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WO2014062143A2 - Anticholinergic agent combinations - Google Patents

Anticholinergic agent combinations Download PDF

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Publication number
WO2014062143A2
WO2014062143A2 PCT/TR2013/000313 TR2013000313W WO2014062143A2 WO 2014062143 A2 WO2014062143 A2 WO 2014062143A2 TR 2013000313 W TR2013000313 W TR 2013000313W WO 2014062143 A2 WO2014062143 A2 WO 2014062143A2
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Prior art keywords
glycopyrrolate
pharmaceutical composition
tiotropium bromide
composition
tiotropium
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PCT/TR2013/000313
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French (fr)
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WO2014062143A3 (en
Inventor
Mahmut Bilgic
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Individual
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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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

  • the present invention relates to combinations consisting of glycopyrrolate and an anticholinergic agent, use of these combinations in treatment of asthma and chronic obstructive pulmonary disease (COPD) and pharmaceutical compositions comprising the same.
  • COPD chronic obstructive pulmonary disease
  • glycopyrrolate is 3-(alpha-cyclopentylmendeloi]oxy)-l, l- dimethylpyrrolidinium and it is first described in the application no US 2956062.
  • Present document describes the glycopyrrolate as an antagonist of acetylcholine and its effectiveness in inhibition of gastrointestinal motility.
  • Glycopyrrolate is available in 0.2 mg/mL injection, 1 mg/5 mL oral solution and 1, 1.5 and 2 mg oral tablet forms.
  • the pharmaceutical composition using glycopyrrolate and an anticholinergic agent in combination or simultaneously shows higher therapeutic benefit compared to compositions using these two agents individually.
  • glycopyrrolate and an anticholinergic agent ensures the achievement of therapeutic effect in a short time and a higher efficacy compared to use of these two active ingredients individually.
  • the patients may be provided with a more efficient therapy.
  • all of these positive effects are observed in combinations where each of the active ingredients are given sequentially as well as in cases where both active ingredients are administered concurrently in a dosage form or given simultaneously in dosage forms independent of each other. High therapeutic benefit may also be observed as longer duration of effect.
  • the present invention relates to pharmaceutical compositions comprising glycopyrrolate and an anticholinergic agent for sequential use in individual dosage forms, simultaneous use in individual dosage forms and simultaneous use in same dosage form.
  • the present invention provides a method to treat asthma and chronic obstructive pulmonary disease (COPD) by administration of effective amounts of glycopyrrolate and an anticholinergic agent.
  • COPD chronic obstructive pulmonary disease
  • the present invention relates to pharmaceutical compositions containing pharmaceutically effective amounts of glycopyrrolate and an anticholinergic agent and at least one pharmaceutically acceptable substance.
  • Glycopyrrolate and an anticholinergic agent may be used together in a single formulation with at least one pharmaceutically acceptable excipient in said pharmaceutical compositions or glycopyrrolate and an anticholinergic agent may be individually formulated with at least one pharmaceutically acceptable excipient.
  • Resulting different formulations may be combined within a single dosage form or prepared in individual dosage forms. In case the formulations are available in individual dosage forms, said dosage forms may be identical with or different from each other.
  • the present invention also relates to the use of glycopyrrolate and an anticholinergic agent of the invention to prepare a medicine to be used in combination treatment by simultaneous, sequential or individual administration in treatment of asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • glycopyrrolate contained in the pharmaceutical compositions of the present invention may be in the forms hydrates, solvates, esters, enantiomers, diastereomers and/or any of the polymorphic forms such as amorphous or crystalline forms or in the form of combination of these.
  • glycopyrrolate is in the form of R,R-glycopyrrolate.
  • Anticholinergic agent that may be used in present invention may be selected from benztropine, ipratropium, tiotropium, tolterodine, oxitropium, oxibutinine.
  • Anticholinergic agent that may be used in present invention is preferably ipratropium and tiotropium, and most preferably tiotropium.
  • the pharmaceutically acceptable salts of tiotropium contained in the pharmaceutical compositions of present invention may be in the forms of hydrates, solvates, esters, enantiomers, diastereomers and/or any of the polymorphic forms such as amorphous or crystalline forms or in the form of combination of these.
  • tiotropium is in the form of tiotropium bromide salt.
  • compositions containing R,R-glycopyrrolate and tiotropium bromide of present invention may be prepared in any of the dosage forms of tablet, effervescent tablet, effervescent granule, effervescent dry powder, film-coated tablet, enteric coated tablet, dry powder, granule, capsule, extended-release tablet, modified-release tablet, delayed-release tablet, orodispersible tablet, chewable tablet, inhalation solution, aerosol or dry powder for inhalation.
  • compositions containing R,R-glycopyrrolate and tiotropium bromide may be available in combination in any of these dosage forms or in case the R,R-glycopyrrolate and tiotropium bromide are stored in individual dosage forms, said formulations may be in any of these dosage forms.
  • compositions containing combination of the present invention may be in any of the above-mentioned dosage forms or in the form of combination of these dosage forms in individual packages or in the form of therapy package comprising this combination.
  • compositions containing R,R-glycopyrrolate and tiotropium bromide of the present invention may contain at least one excipient in addition to active ingredients R,R-glycopyrrolate and tiotropium bromide.
  • compositions containing R,R-glycopyrrolate and tiotropium bromide of the present invention contain at least one excipient selected from the group of disintegrant, diluent, lubricant, oiler, binding agent, effervescent pair composed of at least one acidic agent and at least one basic agent, colorant, pH adjusting agent, surfactant, stabilizer, sweetener and/or flavor regulator, and flavoring agent.
  • physiologically harmless excipients that may be contained in the inhalation formulations may be selected from the group of monosaccharides (glucose, arabinose etc.), disaccharides (lactose, saccharose, maltose etc.), oligo- and polysaccharides (dextran etc.), polyalcohols (sorbitol, mannitol, xylitol), salts (sodium chloride, calcium carbonate etc.) or mixtures of these excipients. , .
  • small and large sized excipient proportions may be composed of identical or different chemical substances.
  • all excipient proportions are preferably composed of identical chemical substances in inhalation formulations.
  • the present invention provides a dry powder formulation containing large sized excipients or small sized excipients only or a mixture composed of both large sized and small sized excipients with two different mean particle sizes.
  • active ingredients and small sized excipients in the formulation are carried out during inhalation by adsorbed onto active sites of large sized excipients.
  • Large particles of excipients are also trapped in the upper respiratory tract of the patient.
  • Active ingredients carried out by the large particles of excipients during inhalation are easily separated from the active sites of large particles of excipients by means of small particles of excipients adsorbed on the same active site and reach the lungs with the respiration of patient. Therefore, small particles of excipients inhibit the active ingredient from trapping in the upper respiratory tract and entering into systemic circulation without reaching to lungs. Consequently, availability of excipient in two different particle sizes in dry powder formulation of the present invention ensures an advantage in the therapy.
