Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
  • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods

Definitions

• the present invention concerns a new pharmaceutical composition
• doxofylline in particular a modified release formulation, for administration once a day only.
• Doxofylline (7-(l,3-dioxalan-2-ylmethyl)-theophylline) is a drug derived from theophylline which is used in therapy as a bronchodilator, with anti-inflammatory action, in reversible airway obstruction. It is commonly administered in doses ranging from 800 to 1200 mg per day, orally, according to a dosage which provides for the intake of two to three dosage units per day in order to maintain therapeutically effective haematic levels.
• the doxofylline tablets commercially available generally contain 400 mg of active ingredient and release almost all the drug within one hour from intake. The half- life of the drug is around 6-7 hours and for this reason several administrations are required during the 24-hour period.
• dosage units containing 400 mg of active ingredient are currently administered two/three times a day for a daily average of approximately 1000 mg of active ingredient, a dosage considered necessary to maintain the therapeutic haematic levels of doxofylline.
• Such a dosage unit is currently marketed by Dr. Reddy's Laboratories Ltd as DOXOBID and has the following quali-quantitative composition: doxofylline (400 mg), colloidal silicon dioxide (13 mg), corn starch (63 mg), mannitol (40 mg), povidone (7 mg), microcrystalline cellulose (64 mg), talc (30 mg), magnesium stearate (3 mg) and water (0.08 ml).
• a further object of the present invention is to provide a composition of doxofylline which lowers the initial haematic peak and the first-pass effect occurring in the conventional compositions.
• a further object of the present invention is to provide a doxofylline composition which maintains the effective concentration of the drug in the blood sufficient to exert the bronchodilatory and anti-inflammatory effect over the 24-hour period, thus reducing the risk of bronchospasm and serious consequences for the patient.
• Another object of the present invention is to provide a modified release doxofylline composition which avoids the need for recourse to rescue medication, such as salbutamol inhalers, to overcome acute asthmatic attacks and bronchospasms.
• rescue medication such as salbutamol inhalers
• the invention concerns a modified release pharmaceutical composition which comprises as active ingredient doxofylline, and a polymer selected from a pharmaceutically acceptable cellulose derivative, a pharmaceutically acceptable methacrylate derivative, their mixtures, and pharmaceutically acceptable salts thereof.
• Doxofylline (or doxophylline) (7-(l,3-dioxalan-2-ylmethyl)-theophylline) has the following structural formula
• active ingredient and is here also called “active ingredient” or “API” (Active Pharmaceutical Ingredient).
• modified release pharmaceutical composition indicates a pharmaceutical composition that retains the active ingredient for a longer period of time than the conventional compositions and releases it slowly in order to maintain at length the plasmatic concentrations of the drug sufficient to exert the desired therapeutic effect.
• Said formulation is here also called “BET” (Bioavailability Enhancing Technology) or “TOP” (Technology Optimized Performance) formulation.
• polymer indicates, according to the present invention, a pharmaceutically acceptable release modulator polymer or copolymer, suitable for prolonging the release time of the active ingredient from the composition. Said polymer will be indicated below also simply as “release modulator polymer”.
• pharmaceutically acceptable cellulose derivative indicates a derivative suitable for prolonging the release time of the drug from the composition, such as pharmaceutically acceptable cellulose esters and ethers, like methyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, their mixtures and their salts.
• pharmaceutically acceptable cellulose esters and ethers like methyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, their mixtures and their salts.
• pharmaceutically acceptable methacrylate derivative indicates a derivative suitable for prolonging the release time of the drug from the composition, for example the copolymer methacrylic acid/methyl methacrylate, the copolymer methacrylic acid/ethyl methacrylate, their mixtures and their salts.
• bioequivalence is demonstrated if the 90% confidence interval of the AUC falls within an acceptance interval of 80% to 125%.
• a preferred release modulator polymer according to the invention is a pharmaceutically acceptable cellulose derivative, advantageously selected from methyl cellulose, ethyl cellulose, hydroxyalkyl cellulose (such as hydroxypropylmethyl cellulose or hydroxypropyl cellulose) and their mixtures.
• the composition of the invention is preferably a composition in the form of a dosage unit suitable for oral administration once a day, advantageously in the form of a tablet.
