.
  • Water soluble film coating agent can be selected among cellulose derivatives such as hydroypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose, synthetic polymers such as polyvinyl diethyl aminoacetate, atninoalkyl metacrylate. copolimers and polyvinylpyrrolidone or any combinations thereof
  • Enteric coating agents can be selected among cellulose derivatives such as hydroypropyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxy ethyl cellulose and cellulose stcetate phthalata and acrylic acid derivatives such ' a's metaerylic acid copolymer L, metacrylic aci&C ' copolymer LD and metacrylic acid copolymer S and natural substaces such as shellac and any combinations thereof.
  • cellulose derivatives such as hydroypropyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxy ethyl cellulose and cellulose stcetate phthalata and acrylic acid derivatives such ' a's metaerylic acid copolymer L, metacrylic aci&C ' copolymer LD and metacrylic acid copolymer S and natural substaces such as shellac and any combinations thereof.
  • Delayed release coating agents can be selected among cellulose derivative such as ethyl cellulose and acrylic acid derivatives such as aminoalkyl metacrylate copolymer RS, ethyl acrylate - methyl metacrylate copolymer emulsion and any combinations thereof.
  • the dosage form containing both active substances or two independent dosage forms containing each of active substances or a dosage form containing only one of active substances can be appropriate for inhalation.
  • the formulation contained in said dosage form can be prepared in any dosage form, including but not limited to solution, aerosol or powder for inhalation in order to enable administration via inhalation route. Any one of below methods can be used to prepare said formulations;
  • micronized excipient (w) is subjected to spheroidizing procedure.
  • the resultant formulation is filled in capsules, blisters or reservoirs.
  • Method 2 ⁇ 2 agonist and glycopyrrolate or pharmaceutically acceptable salt and excipient with small particle size are sieved from a screen with appropriate pore size, preferably from multi-layer screen, minimum once and added to blending container and Premix A is obtained.
  • excipient with large particle size and Premix A are sieved, preferably in different sessions, from a screen with appropriate pore size, preferably from multi-layer screen, and Premix B is prepared by blending them in another container.
  • premix B is sieved from a screen with appropriate pore size, preferably from multi-layer screen, and fed to blending container, where large-particulate excipient is stored, which is sieved from a screen with appropriate pore size, preferably from multi-layer screen, minimum once, and thus, dry powder formulation is obtained.
  • Pharmaceutical composition of the invention can be inhaled using single- or multi-dose dry powder inhalation device. Accordingly, pharmaceutical composition of the invention can be carried in and inhaled using reservoir, capsule or blister.
  • composition of the invention is a dry powder formulation and inhaled from capsule, it is observed that inhalation has highest efficiency if volume of capsule, containing dry powder formation, is 0.1 to 0.6 ml, preferably 0.2 ml to 0.45 ml or more preferably 0.25 to 0.4 ml.
  • composition of the invention is a dry powder formulation and inhaled from capsule, it is characterized with that inhalation has highest efficiency if volume of capsule, which is used for storing and administering drug in the form of dry powder, containing dry powder formation, should be 0.1 to 0.6 ml, preferably 0.2 ml to 0.45 ml or more preferably 0.25 to 0.4 ml.
  • inventors observed that if humidity rate of the capsule package, which has protection against humidity and other adverse environmental effects, is between 5-15% or preferably between 8- 13%, active substances is protected against environmental factors and risk of humidification, originating from internal structure of capsule, is avoided. Thus, agglomeration of dry powder formation is prevented and active substance is efficiently carried to lungs of the patient.
  • composition of the invention is a dry powder formulation and inhaled from capsule, it is characterized with that inhalation has highest efficiency if humidity rate of capsule, which is used for storing and administering drug in the form of dry powder, containing dry powder formation, should be in the range of 5% to 15% or preferably 8% to 13%.
  • the preferred capsule structure of the invention can be made from a substance selected from a group of gelatin, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers, and said capsule is comprised of upper and lower parts.
  • capsule material can be selected from the group comprising of hydroypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hydroxymethyl cellulose and hydroxyethyl cellulose. Accordingly, if pharmaceutical composition of the invention is a dry powder formulation and inhaled from capsule, and if capsule is made from synthetic polymer, capsule material can be selected from the group comprising of polyethylene, polyester, polyethyleneteraphytalate polycarbonate or polypropylene.
  • capsuj,e, and Jf capsule is made from capsuj,e, and Jf capsule.
  • glycol polyethylene oxide - polypropylene oxide block co-polymers and/or other poly-alcohols and polyethers with various molecular weight can be added.
  • composition of the invention is a dry powder formulation and inhaled from capsule
  • inventors determined that the drug is efficiently inhaled if filling rate of capsule is ranging from 0.05% to 25 %, preferably from 0.1% to 20% and more preferably from 0.5% to 15%.
  • composition of the invention is a dry powder formulation and inhaled from capsule, it is characterized with that filling rate of capsule is ranging from 0.05% to 25 %, preferably from 0.1% to 20% and more preferably from 0.5% to 15%.
  • composition of the invention is a dry powder formulation and inhaled from blister
  • inventors determined that efficient inhalation is achieved, if cavity volume of blister, containing dry powder formation, is ranging from 18 to 30 mm 3 , preferably from 20 to 25 mm 3 or more preferably from 21 to 24 mm 3 .
  • composition of the invention is a dry powder formulation and inhaled from blister, it is characterized with that cavity volume of blister, which is used for storing and administering drug in the form of dry powder, containing dry powder formation, is ranging from 18 to 30 mm 3 , preferably from 20 to 25 mm 3 or more preferably from 21 to 24 mm 3 .
  • cavity filling rate of the blister should be ranging from 15% to 95 %, preferably from 20% to 85% and more preferably from 50% to 80% in order to ensure that dry powder formation of pharmaceutical composition of the invention is smoothly inhaled.