  • the inventors determined that both the particle sizes and amounts of active ingredient and excipients in the formulation have influence on the good flow properties of dry powder inhalation formulations. It has been observed that the formulation is homogenously mixed and thus, a formulation with good flow properties can be obtained when weight ratio of small particles of excipient to large particles of excipient in the mixture containing excipient with two different particle sizes is 1 : 1 to 1 :30, preferably 1 : 1 to 1 : 15, and most preferably 1 : 1 to 1 :8.
  • weight ratio of small particles of excipient to large particles of excipient in the mixture containing excipient with two different particle sizes used in the dry powder formulations is 1 : 1 to 1 :30, preferably 1 : 1 to 1 : 15, and most preferably 1 : 1 to 1 :8.
  • amount of active ingredient in the dry powder formulation ranges between 1 ⁇ g and 750 ⁇ g, in other words, 1 ⁇ g, 5 ⁇ g, 10 ⁇ g, 25 ⁇ g, 30 ⁇ g, 40 g, 50 ⁇ g or 75 ⁇ g and 100 ⁇ & 125 ⁇ & 150 ⁇ & 250 ⁇ ⁇ , 300 ⁇ & 350 ⁇ ⁇ , 375 ⁇ ⁇ , 400 ⁇ ⁇ , 425 ⁇ & 450 ⁇ & 475 ⁇ ⁇ , 500 ⁇ & 550 ⁇ g, 600 ⁇ g, 650 ⁇ g, 700 ⁇ g or 750 ⁇ g, preferably between 1 ⁇ g and 500 ⁇ g, in other words, 1 ⁇ g, 5 ⁇ g, 15 ⁇ g, 25 ⁇ g, 50 ⁇ g or 75 ⁇ g or 100 ⁇ g and 125 ⁇ & 150 ⁇ & 175 250 ⁇ 300 ⁇ g, 350 ⁇ g, 400 ⁇ g, 450 ⁇ g,
  • aerodynamic particle radius of active ingredients in the said formulation should range between 0.05 and 25 ⁇ , preferably between 0.1 and 20 ⁇ , and most preferably between 0.5 and 10 ⁇ .
  • Disintegrant to be used in pharmaceutical compositions of the present invention may be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
  • Diluent to be used in pharmaceutical compositions of the present invention may be selected from a group comprising calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talk, xylitol.
  • Lubricant to be used in pharmaceutical compositions of the present invention may be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulfate, talk, stearic acid, zinc stearate.
  • Oiler to be used in pharmaceutical compositions of the present invention may be selected from a group comprising calcium phosphate tribasic, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talk.
  • Binding agent to be used in pharmaceutical compositions of the present invention may be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, povidone, starch.
  • Acidic agent in the effervescent pair composed of at least one acidic agent and at least one basic agent to be used in pharmaceutical compositions of the present invention may be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid and basic agent may be selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
  • pH adjusting agent to be used in pharmaceutical compositions of the present invention may be selected from citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.
  • Surfactant to be used in pharmaceutical compositions of the present invention may be selected from the agents such as sodium lauryl sulfate, polysorbate, polyoxyethylene, polyoxypropylene glycol, oleic acid etc.
  • oleic acid is used in inhalation formulations.
  • Stabilizer to be used in pharmaceutical compositions of the present invention may be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.
  • Sweetener and/or flavor regulator to be used in pharmaceutical compositions of the present invention may be selected from a group comprising acesulfarne, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.
  • Flavoring agent to be used in pharmaceutical compositions of the present invention may be selected from flavors such as menthol, lemon, orange, vanilla, strawberry, raspberry, caramel etc.
  • compositions of the present invention may contain R,R-glycopyrrolate in proportions of 0.1 to 99%, preferably 1 to 98% and most preferably 5 to 95% by weight.
  • compositions of the present invention may contain tiotropium bromide in proportions of 0.1 to 99%, preferably 1 to 98% and most preferably 5 to 95% by weight.
  • compositions of the present invention may contain anticholinergic derivative agent, preferably tiotropium or a pharmaceutically acceptable salt, for example tiotropium bromide, in contents between 1 ⁇ g and 100 ⁇ g, preferably 3 ⁇ g and 50 ⁇ g and most preferably 5 ⁇ g and 30 ⁇ g.
  • anticholinergic derivative agent preferably tiotropium or a pharmaceutically acceptable salt, for example tiotropium bromide
  • compositions of the present invention may contain glycopyrrolate or a pharmaceutically acceptable salt, for example glycopyrrolate bromide, in contents between 0,01 mg and 10 mg, preferably 0,02 mg and 5 mg and most preferably 0, 1 mg and 3 mg.
  • Pharmaceutical compositions containing R,R-glycopyrrolate and tiotropium bromide of the present invention may optionally contain a third active ingredient in addition to R,R-glycopyrrolate and tiotropium bromide.
  • the third active ingredient may be selected from antacids, anticholinergics, antispasmodics, antiemetics, antibiotics, antipropulsives, antiallergics, antidiarrheals, antiobesity agents, antithrombotics, antifibrinolytics, antianemics, antihypertensives, antifungals, antipruritics, antipsoriatics, antiseptics, antiacne-bacterials, antimycotics, antivirals, antineoplastics, antiarrhythmics, antiadrenergics, antiepileptics, anti-parkinson agents, antiprotozoals, anthelmintics, anti-inflammatories, diuretics, laxatives, sulfonamide, imidazol, corticosteroids, thiazolidinediones, biguanides, immunostimulants, immunosuppressants, muscle relaxants, analgesics, psycholeptics, psychoanaleptic peripheral
  • compositions of the present invention contain R,R-glycopyrrolate bromide.
  • compositions of the present invention may be obtained by • homogeneously mixing the active ingredients R,R-glycopyrrolate and tiotropium bromide and adding at least one of the above excipients if necessary; or
  • Resulting pharmaceutical composition(s) may be prepared in any of the dosage forms mentioned above.
  • obtained tablets may 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 coating compositions containing any combination of these.
  • film-coating agents for example sugar- based coating agents, water soluble film-coating agents, enteric coating agents, delayed-release coating agents or coating compositions containing any combination of these.
  • saccharose may be used alone or optionally together with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan or with any combination of these.
  • agents such as talc, calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan or with any combination of these.
  • Water soluble film-coating agent may be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose, synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan or combination of these.
  • cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose
  • synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan or combination of these.
  • Enteric coating agent may be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or combination of these.
  • Delayed-release coating agents may be selected from cellulose derivatives such as ethyl cellulose, acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl acrylate copolymer emulsion or combination of these.
  • a dosage form containing both active ingredients or a dosage form individually containing active ingredients or a dosage form containing only one of the active ingredients may be administered via inhalation.
  • the formulation contained in said dosage form may be prepared in any of the dosage forms of inhalation solution, aerosol or dry powder for inhalation, as described above. Any of the following methods may be used for preparation of said formulations;
  • spheroidizing process is applied to at least 10% of micronized excipient by weight
  • -obtained formulation is filled into capsules, blisters or reservoirs.