• composition of the invention preferably also comprises excipients useful for the processing thereof, for example lubricating agents, such as magnesium stearate, filling agents, such as lactose, talc, microcrystalline cellulose, agents aiding compression and, if necessary or desired, other excipients such as aromatizers, sweeteners, preservatives, etc., well known to a person skilled in the art.
• lubricating agents such as magnesium stearate
• filling agents such as lactose, talc, microcrystalline cellulose
• agents aiding compression such as lactose, talc, microcrystalline cellulose
• other excipients such as aromatizers, sweeteners, preservatives, etc.
• other excipients such as aromatizers, sweeteners, preservatives, etc.
• a quantity of active ingredient between 550 and 800 mg, preferably between 600 and 750, more preferably between 625 and 700 mg, advantageously around 650 mg. It is understood that said dose can vary
• the invention concerns a modified release composition which comprises as active ingredient approximately 650 mg of doxofylline and a release modulator polymer as defined above, advantageously in combination with a filling agent and/or a lubricant.
• the release modulator polymers are used alone or mixed together, in quantities between 30 mg and 200 mg per tablet, preferably between 40 mg and 130 mg, more preferably between 120 and 130 mg; for example, 50, 100 or 125 mg, per dosage unit.
• composition of the invention has proved to be particularly suitable for modified release of the active ingredient and with one single oral administration allows an effective haematic concentration of doxofylline to be maintained for 24 hours, while at the same time avoiding the excessive haematic peaks after the first and particularly after the second daily administration, which characterise the conventional compositions currently on sale.
• composition of the invention advantageously also comprises a lubricant, for example magnesium stearate, for example in quantities between 1 and 15 mg, preferably between 3 and 10 mg, for example approximately 5 mg, per dosage unit.
• a lubricant for example magnesium stearate, for example in quantities between 1 and 15 mg, preferably between 3 and 10 mg, for example approximately 5 mg, per dosage unit.
• the preferred composition of the invention advantageously also comprises one or more filling agents, such as talc, lactose or microcrystalline cellulose, for example in total quantities of between 10 and 200 mg, preferably between 20 and 150 mg, advantageously 30, 50, 70 or 100 mg, per dosage unit; according to a first particularly preferred embodiment, the composition contains between 100 and 150 mg of filling agent; according to a second particularly preferred embodiment, the composition contains both talc and microcrystalline cellulose.
• filling agents such as talc, lactose or microcrystalline cellulose
• the composition comprises between 625 and 675 mg of doxofylline, between 100 and 150 mg of hydroxypropylmethyl cellulose, between 75 and 125 mg of microcrystalline cellulose, between 15 and 20 mg of talc and between 5 and 10 mg of magnesium stearate; more preferably, the composition comprises 650 mg of doxofylline, 125 mg of hydroxypropylmethyl cellulose, 100 mg of microcrystalline cellulose, 18 mg of talc and 7 mg of magnesium stearate.
• composition of the invention is preferably in the form of a tablet and can be prepared by mixing the active ingredient, the release modulator polymer (or the mixture of polymers) and any other components and compressing them to an appropriate hardness, according to the methods known in the art.
• the invention concerns use of the composition of the invention for the preparation of a bronchodilatory medication with antiinflammatory action for the treatment of all forms of asthma and chronic obstructive pulmonary disease (COPD).
• COPD chronic obstructive pulmonary disease
• the invention concerns use of the composition of the invention for the preparation of a medication for oral administration once a day only.
• the invention concerns a method for the bronchodilatory treatment of all forms of asthma and chronic obstructive pulmonary disease (COPD) which comprises administration to a patient in need thereof of a therapeutically effective amount of the composition of the invention.
• COPD chronic obstructive pulmonary disease
• the invention concerns a method for improving bioavailability of doxofylline in a human being, which method comprises administering to said human being the composition of the invention; more in details, it concerns a method for obtaining in a human being a plasmatic level bioequivalent to that obtainable by administering twice a day an immediate release composition containing 400 mg of doxofylline (such as DOXOBID), which method comprises administering the composition of the invention once a day.