  • Current invention is characterized with that if pharmaceutical composition of the invention is a dry powder formulation and inhaled from blister, it is characterized with that cavity filling rate of the blister, which is used for efficient inhalation, should be ranging from 15% to 95 %, preferably from 20% to 85% and more preferably from 50% to 80%.
  • composition of the invention is a dry powder formulation and inhaled from blister
  • a suitable method is used to tightly seal upper and lower layers of perforating blister package of blisters, which contain dry powder formulation and are sequentially arranged on package, in order to ensure impermeability.
  • Upper and lower layers of striped perforating package of blisters, which contain dry powder formulation of current invention, are comprised of multiple lamina. Polymeric lamina, aluminium folio and preferably Aclar® fluoropolymer film are arranged between lower and upper layers.
  • composition of the invention is a dry powder formulation and inhaled from blister
  • addition of desiccant to polymeric layers is effective to maintain stability of said dry powder formulation in order prevent humidity- and gas-impermeability of lower and upper layers of blister package.
  • desiccant agents can be selected among silica gel, zeolite, alumina, bauxite, anhydrous calcium sulphate, active carbon and clays that can absorb water.
  • polymeric lamina forming upper and lower layers of striped perforating package of blisters, which contain dry powder formulation, can be made from same or different polymers. Thickness of this polymeric lamina varies depending on type and characteristics of polymeric substance. Therefore, thickness of polymeric lamina is ranging between 15 and 55 ⁇ or preferably between 20 and 30 ⁇ depending on type of polymeric substance.
  • polymeric lamina can be preferably selected among thermoplastic polymers such as polyethylene, polypropylene, polystyrene, polyolefin, polyamide, polyvinylchloride and polyurethane or from synthetic polymers.
  • Dry powder formulation containing pharmaceutical composition f the invention can be used in treatment of respiratory tract diseases, such as asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD).
  • respiratory tract diseases such as asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary, airway or lung diseases
  • COAD chronic obstructive pulmonary, airway or lung diseases
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • pneumoconiosis aluminosis, anthracosis, asbestosis, calicosis, ptylosis, siderosis, silicosis, tabacosis and bissnosizine.
  • the treatment can be prophylactic or symptomatic.
  • dry powder formulation of the invention is particularly used in treatment of asthma and COPD.
  • the dry powder formulation contains carmoterol and R,R-glycopyrrolate active substances at amount of 0.004 mg and with aerodynamic particle diameter of 2 ⁇ and lactose anhydrate, carrier substance, at amount of 13.98 mg. Active substance combination is first blended with small-particulate lactose. Next, the mixture is blended with large-particulate lactose and the mixture is added to a blending container, where substantially large-particulate lactose is found, and thus, final mixture is obtained. Resultant dry powder formations are filled into blisters.
  • EXAMPLE 2 EXAMPLE 2:
  • the dry powder formulation contains carmoterol and R,R-glycopyrrolate active substances at amount of 0.0000 oz and with aerodynamic particle diameter of 2 ⁇ and lactose anhydrate, carrier substance, at amount of 0.00 oz. Active substance combination is first blended with small-particulate lactose. Next, the mixture is blended with large-particulate lactose and the mixture is added to a blending container, where substantially large-particulate lactose is found, and thus, final mixture is obtained. Resultant dry powder formations are filled into capsules.
  • EXAMPLE 3 EXAMPLE 3:
  • a part of ethanol is added into formulation container, which was previously filled with nitrogen, and oleic acid is added; the solution is stirred at 250 xg for 1 minute.
  • Formulation container and the content is cooled down to 2-6 C and speed of stirrer is decreased to 100 rpm.
  • micronized active substances are added and homogenization is done for 10 minutes by increasing speed of stirrer to 250 rpm.
  • a part of anhydrous ethanol is added to the mixture and stirring is continued for 10 minutes at 250 rpm.
  • Final mixture is cooled down to 2-6 C and the temperature is kept constant throughout filling process.
  • the mixture is filled into aluminium containers and closed with valve.
  • HFA134a gas is fed into aluminium container via said valve.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Current invention related to pharmaceutical compositions containing glycopyrrolate and a β2-agonist which are used in treatment of asthma and chronic obstructive pulmonary disease.

Description

COMBINATIONS INCLUDING ABETA2 AGONIST AND GLYCOPYRROLATE
DESCRIPTION
Current invention is related with combinations of glycopyrrolate and a p2-agonist and their pharmaceutically acceptable combinations
Chemical name of glycopyrrolate is 3-(alpha-cyclopentylmendeloyloxy)-l, l-dimethylpyrrolidinium and it was first described in US Patent No. 2956062. This document describes that glycopyrrolate is a acetyl choline antagonist and it is effective for inhibiting gastrointestinal motility.
Figure imgf000002_0001
Formula I. Glycopyrrolate
Commercial preparations of glycopyrrolate include solution for injection 0.2 mg/ml, oral solution 1 mg/5 ml and oral tablet forms 1, 1.5 and 2 mg.
It is surprisingly found that an unexpected therapeutic benefit, particular a synergistic therapeutic benefit, can be obtained with combination therapy of glycopyrrolate and P2-agonists in treatment of asthma and chronic obstructive pulmonary disease (COPD). Above mention therapeutic benefit can be obtained as defined below;
• In comparison with monotherapy with glycopyrrolate or p2-agonists, use of this combination will offer a therapeutic effect based on following facts;
• Doses required to exert therapeutic effect can be reduced; and/or
• Adverse effects can be minimized, and/or
• Therapeutic effect can be observed within shorter time, and/or
• Therapeutic effect may last for longer time, and/or
• More efficient therapeutic effect is exerted. On the other side, a pharmaceutical composition, comprising or combined or simultaneous use of glycopyrrolate and a p2-agonist, has substantially higher therapeutic benefit in comparison with monotherapies.