  • Anticholinergic agent and glycopyrrolate or a pharmaceutically acceptable salt and fine-grained excipient portion are passed through a sieve of appropriate mesh size, preferably through a layered sieve for at least one time and then, placed and mixed in a mixing container and Premix A is obtained.
  • coarse-grained excipient portion and Premix A are preferably passed through a sieve of appropriate mesh size separately or most preferably through a layered sieve for at least one time and mixed in another mixing container and Premix B is obtained.
  • Premix B is preferably passed through a sieve of appropriate mesh size or most preferably through a layered sieve for at least one time and then, feed into a mixing container containing coarser-grained excipient portion passed through a sieve of appropriate mesh size or most preferably through a layered sieve for at least one time and dry powder formulation is obtained.
  • the pharmaceutical composition of the present invention can be inhaled through single dose or multi- dose dry powder inhalers. Accordingly, pharmaceutical composition of the present invention is inhaled through reservoir, capsule or blister containing it.
  • dry powder formulation of the present invention is inhaled through capsule, which is one of the inhalation methods; the inventors have determined that the most efficient inhalation is achieved when volume of the capsule containing drug as dry powder is between 0.1 and 0.6 ml, preferably between 0.2 and 0.45 ml and most preferably between 0.25 and 0.4 ml.
  • the present invention is characterized by a volume of 0.1 to 0.6 ml, preferably 0.2 to 0.45 ml and most preferably 0.25 to 0.4 ml for capsule used for storage and delivery of drug in dry powder form.
  • inventors have determined that active composition in the capsule is protected from external factors as well as possibility of moisten due to own nature of capsule is excluded when humidity ratio of packaging in the form of capsule with the capability of high protection against humidity and other negative external factors is between 5-15%, and preferably 8-13%.
  • humidity ratio of packaging in the form of capsule with the capability of high protection against humidity and other negative external factors is between 5-15%, and preferably 8-13%.
  • the present invention is characterized by a humidity ratio of 5 to 15% and, preferably 8 to 13% for packaging in the form of capsule used for storage and delivery of drug in dry powder form.
  • the capsule preferred for use in the present formulation is produced from a substance selected from the group of gelatin, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers and composed of engaging top and bottom parts.
  • the capsule material may be selected from the group comprising hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxy ethyl cellulose if capsule to be used is of cellulose or cellulose derivatives.
  • the capsule material may be selected from the group comprising polyethylene, polyester, polyethylene terephthalate, polycarbonate or polypropylene if capsule to be used is of synthetic polymer.
  • dry powder formulation of the present invention is inhaled through capsule; polyethylene glycol, sorbitol, glycerol, propylene glycol, polyethylene oxide - polypropylene oxide block copolymers and/or other polyalcohols and polyethers with different molecular weights may be added as additional substances if capsule material to be used is gelatin.
  • the inventors have determined that the effective inhalation of drug is ensured when fill rate of cavity of capsule used is between 0.05 and 25%, preferably between 0.1 and 20% ml and most preferably between 0.5 and 15%.
  • the present invention is characterized by a fill rate of cavity of 0.05 to 25%, preferably 0.1 to 20% ml and most preferably 0.5 to 15% for capsule to be used.
  • dry powder formulation of the present invention is inhaled through blister, which is one of the inhalation methods; the inventors have determined that the efficient inhalation is achieved when cavity volume is between 18 and 30 mm 3 , preferably between 20 and 25 mm 3 and most preferably between 21 and 24 mm 3 for blister containing drug as dry powder of the present invention.
  • the present invention is characterized by a cavity volume of 18 to 30 mm 3 , preferably 20 to 25 mm 3 and most preferably 21 to 24 mm 3 for blister used for storage and delivery of drug in dry powder form.
  • the fill rate of cavity of blister used should be 15-95%, preferably 20- 85% and most preferably 50-80% to achieve an efficient and smooth inhalation from blister for formulation of the present invention.
  • the present invention is characterized by a fill rate of 15 to 95%, preferably 20 to 85%) and most preferably 50 to 80% for the blister used for storage and delivery of drug in dry powder form.
  • top and bottom layer composing the removable strip blister packaging where blisters containing the dry powder formulation of the present invention are aligned adjacently to each other, are tightly closed, by any suitable method to ensure tightness.
  • Top and bottom layers composing the removable strip blister packaging which contains the dry powder formulation of the present invention, consist of multiple layers.
  • Sheets of the bottom and top layers include polymeric sheets, aluminum foil and preferably Aclar® fluoropolymer film.
  • the inventor have found that in case the formulation of the present invention is inhaled through blister; addition of desiccant to polymeric sheets to reduce the humidity and gas permeability of bottom and top layers composing the blister packaging is effective in protecting the stability of said dry powder formulation.
  • the desiccants added to the sheets composing the strip blister packaging, which contains the dry powder formulation of the present invention are selected from the group comprising silica gel, zeolite, alumina, bauxite, anhydrous calcium sulfate, activated carbon, water-absorbing clays.
  • the polymeric sheets in the top and bottom layers of removable strip blister packaging which contains the said dry powder formulation, are composed of identical or different polymers. Thickness of these polymeric sheets varies based on the type and characteristics of polymeric substance used. Thus, thickness of the polymeric sheet ranges between 15 and 55 ⁇ , and preferably between 20 and 30 ⁇ based on the type of polymeric substance used.
  • polymeric sheet In the event that sheet in contact with dry powder formulation in blister cavity is selected as aluminum foil, some of the dry powder formulation will adhere to inner surface of blister cavity and lead to uncontrolled dose inhalation due to porous structure of aluminum foil and electrostatic forces, and thus, the sheet covering the inner surface of cavity is polymeric sheet.
  • Polymers composing the polymeric sheet may be preferably selected from thermoplastic polymers such as polyethylene, polypropylene, polystyrene, polyolephine, polyamide, polyvinylchloride, polyurethane or from the synthetic polymers.
  • Dry powder formulation of the present invention may be used in treatment of several respiratory diseases including particularly asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD). Accordingly, it is used in the treatment of respiratory diseases including but not limited to all levels of asthma, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airway hyperactivity, bronchiectasis, chronic obstructive pulmonary disease including emphysema and chronic bronchitis, respiratory or pulmonary disease (COPD, COAD or COLD), pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis. Treatment may be prophylactic or symptomatic. However, dry powder formulation of the present invention is primarily used in treatment of asthma and COPD.
  • a total of 25.6 mg of dry powder formulation prepared to store in a blister contains 0.018 mg of tiotropium bromide and R,R-glycopyrrolate active ingredients with an aerodynamic particle radius of 2 ⁇ and 13.98 mg of large sized lactose anhydride as carrier.
  • the active ingredient combination is mixed with the small sized lactose.
  • resulting mixture is mixed with the large sized lactose and the final mixture is added to and mixed in a mixing vessel containing coarser-grained lactose and thus, the final mixture is obtained.
  • Resulting dry powder formulations are filled into blisters.
  • a total of 22, 149 mg of dry powder formulation prepared to store in a blister contains 0.009 mg of tiotropium bromide and R,R-glycopyrrolate active ingredients with an aerodynamic particle radius of 2 ⁇ and 12.95 mg of large sized lactose anhydride as carrier.
  • the active ingredient combination is mixed with the small sized lactose.
  • resulting mixture is mixed with the large sized lactose and the final mixture is added to and mixed in a mixing vessel containing coarser-grained lactose and thus, the final mixture is obtained.
  • Resulting dry powder formulations are filled into capsules.
  • oleic acid is added to the container and resulting solution is mixed at approximately 250 rpm for 1 minute.
  • Formulation container and the contents are cooled to 2-6°C and mixer speed is reduced to 100 rpm.
  • micronized active ingredients are added to the mixture, mixing speed is increased to 250 rpm and homogenization process is performed for 10 minutes.
  • remaining quantity of anhydrous ethanol is added to the mixture and mixing is continued at 250 rpm for 10 minutes.
  • Final mixture is cooled to 2-6°C and this temperature is maintained throughout the filling process.
  • Mixture is filled into aluminum containers and closed with a valve. Then, FIFA 134a gas is filled into the aluminum container through this valve.

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Abstract

The present invention relates to pharmaceutical compositions comprising glycopyrrolate and an anticholinergic agent for use in treatment of asthma and chronic obstructive pulmonary disease (COPD). "i

Description

ANTICHOLINERGIC AGENT COMBINATIONS
The present invention relates to combinations consisting of glycopyrrolate and an anticholinergic agent, use of these combinations in treatment of asthma and chronic obstructive pulmonary disease (COPD) and pharmaceutical compositions comprising the same.
The chemical name of glycopyrrolate is 3-(alpha-cyclopentylmendeloi]oxy)-l, l- dimethylpyrrolidinium and it is first described in the application no US 2956062. Present document describes the glycopyrrolate as an antagonist of acetylcholine and its effectiveness in inhibition of gastrointestinal motility.
Figure imgf000002_0001
Formula I. Glycopyrrolate
Glycopyrrolate is available in 0.2 mg/mL injection, 1 mg/5 mL oral solution and 1, 1.5 and 2 mg oral tablet forms.
It has been surprisingly determined that an unexpected therapeutic benefit, especially a synergistic therapeutic benefit, may be obtained with the combination therapy using glycopyrrolate and anticholinergics in treatment of asthma and chronic obstructive pulmonary disease (COPD). This therapeutic benefit may be defined as
• a reduction in dosages required for necessary therapeutic effect in case of use of these combinations compared to those required in treatment with glycopyrrolate alone or anticholinergics alone; and/or
• a reduction in undesirable side effects and/or
• achievement of therapeutic effect after a shorter time and/or
• observation of therapeutic effect for a longer time and/or
• achievement of a more efficient therapy In another embodiment, the pharmaceutical composition using glycopyrrolate and an anticholinergic agent in combination or simultaneously shows higher therapeutic benefit compared to compositions using these two agents individually.
In another embodiment, combined use of glycopyrrolate and an anticholinergic agent ensures the achievement of therapeutic effect in a short time and a higher efficacy compared to use of these two active ingredients individually. Thus, the patients may be provided with a more efficient therapy. Surprisingly, all of these positive effects are observed in combinations where each of the active ingredients are given sequentially as well as in cases where both active ingredients are administered concurrently in a dosage form or given simultaneously in dosage forms independent of each other. High therapeutic benefit may also be observed as longer duration of effect.
Accordingly, the present invention relates to pharmaceutical compositions comprising glycopyrrolate and an anticholinergic agent for sequential use in individual dosage forms, simultaneous use in individual dosage forms and simultaneous use in same dosage form.
In another embodiment, the present invention provides a method to treat asthma and chronic obstructive pulmonary disease (COPD) by administration of effective amounts of glycopyrrolate and an anticholinergic agent.
In one embodiment, the present invention relates to pharmaceutical compositions containing pharmaceutically effective amounts of glycopyrrolate and an anticholinergic agent and at least one pharmaceutically acceptable substance. Glycopyrrolate and an anticholinergic agent may be used together in a single formulation with at least one pharmaceutically acceptable excipient in said pharmaceutical compositions or glycopyrrolate and an anticholinergic agent may be individually formulated with at least one pharmaceutically acceptable excipient. Resulting different formulations may be combined within a single dosage form or prepared in individual dosage forms. In case the formulations are available in individual dosage forms, said dosage forms may be identical with or different from each other.
The present invention also relates to the use of glycopyrrolate and an anticholinergic agent of the invention to prepare a medicine to be used in combination treatment by simultaneous, sequential or individual administration in treatment of asthma and chronic obstructive pulmonary disease (COPD).
Pharmaceutically acceptable salts of glycopyrrolate contained in the pharmaceutical compositions of the present invention may be in the forms hydrates, solvates, esters, enantiomers, diastereomers and/or any of the polymorphic forms such as amorphous or crystalline forms or in the form of combination of these. Preferably, glycopyrrolate is in the form of R,R-glycopyrrolate. Anticholinergic agent that may be used in present invention may be selected from benztropine, ipratropium, tiotropium, tolterodine, oxitropium, oxibutinine.
Anticholinergic agent that may be used in present invention is preferably ipratropium and tiotropium, and most preferably tiotropium.
The pharmaceutically acceptable salts of tiotropium contained in the pharmaceutical compositions of present invention may be in the forms of hydrates, solvates, esters, enantiomers, diastereomers and/or any of the polymorphic forms such as amorphous or crystalline forms or in the form of combination of these.
Preferably, tiotropium is in the form of tiotropium bromide salt.
Pharmaceutical compositions containing R,R-glycopyrrolate and tiotropium bromide of present invention may be prepared in any of the dosage forms of tablet, effervescent tablet, effervescent granule, effervescent dry powder, film-coated tablet, enteric coated tablet, dry powder, granule, capsule, extended-release tablet, modified-release tablet, delayed-release tablet, orodispersible tablet, chewable tablet, inhalation solution, aerosol or dry powder for inhalation. Pharmaceutical compositions containing R,R-glycopyrrolate and tiotropium bromide may be available in combination in any of these dosage forms or in case the R,R-glycopyrrolate and tiotropium bromide are stored in individual dosage forms, said formulations may be in any of these dosage forms. In other words, compositions containing combination of the present invention may be in any of the above-mentioned dosage forms or in the form of combination of these dosage forms in individual packages or in the form of therapy package comprising this combination.
Pharmaceutical compositions containing R,R-glycopyrrolate and tiotropium bromide of the present invention may contain at least one excipient in addition to active ingredients R,R-glycopyrrolate and tiotropium bromide.