On the other side, combined use of glycopyrrolate and a P2-agonist ensures that therapeutic effect is exerted within shorter time and the effect is more stronger in comparison with that of monotherapies. Thus, it is possible to provide patients with more efficient treatment. Surprisingly, those favorable effects are not only obtained with combination therapy comprising of two active substance, but they can be also obtained when two active substances are concurrently administered in a single dosage form or when they are administered simultaneously in two independent dosage forms. Higher therapeutic effect can be also manifested longer action time.
Accordingly, current invention is related with pharmaceutical compositions containing glycopyrrolate and a p2-agonist which can be administered sequentially in different dosage forms or simultaneously administered in different dosage forms or concurrently administered in same dosage form.
In another aspect, current invention provides with a method which treats asthma and chronic obstructive pulmonary disease (COPD) by administering therapeutic doses of glycopyrrolate and a β2- agonist.
Yet, in another aspect, current invention is related with pharmaceutical compositions, which include therapeutic amount of glycopyrrolate and a p2-agonist and at least one pharmaceutically acceptable substance. Said pharmaceutical compositions can be found in combination in a single formulation, which includes glycopyrrolate and a p2-agonist and at least one pharmaceutically acceptable excipient, but they can be also formulated with different preparations of glycopyrrolate and β2 -agonist with at least one pharmaceutically acceptable excipient. Resultant different formulations can be further processed into a single dosage form or they can be prepared as independent dosage forms. If formulations are prepared in independent dosage forms, said dosage forms can be similar or different. Current invention is related with use of glycopyrrolate and a p2-agonist in accordance with the invention in order to prepare a drug, which can be sequentially, simultaneously or independently administered in a combination therapy, which aims to treat asthma and chronic obstructive pulmonary disease (COPD).
The glycopyrrolate, included in pharmaceutical compositions of current invention, can be pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers or diasteromers an/or any one of polymorphic forms, such as amorphous substance and crystal or combinations thereof. Glycopyrrolate is preferably in the form of R,R-glycopyrrolate. P2-agonist of current invention can be selected from a group comprising of albuterol, terbutaline, formoterol, tolobuterol, salmeterol or carmoterol. p2-agonist of current invention is preferably formoterol and carmoterol or more preferably carmoterol.
The formoterol, included in pharmaceutical compositions of current invention, can be pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers or diasteromers an or any one of polymorphic forms, such as amorphous substance and crystal or combinations thereof. Accordingly, formoterol has R or S form, and preferably, R-formoterol is used. Moreover, formoterol can be in the form of various organic and inorganic salts, such as hydrochloride, hydrobromide, tartarate, maleate and citrate, or a salt form containing their optically active forms. Carmoterol, included in pharmaceutical compositions of current invention, can be pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers or diasteromers an/or any one of polymorphic forms, such as amorphous substance and crystal or combinations thereof. Accordingly, carmoterol has R,R, S,R, S,S or R,S form, but preferably, R,R carmoterol is used. Moreover, carmoterol can be in the form of various organic and inorganic salts, such as hydrochloride, hydrobromide, tartarate, maleate and citrate, and preferably, it has form of hydrochloride salt.
Pharmaceutical compositions of current invention, containing R,R-glycopyrrolate and carmoterol or formoterol, can be prepared in any one of dosage forms, including but not limited to tablet, effervescent tablet, effervescent granule, effervescent dry power, film coated tablet, enteric coated tablet, dry powder, granule, capsule, extended release tablet, modified release tablet, delayed release tablet, orodispersible tablet, chewing tablet, inhalation solution, aerosol or dry powder for inhalation. Pharmaceutical compositions containing R,R-glycopyrrolate and carmoterol or formoterol can be preparaed in any one of those dosage forms, but said formulation can be also prepared in any one of those dosage forms if R,R-glycopyrrolate and carmoterol or formoterol are stored in independent dosage forms. In other words, compositions containing combination of invention can be found in different packages, comprising of any one of above mentioned dosage forms or combinations thereof, or a treatment package comprising of this combination.
Pharmaceutical compositions containing R,R-glycopyrrolate and carmoterol or formoterol, in accordance with the invention, can also contain at least one excipient in addition to active substances R,R-glycopyrrolate and carmoterol or formoterol. Pharmaceutical compositions containing R,R-glycopyrrolate and carmoterol or formoterol, in accordance with the invention, can also contain at least one excipient which selected from a group comprising of dispersant, diluent, lubricant, glidant, binder, effervescent pair comprising of at least one acidic agent and at least one basic agent, coloring agent, pH regulating agent, surfactant, sweetener and/or flavoring agent and aroma agent. Physiologically non-hazardous excipients, which can be found in inhalation formulations of the invention, can be selected from monosaccharides (glucose, arabinose etc.), disaccharides (lactose, saccharose, maltose etc.), oligo- and poly-saccharides (dextran ext.), poly-alcohols (sorbide, mannite, xylite), salts (sodium chloride, calcium carbonate etc) or a group comprising of mixtures of those excipients.
According to the invention, small- and large-sized excipients can be comprised of same or different chemical substances. According to the invention, all excipients are preferably comprised of same chemical substance in inhalation formulations.