In addition to active ingredients, the pharmaceutical compositions containing R,R-glycopyrrolate and tiotropium bromide of the present invention contain at least one excipient selected from the group of disintegrant, diluent, lubricant, oiler, binding agent, effervescent pair composed of at least one acidic agent and at least one basic agent, colorant, pH adjusting agent, surfactant, stabilizer, sweetener and/or flavor regulator, and flavoring agent.
According to invention, physiologically harmless excipients that may be contained in the inhalation formulations may be selected from the group of monosaccharides (glucose, arabinose etc.), disaccharides (lactose, saccharose, maltose etc.), oligo- and polysaccharides (dextran etc.), polyalcohols (sorbitol, mannitol, xylitol), salts (sodium chloride, calcium carbonate etc.) or mixtures of these excipients. , . According to invention, small and large sized excipient proportions may be composed of identical or different chemical substances. According to invention, all excipient proportions are preferably composed of identical chemical substances in inhalation formulations.
In another embodiment, the present invention provides a dry powder formulation containing large sized excipients or small sized excipients only or a mixture composed of both large sized and small sized excipients with two different mean particle sizes. In case the particles of excipients are available in two fractions, active ingredients and small sized excipients in the formulation are carried out during inhalation by adsorbed onto active sites of large sized excipients. Large particles of excipients are also trapped in the upper respiratory tract of the patient. Active ingredients carried out by the large particles of excipients during inhalation are easily separated from the active sites of large particles of excipients by means of small particles of excipients adsorbed on the same active site and reach the lungs with the respiration of patient. Therefore, small particles of excipients inhibit the active ingredient from trapping in the upper respiratory tract and entering into systemic circulation without reaching to lungs. Consequently, availability of excipient in two different particle sizes in dry powder formulation of the present invention ensures an advantage in the therapy.
Large sized excipient mentioned in the text refers to excipient with particle size between 10 and 90 μιη and small sized excipient refers to excipient with mean particle size below 10 μπι.
In result of the studies conducted, the inventors determined that both the particle sizes and amounts of active ingredient and excipients in the formulation have influence on the good flow properties of dry powder inhalation formulations. It has been observed that the formulation is homogenously mixed and thus, a formulation with good flow properties can be obtained when weight ratio of small particles of excipient to large particles of excipient in the mixture containing excipient with two different particle sizes is 1 : 1 to 1 :30, preferably 1 : 1 to 1 : 15, and most preferably 1 : 1 to 1 :8.
In another embodiment of the present invention, weight ratio of small particles of excipient to large particles of excipient in the mixture containing excipient with two different particle sizes used in the dry powder formulations is 1 : 1 to 1 :30, preferably 1 : 1 to 1 : 15, and most preferably 1 : 1 to 1 :8.
According to present invention, amount of active ingredient in the dry powder formulation ranges between 1 μg and 750 μg, in other words, 1 μg, 5 μg, 10 μg, 25 μg, 30 μg, 40 g, 50 μg or 75 μg and 100 μ& 125 μ& 150 μ& 250 μδ, 300 μ& 350 μ§, 375 μβ, 400 μδ, 425 μ& 450 μ& 475 μβ, 500 μ& 550 μg, 600μg, 650 μg, 700 μg or 750 μg, preferably between 1 μg and 500 μg, in other words, 1 μg, 5 μg, 15 μg, 25 μg, 50 μg or 75 μg or 100 μg and 125 μ& 150 μ& 175 250 μ 300 μg, 350 μg, 400 μg, 450 μg, 475 μg or 500 μg and most preferably between 1 μg and 400 μg. In case the synergistic combination of the present invention is formulated to be given by inhalation, aerodynamic particle radius of active ingredients in the said formulation should range between 0.05 and 25 μιη, preferably between 0.1 and 20 μιη, and most preferably between 0.5 and 10 μηι.
Disintegrant to be used in pharmaceutical compositions of the present invention may be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
Diluent to be used in pharmaceutical compositions of the present invention may be selected from a group comprising calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talk, xylitol.
Lubricant to be used in pharmaceutical compositions of the present invention may be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulfate, talk, stearic acid, zinc stearate.
Oiler to be used in pharmaceutical compositions of the present invention may be selected from a group comprising calcium phosphate tribasic, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talk.
Binding agent to be used in pharmaceutical compositions of the present invention may be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, povidone, starch.
Acidic agent in the effervescent pair composed of at least one acidic agent and at least one basic agent to be used in pharmaceutical compositions of the present invention may be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid and basic agent may be selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate. pH adjusting agent to be used in pharmaceutical compositions of the present invention may be selected from citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.
Surfactant to be used in pharmaceutical compositions of the present invention may be selected from the agents such as sodium lauryl sulfate, polysorbate, polyoxyethylene, polyoxypropylene glycol, oleic acid etc. Preferably, oleic acid is used in inhalation formulations. Stabilizer to be used in pharmaceutical compositions of the present invention may be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.
Sweetener and/or flavor regulator to be used in pharmaceutical compositions of the present invention may be selected from a group comprising acesulfarne, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.
Flavoring agent to be used in pharmaceutical compositions of the present invention may be selected from flavors such as menthol, lemon, orange, vanilla, strawberry, raspberry, caramel etc.
Pharmaceutical compositions of the present invention may contain R,R-glycopyrrolate in proportions of 0.1 to 99%, preferably 1 to 98% and most preferably 5 to 95% by weight.
Pharmaceutical compositions of the present invention may contain tiotropium bromide in proportions of 0.1 to 99%, preferably 1 to 98% and most preferably 5 to 95% by weight.
Pharmaceutical compositions of the present invention may contain anticholinergic derivative agent, preferably tiotropium or a pharmaceutically acceptable salt, for example tiotropium bromide, in contents between 1 μg and 100 μg, preferably 3 μg and 50 μg and most preferably 5 μg and 30 μg.
Pharmaceutical compositions of the present invention may contain glycopyrrolate or a pharmaceutically acceptable salt, for example glycopyrrolate bromide, in contents between 0,01 mg and 10 mg, preferably 0,02 mg and 5 mg and most preferably 0, 1 mg and 3 mg. Pharmaceutical compositions containing R,R-glycopyrrolate and tiotropium bromide of the present invention may optionally contain a third active ingredient in addition to R,R-glycopyrrolate and tiotropium bromide. The third active ingredient may be selected from antacids, anticholinergics, antispasmodics, antiemetics, antibiotics, antipropulsives, antiallergics, antidiarrheals, antiobesity agents, antithrombotics, antifibrinolytics, antianemics, antihypertensives, antifungals, antipruritics, antipsoriatics, antiseptics, antiacne-bacterials, antimycotics, antivirals, antineoplastics, antiarrhythmics, antiadrenergics, antiepileptics, anti-parkinson agents, antiprotozoals, anthelmintics, anti-inflammatories, diuretics, laxatives, sulfonamide, imidazol, corticosteroids, thiazolidinediones, biguanides, immunostimulants, immunosuppressants, muscle relaxants, analgesics, psycholeptics, psychoanaleptic peripheral vasodilators, beta blockers, calcium channel blockers and lipid modifying agents; alpha-glucosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and analogs, vitamin Bls vitamin C, vitamin E, vitamin B6, vitamin B2, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.
Preferably, pharmaceutical compositions of the present invention contain R,R-glycopyrrolate bromide.
Pharmaceutical compositions of the present invention may be obtained by • homogeneously mixing the active ingredients R,R-glycopyrrolate and tiotropium bromide and adding at least one of the above excipients if necessary; or
• granulating the active ingredients R,R-gIycopyrrolate and tiotropium bromide with a granulation solution containing at least one of the excipients and then, homogeneously mixing the same with other excipients; or
• granulating the mixture of active ingredients R,R-glycopyrrolate and tiotropium bromide containing at least one of the above excipients with a granulation solution and then, homogeneously mixing the same with other excipients; or
• mixing the active ingredients R,R-glycopyrrolate and tiotropium bromide with at least one of the above excipients and granulating the same with a granulation solution containing at least one excipient; or
• in case the R,R-glycopyrrolate and tiotropium bromide are prepared in two individual formulations, using any of the above-mentioned methods separately for active ingredient compositions and incorporating formulations obtained or storing the said formulations in different dosage forms.
Resulting pharmaceutical composition(s) may be prepared in any of the dosage forms mentioned above. For tablet form, obtained tablets may 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 coating compositions containing any combination of these.
As sugar-based coating agent, saccharose may be used alone or optionally together with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan or with any combination of these.
Water soluble film-coating agent may be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose, synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan or combination of these.
Enteric coating agent may be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or combination of these. Delayed-release coating agents may be selected from cellulose derivatives such as ethyl cellulose, acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl acrylate copolymer emulsion or combination of these.
In case the combination of the present invention is used sequentially or simultaneously in different or identical dosage forms, a dosage form containing both active ingredients or a dosage form individually containing active ingredients or a dosage form containing only one of the active ingredients may be administered via inhalation. The formulation contained in said dosage form may be prepared in any of the dosage forms of inhalation solution, aerosol or dry powder for inhalation, as described above. Any of the following methods may be used for preparation of said formulations;
Method 1 :
- active ingredient(s), small sized excipient and/or large sized excipient are micronized separately,
-optionally, spheroidizing process is applied to at least 10% of micronized excipient by weight,
-micronized active ingredient(s), excipient(s) and if any, particles of excipients subjected to spheroidizing process are mixed,
-final dry powder formulation is obtained,
-obtained formulation is filled into capsules, blisters or reservoirs.
Method 2:
Anticholinergic agent and glycopyrrolate or a pharmaceutically acceptable salt and fine-grained excipient portion are passed through a sieve of appropriate mesh size, preferably through a layered sieve for at least one time and then, placed and mixed in a mixing container and Premix A is obtained.
Then, coarse-grained excipient portion and Premix A are preferably passed through a sieve of appropriate mesh size separately or most preferably through a layered sieve for at least one time and mixed in another mixing container and Premix B is obtained.
Finally, Premix B is preferably passed through a sieve of appropriate mesh size or most preferably through a layered sieve for at least one time and then, feed into a mixing container containing coarser-grained excipient portion passed through a sieve of appropriate mesh size or most preferably through a layered sieve for at least one time and dry powder formulation is obtained.
The pharmaceutical composition of the present invention can be inhaled through single dose or multi- dose dry powder inhalers. Accordingly, pharmaceutical composition of the present invention is inhaled through reservoir, capsule or blister containing it. In the event that dry powder formulation of the present invention is inhaled through capsule, which is one of the inhalation methods; the inventors have determined that the most efficient inhalation is achieved when volume of the capsule containing drug as dry powder is between 0.1 and 0.6 ml, preferably between 0.2 and 0.45 ml and most preferably between 0.25 and 0.4 ml.
Accordingly, in the event that dry powder formulation of the present invention is inhaled through capsule; the present invention is characterized by a volume of 0.1 to 0.6 ml, preferably 0.2 to 0.45 ml and most preferably 0.25 to 0.4 ml for capsule used for storage and delivery of drug in dry powder form.
In another embodiment, inventors have determined that active composition in the capsule is protected from external factors as well as possibility of moisten due to own nature of capsule is excluded when humidity ratio of packaging in the form of capsule with the capability of high protection against humidity and other negative external factors is between 5-15%, and preferably 8-13%. Thus, agglomeration of dry powder formulation of the present invention is prevented and efficient delivery to the lungs of the patient is ensured.
Accordingly, in the event that dry powder formulation of the present invention is inhaled through capsule; the present invention is characterized by a humidity ratio of 5 to 15% and, preferably 8 to 13% for packaging in the form of capsule used for storage and delivery of drug in dry powder form.
In another embodiment, in the event that dry powder formulation of the present invention is inhaled through capsule; the capsule preferred for use in the present formulation is produced from a substance selected from the group of gelatin, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers and composed of engaging top and bottom parts.
Accordingly, in the event that dry powder formulation of the present invention is inhaled through capsule; the capsule material may be selected from the group comprising hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxy ethyl cellulose if capsule to be used is of cellulose or cellulose derivatives. In the event that dry powder formulation of the present invention is inhaled through capsule; the capsule material may be selected from the group comprising polyethylene, polyester, polyethylene terephthalate, polycarbonate or polypropylene if capsule to be used is of synthetic polymer.
In the event that dry powder formulation of the present invention is inhaled through capsule; polyethylene glycol, sorbitol, glycerol, propylene glycol, polyethylene oxide - polypropylene oxide block copolymers and/or other polyalcohols and polyethers with different molecular weights may be added as additional substances if capsule material to be used is gelatin. In another embodiment, in the event that said dry powder formulation is inhaled through capsule; the inventors have determined that the effective inhalation of drug is ensured when fill rate of cavity of capsule used is between 0.05 and 25%, preferably between 0.1 and 20% ml and most preferably between 0.5 and 15%.
Accordingly, in the event that said dry powder formulation is inhaled through capsule; the present invention is characterized by a fill rate of cavity of 0.05 to 25%, preferably 0.1 to 20% ml and most preferably 0.5 to 15% for capsule to be used.
In the event that dry powder formulation of the present invention is inhaled through blister, which is one of the inhalation methods; the inventors have determined that the efficient inhalation is achieved when cavity volume is between 18 and 30 mm3, preferably between 20 and 25 mm3 and most preferably between 21 and 24 mm3 for blister containing drug as dry powder of the present invention.
Accordingly, in the event that said dry powder formulation is inhaled through blister; the present invention is characterized by a cavity volume of 18 to 30 mm3, preferably 20 to 25 mm3 and most preferably 21 to 24 mm3 for blister used for storage and delivery of drug in dry powder form.