Yet, in another aspect, the invention provides a dry powder formulation which is comprised of only large-sized excipients or only small-sized excipients or both large- and small-sized excipients, such that the formulation has two different average particle sizes. If excipient particles are found in two fractions, active substances of formulation and small particulate excipients are carried during inhalation by binding to active zone of large particulate excipients. Large excipient particles are entrapped in upper respiratory tract of the patient. Active substances care carried by large excipient particles during inhalation and thanks to small particulate excipients, which bind to same active zone, active substances disintegrate from large particulate excipients and they reach lung when patient breaths. Accordingly, small excipient particles ensures that active substance is entrapped in upper respiratory tract and not released to systemic circulation before it reaches lungs. In conclusion, two different particule size of excipients in dry powder formulation offers a therapeutic advantage. The term "large particulate excipient" implies an excipient with mean particle size of 10 μπι to 90μιη, whereas the term "small particulate excipient" implies an excipient with mean particle size below 10 μιη.
Inventors observed in studies that good viscosity of dry powder inhalation powders is not only influenced by particle size of active substances and excipient, but it is also controlled by amount of each substance in the formulation. If ratio of small-sized excipient particles, which are contained in the excipient that has two different particle size, to large-sized excipient particles ranges from 1 : 1 to 1 :30, preferably from 1: 1 to 1 : 15 and more preferably 1 : 1 to 1 :8, it is observed that formulation is homogeneously blended and thus, a formulation with good viscosity features is obtained.
Another aspect of the invention is that ratio of small-sized excipient particles, which are contained in the excipient that has two different particle size, to large-sized excipient particles ranges from 1 : 1 to 1 :30, preferably from 1 : 1 to 1 : 15 and more preferably 1 : 1 to 1 :8.
In current invention, quantity of active substance in dry powder formulation is ranging from 1 μg to 750μg or in other words, in the range of 1 μg, 5 μg, 10 μg, 25 μg, 30 μg, 40 μg, 50 μg or 75 μg to 100 μ& 600μ§, 650 μg, 700 μg or 750 μ , preferably in the range of 1 μg to 500 μg , or in other words, in the range of 1 μ 5 μ& 15 μg, 25 μg, 50 g ya da 75 μg or 100 μg to 125 μ& 150 μ^ 175 μ& 250 μ¾ 300 μg, 350 g, 400 μg, 450 μ& 475 μg or 500 μg and preferably in the range of 1 μg to 400 μg.
If the synergistic combination of the invention is formulated as inhalation dosage form, aerodynamic particle diameter of active substances contained in said formulation will be in the range of 0,05- 25 μιη , preferably in the range of 0, 1 - 20 μπι and more preferably in the range of 0,5- 10 μιη.
Dispersant used in pharmaceutical compositions of the invention can be selected from the group comprising of carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, micro-crystallized cellulose, methyl cellulose, chitosan, starch, sodium starch and glycolate.
Diluent used in pharmaceutical compositions of the invention can be selected from the group comprising of calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, micro-crystallized cellulose, dextrose, fructose, lactylol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc and xylitol.
Lubricant used in pharmaceutical compositions of the invention can be selected from the group comprising of calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc powder, stearic acid and zinc stearate.
Glidants used in pharmaceutical compositions of the invention can be selected from the group comprising of tribasic calcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate and talc.
Binder used in pharmaceutical compositions of the invention can be selected from the group comprising of carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone and starch.
Considering effervescent pair comprising of at least one acidic agent and at least one basic agent used in pharmaceutical compositions of the invention, the acidic agent can be selected from a group of organic acids such as malic acid, citric acid, tartaric acid and fumaric acid, while basic agent can be selected from a group comprising of sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. pH regulating agent used in pharmaceutical compositions of the invention can be selected among citrate, phosphate, carbonate, tartarate, fumarate, acetate and amino acid salts. Surfactant used in pharmaceutical compositions of the invention can be selected among sodium lauryl sulphate, polysorbate, polyoxyethylene, polypropylene glycol, oleic acid and similar agents. Oleic acid is preferably used in inhalation formulations.
Stabilizer used in pharmaceutical compositions of the invention can be selected from a group comprising of tocopherol, tetrasodium edetate, nicotinamide and cyclodextrin.
Sweetener and/or flavoring agent used in pharmaceutical compositions of the invention can be selected from a group comprising of acesulfame, aspartam, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol and sodium chloride. Aroma agent used in pharmaceutical compositions of the invention can be selected among menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar aromas.
Pharmaceutical compositions of the invention contains R-R glycopyrrolate at rate of 0.1-99 % by weight, preferably at rate of 1-98 % by weight and more preferably at rate of 5-95 % by weight.
Pharmaceutical compositions of the invention contains carmoterol or formoterol at rate of 0.1-99 % by weight, preferably at rate of 1-98 % by weight and more preferably at rate of 5-95 % by weight. agonist contained in pharmaceutical compositions of the invention is preferably carmoterol or formoterol or their pharmaceutically acceptable salt and quantity of active substances ranges from 1 μg to 100 μg , preferably from 1.5 μg to 50 μg and more preferably from 2 μg to 30 μg in pharmaceutical composition. Amount of glycopyrrolate or pharmaceutically acceptable salt, for example glycopyrrolate bromide, used in pharmaceutical compositions of the invention can be in the range of 0.01 mg to 10 mg, preferably in the range of 0.02 mg to 5 mg and more preferably in the range of 0.1 mg to 3 mg. Pharmaceutical compositions of the invention, containing R,R-glycopyrrolate and carmoterol or formoterol, can also contain a third active substance in addition to active substances R,R- glycopyrrolate and carmoterol. Third active substance can be selected among antacid, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, anti-diarrheal, anti-obesity, antithrombotic, antifmrino lytic, anti-anemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, anti-acne, anti-bacterial, antimicotic, antiviral, antineoplastic, anti-arrhythmic, anti-adrenergic, anti-epileptic, anti-parkinson, antiprotozoal, antihelminthic, antiinflammatory, diurective, laxative, sulphonamide, imidazol, corticosteroid, tiozolydyndion, biguanide, immuno- stimulant, immunosuppressive, muscle relaxant, analgesic, psychoepileptic, psychoanaleptic, peripheral vasodilator, beta blocker, calcium channel blocker and lipid mofidiers, alpha glucosidase inhibitors, aldose reductase inhibitors,. ACE.ί, inhibitors, multivitamin and minerals, Vita 'm ' IinS.' , A, Vitamin D and analogues, Vitamin B l, Vitamin C, Vitamin E, Vitamin B6, Vitamin B2, Vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride and selenium.