The inventors have determined that the fill rate of cavity of blister used should be 15-95%, preferably 20- 85% and most preferably 50-80% to achieve an efficient and smooth inhalation from blister for formulation of the present invention.
In the event that said dry powder formulation is inhaled through blister; the present invention is characterized by a fill rate of 15 to 95%, preferably 20 to 85%) and most preferably 50 to 80% for the blister used for storage and delivery of drug in dry powder form.
In the event that dry powder formulation of the present invention is inhaled through blister; top and bottom layer composing the removable strip blister packaging, where blisters containing the dry powder formulation of the present invention are aligned adjacently to each other, are tightly closed, by any suitable method to ensure tightness.
Top and bottom layers composing the removable strip blister packaging, which contains the dry powder formulation of the present invention, consist of multiple layers. Sheets of the bottom and top layers include polymeric sheets, aluminum foil and preferably Aclar® fluoropolymer film.
The inventor have found that in case the formulation of the present invention is inhaled through blister; addition of desiccant to polymeric sheets to reduce the humidity and gas permeability of bottom and top layers composing the blister packaging is effective in protecting the stability of said dry powder formulation. The desiccants added to the sheets composing the strip blister packaging, which contains the dry powder formulation of the present invention, are selected from the group comprising silica gel, zeolite, alumina, bauxite, anhydrous calcium sulfate, activated carbon, water-absorbing clays.
In the event that dry powder formulation of the present invention is inhaled through blister; the polymeric sheets in the top and bottom layers of removable strip blister packaging, which contains the said dry powder formulation, are composed of identical or different polymers. Thickness of these polymeric sheets varies based on the type and characteristics of polymeric substance used. Thus, thickness of the polymeric sheet ranges between 15 and 55 μιη, and preferably between 20 and 30 μηι based on the type of polymeric substance used.
In the event that sheet in contact with dry powder formulation in blister cavity is selected as aluminum foil, some of the dry powder formulation will adhere to inner surface of blister cavity and lead to uncontrolled dose inhalation due to porous structure of aluminum foil and electrostatic forces, and thus, the sheet covering the inner surface of cavity is polymeric sheet. Polymers composing the polymeric sheet may be preferably selected from thermoplastic polymers such as polyethylene, polypropylene, polystyrene, polyolephine, polyamide, polyvinylchloride, polyurethane or from the synthetic polymers.
Dry powder formulation of the present invention may be used in treatment of several respiratory diseases including particularly asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD). Accordingly, it is used in the treatment of respiratory diseases including but not limited to all levels of asthma, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airway hyperactivity, bronchiectasis, chronic obstructive pulmonary disease including emphysema and chronic bronchitis, respiratory or pulmonary disease (COPD, COAD or COLD), pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis. Treatment may be prophylactic or symptomatic. However, dry powder formulation of the present invention is primarily used in treatment of asthma and COPD.
The following examples are provided only for illustrative purposes for combinations of the present invention, but are not to be construed as limiting the scope of the present invention. EXAMPLE 1:
Figure imgf000013_0001
For use in an inhalation device; a total of 25.6 mg of dry powder formulation prepared to store in a blister contains 0.018 mg of tiotropium bromide and R,R-glycopyrrolate active ingredients with an aerodynamic particle radius of 2 μιη and 13.98 mg of large sized lactose anhydride as carrier. First, the active ingredient combination is mixed with the small sized lactose. Then, resulting mixture is mixed with the large sized lactose and the final mixture is added to and mixed in a mixing vessel containing coarser-grained lactose and thus, the final mixture is obtained. Resulting dry powder formulations are filled into blisters.
EXAMPLE 2:
Figure imgf000013_0002
For use in an inhalation device; a total of 22, 149 mg of dry powder formulation prepared to store in a blister contains 0.009 mg of tiotropium bromide and R,R-glycopyrrolate active ingredients with an aerodynamic particle radius of 2 μιη and 12.95 mg of large sized lactose anhydride as carrier. First, the active ingredient combination is mixed with the small sized lactose. Then, resulting mixture is mixed with the large sized lactose and the final mixture is added to and mixed in a mixing vessel containing coarser-grained lactose and thus, the final mixture is obtained. Resulting dry powder formulations are filled into capsules. EXAMPLE 3:
Figure imgf000014_0001
Some of the total amount of ethanol is transferred into a formulation container pre-filled with nitrogen, oleic acid is added to the container and resulting solution is mixed at approximately 250 rpm for 1 minute. Formulation container and the contents are cooled to 2-6°C and mixer speed is reduced to 100 rpm. Then, micronized active ingredients are added to the mixture, mixing speed is increased to 250 rpm and homogenization process is performed for 10 minutes. Afterwards, remaining quantity of anhydrous ethanol is added to the mixture and mixing is continued at 250 rpm for 10 minutes. Final mixture is cooled to 2-6°C and this temperature is maintained throughout the filling process. Mixture is filled into aluminum containers and closed with a valve. Then, FIFA 134a gas is filled into the aluminum container through this valve.

Claims

1. A pharmaceutical composition comprising the combination of glycopyrrolate or a pharmaceutically acceptable salt as active ingredient and an anticholinergic agent.
2. A pharmaceutical composition comprising glycopyrrolate and an anticholinergic agent according to Claim 1 , wherein the pharmaceutically acceptable salts of glycopyrrolate may be in the forms of hydrates, solvates, esters, enantiomers, diastereomers and/or any of the polymorphic forms such as amorphous or crystalline forms or in the form of combination of these.
3. A pharmaceutical composition according to Claims 1-2, wherein glycopyrrolate is in the form of R,R-glycopyrrolate, preferably in the form of R,R-glycopyrrolate bromide.
4. A pharmaceutical composition according to Claim 1 , wherein the anticholinergic agent to be used is selected from benztropine, ipratropium, tiotropium, tolterodine, oxitropium, oxibutinine.
5. A pharmaceutical composition according to Claims 1-4, wherein the anticholinergic agent to be used is selected from ipratropium and tiotropium.
6. A pharmaceutical composition according to Claim 5, wherein the anticholinergic agent to be used is tiotropium.
7. A pharmaceutical composition according to Claim 6, wherein the pharmaceutically acceptable salts of tiotropium may be in the forms of hydrates, solvates, esters, enantiomers, diastereomers and/or any of the polymorphic forms such as amorphous or crystalline forms or in the form of combination of these.
8. A pharmaceutical composition according to Claim 7, wherein the tiotropium used is in the form of tiotropium bromide.
9. A pharmaceutical composition comprising the combination of R,R-glycopyrrolate and tiotropium bromide according to Claims 1-8, wherein R,R-glycopyrrolate and tiotropium bromide are contained in the same pharmaceutical formulation.
10. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to Claims 1-8, wherein R,R-glycopyrrolate and tiotropium bromide are contained in the different pharmaceutical formulations.
11. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to Claims 1-8, 10, wherein the different formulations containing R,R-glycopyrrolate and tiotropium bromide are incorporated in the same dosage form.
12. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to Claims 1-8, 10, wherein the different formulations containing R,R-glycopyrrolate and tiotropium bromide are contained in the different dosage forms.
13. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to Claims 1-12, wherein said composition is in any of the forms of tablet, effervescent tablet, effervescent granule, effervescent dry powder, film-coated tablet, enteric coated tablet, dry powder, granule, capsule, extended-release tablet, modified-release tablet, delayed-release tablet, orodispersible tablet, chewable tablet, inhalation solution, aerosol or dry powder for inhalation or in the form of combination of these.
14. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to any of the preceding claims, wherein said composition contains at least one pharmaceutically acceptable excipient in addition to R,R-gIycopyrroIate and tiotropium bromide.
15. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to any of the preceding claims, wherein said composition contains at least one excipient selected from the group of disintegrant, diluent, lubricant, oiler, binding agent, effervescent pair composed of at least one acidic agent and at least one basic agent, colorant, pH adjusting agent, surfactant, stabilizer, sweetener and/or flavor regulator and flavoring agent in addition to R,R-glycopyrrolate and tiotropium bromide.
16. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to Claim 15, wherein said composition provides a dry powder formulation containing large sized excipients or small sized excipients only or a mixture composed of both large sized and small sized excipients with two different mean particle sizes.
17. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to Claim 16, wherein the weight ratio of small particles of excipient to large particles of excipient is 1 : 1 to 1 :30, in the event that said composition contains both the large sized and small sized excipients.
18. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to Claim 16, wherein the weight ratio of small particles of excipient to large particles of excipient is 1 :1 to 1 : 15, in the event that said composition contains both the large sized and small sized excipients.
19. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to Claim 16, wherein the weight ratio of small particles of excipient to large particles of excipient is 1 : 1 to 1 :8, in the event that said composition contains both the large sized and small sized excipients.
20. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to Claim 13, wherein the aerodynamic particle radius of active ingredients in the said formulation is between 0.05 and 25 μηι, in the event that said composition is formulated to be given by inhalation.
21. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to Claim 13, wherein the aerodynamic particle radius of active ingredients in the said formulation is between 0.1 and 20 μηι, in the event that said composition is formulated to be given by inhalation.
22. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to Claim 13, wherein the aerodynamic particle radius of active ingredients in the said formulation is between 0.5 and 10 μπι, in the event that said composition is formulated to be given by inhalation.
23. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to any of the preceding claims, wherein said composition contains R,R-glycopyrrolate in proportions of 0.1 to 99% by weight.
24. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to any of the preceding claims, wherein said composition contains R,R-glycopyrrolate in proportions of 1 to 98% by weight.
25. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to any of the preceding claims, wherein said composition contains R,R-glycopyrrolate in proportions of 5 to 95% by weight.
26. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to any of the preceding claims, wherein said composition contains tiotropium bromide in proportions of 0.1 to 99% by weight.
27. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to any of the preceding claims, wherein said composition contains tiotropium bromide in proportions of 1 to 98% by weight.
28. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to any of the preceding claims, wherein said composition contains tiotropium bromide in proportions of 5 to 95% by weight.
29. A pharmaceutical composition comprising the combination of glycopyrrolate and an anticholinergic agent according to Claim 1, wherein said composition contains 1 μg to 100 μg of tiotropium.
30. A pharmaceutical composition comprising the combination of glycopyrrolate and an anticholinergic agent according to Claims 1 -2, wherein said composition contains 3 μg to 50 g of tiotropium.
31. A pharmaceutical composition comprising the combination of glycopyrrolate and an anticholinergic agent according to Claims 1-3, wherein said composition contains 5 μg to 30 μg of tiotropium.
32. A pharmaceutical composition comprising the combination of glycopyrrolate and an anticholinergic agent according to Claims 1-4, wherein said composition contains 0.01 mg to 10 mg of glycopyrrolate.
33. A pharmaceutical composition comprising the combination of glycopyrrolate and an anticholinergic agent according to Claims 1-5, wherein said composition contains 0.02 mg to 5 mg of glycopyrrolate.
34. A pharmaceutical composition comprising the combination of glycopyrrolate and an anticholinergic agent according to Claims 1 -6, wherein said composition contains 0.1 mg to 3 mg of glycopyrrolate.
35. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to Claims 14 and 18, wherein said composition is in the form of inhalation solution, aerosol or dry powder for inhalation.
36. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide according to any of the preceding claims, wherein said composition contains, in addition to R,R- glycopyrrolate and tiotropium bromide, at least one third active ingredient selected from antacids, anticholinergics, antispasmodics, antiemetics, antibiotics, antipropulsives, antiallergics, antidiarrheals, antiobesity agents, antithrombotics, antifibrinolytics, antianemics, antihypertensives, antifungals, antipruritics, antipsoriatics, antiseptics, antiacne-bacterials, antimycotics, antivirals, antineoplastics, antiarrhythmics, antiadrenergics, antiepileptics, anti- parkinson agents, antiprotozoals, anthelmintics, anti-inflammatories, diuretics, laxatives, sulfonamide, imidazol, corticosteroids, thiazolidinediones, biguanides, immunostimulants, immunosuppressants, muscle relaxants, analgesics, psycholeptics, psychoanaleptic peripheral vasodilators, beta blockers, calcium channel blockers and lipid modifying agents; alpha- glucosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and analogs, vitamin B1; vitamin C, vitamin E, vitamin B6, vitamin B2, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.
37. A pharmaceutical composition comprising the combination of R,R-glycopyrrolate and tiotropium bromide according to any of the preceding claims, wherein said composition is used for the manufacturing of a drug to be used in treatment of asthma and chronic obstructive pulmonary disease (COPD).
38. A pharmaceutical composition comprising R,R-glycopyrrolate and tiotropium bromide active ingredients as active agent in the same or different dosage forms, wherein said composition is used sequentially, concurrently or simultaneously.
39. A pharmaceutical composition comprising the combination of tiotropium bromide in amounts of 5 μg to 30 μg and R,R-glycopyrrolate bromide in amounts of 0.01 mg to 10 mg as active ingredient.
PCT/TR2013/000313 2012-10-19 2013-10-11 Anticholinergic agent combinations Ceased WO2014062143A2 (en)

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Citations (1)

* 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

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Publication number Priority date Publication date Assignee Title
GB0410398D0 (en) * 2004-05-10 2004-06-16 Arakis Ltd The treatment of respiratory disease
GB0410399D0 (en) * 2004-05-10 2004-06-16 Arakis Ltd The treatment of respiratory disease
US20070287727A1 (en) * 2006-06-08 2007-12-13 Jacob Hiller Anti-Nicotine Treatment
WO2012028745A1 (en) * 2010-09-03 2012-03-08 Pharmaterials Limited Pharmaceutical composition suitable for use in a dry powder inhaler

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US2956062A (en) 1959-02-26 1960-10-11 Robins Co Inc A H Esters of amino alcohols

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