R,R glycpyrrolate is preferably used in pharmaceutical compositions of the invention.
A pharmaceutical composition of the invention can be obtained using one of below specified methods: · The active substance, R,R glycopyrrolate and carmoterol or formoterol, is homogeneously blended and if required, minimum one of above written excipients is added, or
• The active substance, R,R glycopyrrolate and carmoterol or formoterol, is granulated with granulation solution, which contains minimum one of above written excipients, and next, it is homogeneously blended with other excipients, or
· The active substance, R,R glycopyrrolate and carmoterol or formoterol, is blended with minimum one of above written excipients and the blend is granulated with granulation solution, and next, it is homogeneously blended with other excipients, or
• The active substance, R,R glycopyrrolate and carmoterol or formoterol, is blended with minimum one of above written excipients and the blend is granulated with granulation solution, which contains minimum one of above mentioned excipients, and next, it is homogeneously blended with other excipients, or
• If R,R-glycopyrrolate and carmoterol or formoterol are prepared in two independent formulations, any one of active substance compositions, mentioned in above written methods, is separately used and resultant formulations are combined or stored in different dosage forms. Resultant pharmaceutical composition or compositions can be converted into any one of above specified dosage forms. If it is a tablet form, tablets can be treated with film coating agents, for example sugar-based coating agents, water-soluble film coating agents, enteric coating agents, delayed release coating agents or other coating compositions, which contain any combination thereof.
Considering sugar-based coating agents, saccharose can be used alone or optionally with talc, calcium, carbonate, calcium phosphate, calcium sulphate, gelatin, arabic gum, polyvinylpyrrolidone and pullulan or any combination thereof.
Water soluble film coating agent can be selected among cellulose derivatives such as hydroypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose, synthetic polymers such as polyvinyl diethyl aminoacetate, atninoalkyl metacrylate. copolimers and polyvinylpyrrolidone or any combinations thereof
Enteric coating agents can be selected among cellulose derivatives such as hydroypropyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxy ethyl cellulose and cellulose stcetate phthalata and acrylic acid derivatives such' a's metaerylic acid copolymer L, metacrylic aci&C ' copolymer LD and metacrylic acid copolymer S and natural substaces such as shellac and any combinations thereof.
Delayed release coating agents can be selected among cellulose derivative such as ethyl cellulose and acrylic acid derivatives such as aminoalkyl metacrylate copolymer RS, ethyl acrylate - methyl metacrylate copolymer emulsion and any combinations thereof.
If any combination of the invention is sequentially or simultaneously used in different or same dosage forms, the dosage form containing both active substances or two independent dosage forms containing each of active substances or a dosage form containing only one of active substances can be appropriate for inhalation. As specified above, the formulation contained in said dosage form can be prepared in any dosage form, including but not limited to solution, aerosol or powder for inhalation in order to enable administration via inhalation route. Any one of below methods can be used to prepare said formulations;
Method 1 :
- Active substance(s), excipient with small particle size and/or excipient with large particle size are separately micronized;
- Optionally, minimum 10% of micronized excipient (w) is subjected to spheroidizing procedure.
- Micronized active substance(s), excipient(s) and spheroidized excipients, if any, are blended
- Final dry powder formulation is obtained.
- The resultant formulation is filled in capsules, blisters or reservoirs.
Method 2: β2 agonist and glycopyrrolate or pharmaceutically acceptable salt and excipient with small particle size are sieved from a screen with appropriate pore size, preferably from multi-layer screen, minimum once and added to blending container and Premix A is obtained.
Next, excipient with large particle size and Premix A are sieved, preferably in different sessions, from a screen with appropriate pore size, preferably from multi-layer screen, and Premix B is prepared by blending them in another container.
Finally, premix B is sieved from a screen with appropriate pore size, preferably from multi-layer screen, and fed to blending container, where large-particulate excipient is stored, which is sieved from a screen with appropriate pore size, preferably from multi-layer screen, minimum once, and thus, dry powder formulation is obtained. Pharmaceutical composition of the invention can be inhaled using single- or multi-dose dry powder inhalation device. Accordingly, pharmaceutical composition of the invention can be carried in and inhaled using reservoir, capsule or blister.
If pharmaceutical composition of the invention is a dry powder formulation and inhaled from capsule, it is observed that inhalation has highest efficiency if volume of capsule, containing dry powder formation, is 0.1 to 0.6 ml, preferably 0.2 ml to 0.45 ml or more preferably 0.25 to 0.4 ml.
Accordingly, if pharmaceutical composition of the invention is a dry powder formulation and inhaled from capsule, it is characterized with that inhalation has highest efficiency if volume of capsule, which is used for storing and administering drug in the form of dry powder, containing dry powder formation, should be 0.1 to 0.6 ml, preferably 0.2 ml to 0.45 ml or more preferably 0.25 to 0.4 ml.
In another aspect, inventors observed that if humidity rate of the capsule package, which has protection against humidity and other adverse environmental effects, is between 5-15% or preferably between 8- 13%, active substances is protected against environmental factors and risk of humidification, originating from internal structure of capsule, is avoided. Thus, agglomeration of dry powder formation is prevented and active substance is efficiently carried to lungs of the patient.
Accordingly, if pharmaceutical composition of the invention is a dry powder formulation and inhaled from capsule, it is characterized with that inhalation has highest efficiency if humidity rate of capsule, which is used for storing and administering drug in the form of dry powder, containing dry powder formation, should be in the range of 5% to 15% or preferably 8% to 13%. Yet, in another aspect, if pharmaceutical composition of the invention is a dry powder formulation and inhaled from capsule, the preferred capsule structure of the invention can be made from a substance selected from a group of gelatin, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers, and said capsule is comprised of upper and lower parts.
Accordingly, if pharmaceutical composition of the invention is a dry powder formulation and inhaled from capsule, and if capsule is made from cellulose or derivatives, capsule material can be selected from the group comprising of hydroypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hydroxymethyl cellulose and hydroxyethyl cellulose. Accordingly, if pharmaceutical composition of the invention is a dry powder formulation and inhaled from capsule, and if capsule is made from synthetic polymer, capsule material can be selected from the group comprising of polyethylene, polyester, polyethyleneteraphytalate polycarbonate or polypropylene.
Accordingly, if pharmaceutical composition
from capsuj,e, and Jf capsule is made from
Figure imgf000010_0001
glycol, polyethylene oxide - polypropylene oxide block co-polymers and/or other poly-alcohols and polyethers with various molecular weight can be added.
In another aspect, if pharmaceutical composition of the invention is a dry powder formulation and inhaled from capsule, inventors determined that the drug is efficiently inhaled if filling rate of capsule is ranging from 0.05% to 25 %, preferably from 0.1% to 20% and more preferably from 0.5% to 15%.
Accordingly, if pharmaceutical composition of the invention is a dry powder formulation and inhaled from capsule, it is characterized with that filling rate of capsule is ranging from 0.05% to 25 %, preferably from 0.1% to 20% and more preferably from 0.5% to 15%.
If pharmaceutical composition of the invention is a dry powder formulation and inhaled from blister, inventors determined that efficient inhalation is achieved, if cavity volume of blister, containing dry powder formation, is ranging from 18 to 30 mm3, preferably from 20 to 25 mm3 or more preferably from 21 to 24 mm3.
Accordingly, if pharmaceutical composition of the invention is a dry powder formulation and inhaled from blister, it is characterized with that cavity volume of blister, which is used for storing and administering drug in the form of dry powder, containing dry powder formation, is ranging from 18 to 30 mm3, preferably from 20 to 25 mm3or more preferably from 21 to 24 mm3.
Inventors found that cavity filling rate of the blister, which is used for efficient inhalation, should be ranging from 15% to 95 %, preferably from 20% to 85% and more preferably from 50% to 80% in order to ensure that dry powder formation of pharmaceutical composition of the invention is smoothly inhaled. Current invention is characterized with that if pharmaceutical composition of the invention is a dry powder formulation and inhaled from blister, it is characterized with that cavity filling rate of the blister, which is used for efficient inhalation, should be ranging from 15% to 95 %, preferably from 20% to 85% and more preferably from 50% to 80%.
If pharmaceutical composition of the invention is a dry powder formulation and inhaled from blister, a suitable method is used to tightly seal upper and lower layers of perforating blister package of blisters, which contain dry powder formulation and are sequentially arranged on package, in order to ensure impermeability. Upper and lower layers of striped perforating package of blisters, which contain dry powder formulation of current invention, are comprised of multiple lamina. Polymeric lamina, aluminium folio and preferably Aclar® fluoropolymer film are arranged between lower and upper layers.
Inventors observed that if pharmaceutical composition of the invention is a dry powder formulation and inhaled from blister, addition of desiccant to polymeric layers is effective to maintain stability of said dry powder formulation in order prevent humidity- and gas-impermeability of lower and upper layers of blister package. Added to layers forming striped package of blisters, which contain dry powder formulation of the invention, desiccant agents can be selected among silica gel, zeolite, alumina, bauxite, anhydrous calcium sulphate, active carbon and clays that can absorb water. If pharmaceutical composition of the invention is a dry powder formulation and inhaled from blister, polymeric lamina forming upper and lower layers of striped perforating package of blisters, which contain dry powder formulation, can be made from same or different polymers. Thickness of this polymeric lamina varies depending on type and characteristics of polymeric substance. Therefore, thickness of polymeric lamina is ranging between 15 and 55 μπι or preferably between 20 and 30 μπι depending on type of polymeric substance.
If layers is made from aluminium folia, which contacts with dry powder formulation stored in cavity of blister, interior surface of cavity is lined with polymeric lamina since aluminium folio has porous structure and it leads to uncontrolled inhalation of dose as a part of dry powder formulation adheres on interior surface of blister cavity due to electrostatic forces. Polymers, forming the polymeric lamina, can be preferably selected among thermoplastic polymers such as polyethylene, polypropylene, polystyrene, polyolefin, polyamide, polyvinylchloride and polyurethane or from synthetic polymers.
Dry powder formulation containing pharmaceutical composition f the invention can be used in treatment of respiratory tract diseases, such as asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD). Accordingly, there is no limitation on respiratory tract diseases and it can be used in treatment of chronic obstructive pulmonary, airway or lung diseases (COPD, COAD or COLD) including asthma (at any stage), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airway hyperactivity, bronchiectasis, emphysema and chronic bronchitis, and pneumoconiosis, aluminosis, anthracosis, asbestosis, calicosis, ptylosis, siderosis, silicosis, tabacosis and bissnosizine. The treatment can be prophylactic or symptomatic. However, dry powder formulation of the invention is particularly used in treatment of asthma and COPD.
Following examples are given to describe combinations of the invention and the invention shall be no means limited with them. EXAMPLE 1 :
Figure imgf000013_0001
Prepared at amount of 25.2 mg and appropriate for storing in blister to be delivered in inhalation device, the dry powder formulation contains carmoterol and R,R-glycopyrrolate active substances at amount of 0.004 mg and with aerodynamic particle diameter of 2 μηι and lactose anhydrate, carrier substance, at amount of 13.98 mg. Active substance combination is first blended with small-particulate lactose. Next, the mixture is blended with large-particulate lactose and the mixture is added to a blending container, where substantially large-particulate lactose is found, and thus, final mixture is obtained. Resultant dry powder formations are filled into blisters. EXAMPLE 2:
Figure imgf000013_0002
Prepared at amount of 0.001 oz and appropriate for storing in blister to be delivered in inhalation device, the dry powder formulation contains carmoterol and R,R-glycopyrrolate active substances at amount of 0.0000 oz and with aerodynamic particle diameter of 2 μιη and lactose anhydrate, carrier substance, at amount of 0.00 oz. Active substance combination is first blended with small-particulate lactose. Next, the mixture is blended with large-particulate lactose and the mixture is added to a blending container, where substantially large-particulate lactose is found, and thus, final mixture is obtained. Resultant dry powder formations are filled into capsules. EXAMPLE 3:
Figure imgf000014_0001
A part of ethanol is added into formulation container, which was previously filled with nitrogen, and oleic acid is added; the solution is stirred at 250 xg for 1 minute. Formulation container and the content is cooled down to 2-6 C and speed of stirrer is decreased to 100 rpm. Next, micronized active substances are added and homogenization is done for 10 minutes by increasing speed of stirrer to 250 rpm. Next, a part of anhydrous ethanol is added to the mixture and stirring is continued for 10 minutes at 250 rpm. Final mixture is cooled down to 2-6 C and the temperature is kept constant throughout filling process. The mixture is filled into aluminium containers and closed with valve. Next, HFA134a gas is fed into aluminium container via said valve.

Claims

1. A pharmaceutical composition comprising of active agent, glycopyrrolate, or pharmaceutically acceptable salt and a β2 agonist.
2. It is a pharmaceutical composition containing glycpyrrolate and β2 agonist according to Claim 1 characterized in that glycopyrrolate can be pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers or diasteromers an/or any one of polymorphic forms, such as amorphous substance and crystal or combinations thereof.
3. A pharmaceutical composition according to Claims 1 and 2 characterized in that glycopyrrolate is found in form of R,R-Glycopyrrolate or preferably R,R-glycopyrrolate bromide.
4. A pharmaceutical composition according to Claims 1 characterized in that p2-agonist is selected from albuterol, terbutaline, formoterol, tolobuterol, salmeterol or carmoterol.
5. A pharmaceutical composition according to Claims 1 to 4 characterized in that p2-agonist is formoterol or carmoterol.
6. It is a pharmaceutical composition according to Claim 5 characterized in that carmoterol or formoterol can be pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers or diasteromers an/or any one of polymorphic forms, such as amorphous substance and crystal or combinations thereof.
7. A pharmaceutical composition according to Claim 6 characterized in that carmoterol is found in any one of RR, SS, SR or RS forms and it is preferably in RR form.
8. A pharmaceutical composition according to Claims 6 and 7 characterized in that carmoterol is found in any one of hydrochloride, hydrobromide, tartrate, maleate and citrate salt forms.
9. A pharmaceutical composition according to Claim 6 characterized in that formoterol is found in any one of R or S forms and it is preferably in R form.
10. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to Claims 5 to 9 characterized in that R,R-glycopyrrolate and carmoterol are found in same pharmaceutical formulation.
11. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to Claims 5 to 9 characterized in that R,R-glycopyrrolate and carmoterol are found in different pharmaceutical formulations.
12. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to Claims 5 to 9 and 11 characterized in that formulations containing R,R- glycopyrrolate and carmoterol can be combined in same dosage form.
13. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to Claims 5 to 9 and 1 1 characterized in that formulations containing R,R- glycopyrrolate and carmoterol are found in different dosage forms.
14. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to Claims 1 to 13 characterized in that it can be prepared in any one of dosage forms, including but not limited to tablet, effervescent tablet, effervescent granule, effervescent dry power, film coated tablet, enteric coated tablet, dry powder, granule, capsule, extended release tablet, modified release tablet, delayed release tablet, orodispersible tablet, chewing tablet, inhalation solution, aerosol or dry powder for inhalation or any combinations thereof.
15. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to any previous Claims characterized in that it contains at least one pharmaceutically acceptable excipient in addition to R,R-glycopyrrolate and carmoterol.
16. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to any previous Claims characterized in that it can also contain at least one excipient which is selected from a group comprising of dispersant, diluent, lubricant, glidant, binder, effervescent pair comprising of at least one acidic agent and at least one basic agent, coloring agent, pH regulating agent, surfactant, sweetener and/or flavoring agent and aroma agent.
17. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to Claim 16 characterized in that it provides a dry powder formulation which is comprised of only large-sized excipients or only small-sized excipients or both large- and small-sized excipients, such that the formulation has two different average particle sizes.
18. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to Claim 17 characterized in that if small- and large-particulate excipients are simultaneously contained, ratio of small-sized excipient particles to large-sized excipient particles is between 1 : 1 and 1 :30 by weight.
19. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to Claim 17 characterized in that if small- and large-particulate excipients are simultaneously contained, ratio of small-sized excipient particles to large-sized excipient particles is between 1 : 1 and 1 : 15 by weight.
20. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to Claim 17 characterized in that if small- and large-particulate excipients are simultaneously contained, ratio of small-sized excipient particles to large-sized excipient particles is between 1 :1 and 1 :8 by weight.
21. A pharmaceutical composition, containing combination of R,R-g]ycopyrrolate and carmoterol or formoterol, according to Claim 17 characterized in that if composition is formulated to enable administration via inhalation, aerodynamic particle diameter of active substances, contained in said formulation, is ranging from 0.05 to 25 μπι.
22. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to Claim 17 characterized in that if composition is formulated to enable administration via inhalation, aerodynamic particle diameter of active substances, contained in said formulation, is ranging from 0.1 to 20 μιη.
23. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to Claim 17 characterized in that if composition is formulated to enable administration via inhalation, aerodynamic particle diameter of active substances, contained in said formulation, is ranging from 0.5 to 10 μηι.
24. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to any previous Claims characterized in that R,R-glycopyrrolate is found at amount of 0.1 % to 99% by weight.
25. A pharmaceutical composition, containing combination of R,R-glycopyrroiate and carmoterol or formoterol, according to any previous Claims characterized in that R,R-glycopyrrolate is found at amount of 1 % to 98% by weight.
26. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to any previous Claims characterized in that R,R-glycopyrrolate is found at amount of 5 % to 95% by weight.
27. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to any previous Claims characterized in that carmoterol or formoterol is found at amount of 0.1 % to 99% by weight.
28. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to any previous Claims characterized in that carmoterol or formoterol is found at amount of 1 % to 98% by weight.
29. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to any previous Claims characterized in that carmoterol or formoterol is found at amount of 5 % to 95% by weight.
30. A pharmaceutical composition, containing combination of glycopyrrolate and β2 agonist, according to any previous Claims characterized in that it contains carmoterol or formoterol at an amount ranging from 1 μg to 100 μg.
31. A pharmaceutical composition, containing combination of glycopyrrolate and β2 agonist, according to any previous Claims characterized in that it contains carmoterol or formoterol at an amount ranging from 1.5 μg to 50 μg.
32. A pharmaceutical composition, containing combination of glycopyrrolate and β2 agonist, according to any previous Claims characterized in that it contains carmoterol or formoterol at an amount ranging from 2 μg to 30 μg.
33. A pharmaceutical composition, containing combination of glycopyrrolate and β2 agonist, according to any previous Claims characterized in that it contains glycopyrrolate at an amount ranging from 0,01 mg to 10 mg.
34. A pharmaceutical composition, containing combination of glycopyrrolate and β2 agonist, according to any previous Claims characterized in that it contains glycopyrrolate at an amount ranging from 0,02 mg to 5 mg .
35. A pharmaceutical composition, containing combination of glycopyrrolate and β2 agonist, according to any previous Claims characterized in that it contains glycopyrrolate at an amount ranging from 0,1 mg to 3 mg.
36. A pharmaceutical composition, containing combination of R,R-glycopyrrolate and carmoterol or formoterol, according to Claims 5 and 35 characterized in that it is in the form of solution, aerosol or dry powder for inhalation.
37. A pharmaceutical composition, containing combination of glycopyrrolate and β2 agonist, preferably carmoterol or formoterol, according to any previous Claims characterized in that it contains at least one third active substance selected among antacid, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, anti-diarrheal, anti-obesity, anti-thrombotic, antifinrinolytic, anti-anemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, anti-acne, anti-bacterial, antimicotic, antiviral, antineoplastic, anti-arrhythmic, anti- adrenergic, anti-epileptic, anti-parkinson, antiprotozoal, antihelminthic, antiinflammatory, diurective, laxative, sulphonamide, imidazol, corticosteroid, tiozolydyndion, biguanide, immuno- stimulant, immunosuppressive, muscle relaxant, analgesic, psychoepileptic, psychoanaleptic, peripheral vasodilator, beta blocker, calcium channel blocker and lipid mofidiers, alpha glucosidase inhibitors, aldose reductase inhibitors, ACE inhibitors, multivitamin and minerals, Vitamin A, Vitamin D and analogues, Vitamin Bl, Vitamin C, Vitamin E, Vitamin B6, Vitamin B2, Vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride and selenium.
38. A pharmaceutical composition, containing combination of glycopyrrolate and β2 agonist, preferably carmoterol or formoterol, according to any previous Claims characterized in that it is used for manufacturing a drug which will be used in treatment of asthma and chronic obstructive pulmonary disease (COPD).
39. A pharmaceutical composition containing active agent R,R-glycopyrrolate and a agonist, preferably carmoterol or formoterol, in same or different dosage forms which are used sequentially, concurrently and simultaneously.
40. Pharmaceutical composition containing combinationg of active agent carmoterol between 2 μg and 30 μg and R,R glycopyrrolate bromide between 0.01 mg and 10 mg.
PCT/TR2013/000314 2012-11-16 2013-10-11 Combinations including abeta2 agonist and glycopyrrolate Ceased WO2014077787A1 (en)

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TR201213249 2012-11-16

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2956062A (en) 1959-02-26 1960-10-11 Robins Co Inc A H Esters of amino alcohols
WO2005107872A2 (en) * 2004-05-10 2005-11-17 Sosei R&D Ltd. Treating respiratory diseases with gycopyrrolate and analogues
WO2005107873A2 (en) * 2004-05-10 2005-11-17 Sosei R&D Ltd. Glycopyrrolate for treating childhood asthma

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2956062A (en) 1959-02-26 1960-10-11 Robins Co Inc A H Esters of amino alcohols
WO2005107872A2 (en) * 2004-05-10 2005-11-17 Sosei R&D Ltd. Treating respiratory diseases with gycopyrrolate and analogues
WO2005107873A2 (en) * 2004-05-10 2005-11-17 Sosei R&D Ltd. Glycopyrrolate for treating childhood asthma

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CYDULKA ET AL: "Effects of Combined Treatment With Glycopyrrolate and Albuterol in Acute Exacerbation of Asthma", ANNALS OF EMERGENCY MEDICINE, LANSING, MI, US, vol. 23, no. 2, 1 February 1994 (1994-02-01), pages 270 - 274, XP022471166, ISSN: 0196-0644, DOI: 10.1016/S0196-0644(94)70039-7 *

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