• DOXOBID immediate release composition containing 400 mg of doxofylline
• the invention comprises a process for preparation of the composition of the invention, in the form of tablets, which comprises:
• phase (b) compressing is performed to obtain a tablet hardness of between 1 and 3 kg/cm 2 .
• phase (d) in phase (d) a lubricating agent and/or a filling agent are mixed.
• composition of the invention can also be formulated in the form of coated pellets.
• the compositions of the invention have undergone various tests to assess their dissolution profile and stability, as well as their in vivo bioavailability. The tests conducted enabled us to conclude that the composition of the invention, in particular the preferred composition in the form of a tablet, as defined above, is stable and has an optimal dissolution profile for maintaining the haematic concentration of doxofylline effective for 24 hours.
• compositions of the invention are therefore suitable for administration once a day only and, surprisingly, at a dosage even approximately 35% lower than the average daily dosage of the conventional formulations.
• EXPERIMENTAL SECTION EXAMPLE 1 A modified release composition in tablet form is prepared which contains, for each tablet: • doxofylline 650.00 mg
• microcrystalline cellulose 30.00 mg
• a modified release composition in tablet form is prepared which contains, for each tablet:
• a modified release composition in tablet form is prepared which contains, for each tablet:
• microcrystalline cellulose 30.00 mg
• a randomized, open-label, balanced, three-treatment, three-period, three sequence, single dose, crossover bioavailability study has been done in twelve healthy, adult, male, human subjects under fasting conditions using the 650 mg tablet of example 2 (Doxofylline SR 650) the 600 mg tablet of example 3 (Doxofylline SR 600) and the 400 mg tablet currently available on the market (DOXOBID); Doxofylline SR 650 and Doxofylline SR 600 have been administered once-a-day, whereas DOXOBID has been administered twice a day. Pharmacokinetic parameters have been calculated using KINETICA software. The area under the curve (AUC) was subjected to statistical treatment for significance by one-way analysis of variance ANOVA) using software, Jandel Scientif ⁇ ca, California.
• FIG. 1 shows the data of Doxofylline SR 650 compared to that of DOXOBID whereas figure 2 shows the data of Doxofylline SR 600 compared to that of DOXOBID.
• T/R relative bioavailabilities
• Doxofylline SR 650 mg tablets Excellent results were obtained for Doxofylline SR 650 mg tablets.
• the bioavailability of doxofylline was found to be about 0.98 and 0.92 times after administration of Doxofylline SR 650 mg and Doxofylline SR 600 mg tablets, respectively.
• the bioavailability of Doxofylline 650 mg was almost identical to that of DOXOBID 400 mg twice daily, 12 hourly, therefore it could be possible to administer a single dose of Doxofylline SR 650 mg tablet instead of doxofylline 400 mg twice daily to treat symptoms associated with asthma and. COPD (chronic obstructive pulmonary disease).
• DOXOBID immediate release tablets containing doxofylline 400mg for twice daily administration.
• the open-label bioequivalence study was performed in 24 healthy, adult, male subjects. Each subject received 1 dose of the 650 mg tablet of example 2 (Doxofylline SR 650, herinafter indicated as DOXOTOP) and 2 doses of DOXOBID tablet at 0 and 12 hours. There was a wash-out period of 7 days between each study drug to prevent any carry-over effect. The order of the study drug administrations was randomized for all patients.
• Doxofylline serum concentrations of DOXOTOP were tested 1 hour before drug administration and post-dose at 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 3.00, 4.00, 6.00, 9.00, 12.00, 16.00 and 24.00 hours. At each time point 5 ml of blood was taken from the subject. Because the reference product (DOXOBID) is administered twice daily, the plasma levels should be tested at additional time points in order to measure the plasma peak after the second administration.
• time points are measured, 1 hour before drug administration and post-dose at 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 3.00, 4.00, 6.00, 9.00, 12.00, 12.25, 12.50, 12.75, 13.00, 13.25, 13.50, 13.75, 14.00, 15.00, 16.00, 18.00, 21.00 and 24.00 hours.
• 5 ml of blood was collected from the subject. All blood samples were collected via indwelling cannula placed in the forearm vein.
• DOXOTOP 650mg
• DOXOBID 400mg tablets twice daily This sustained release formulation therefore has an equal efficacy as the conventional tablets, but may have an even better safety profile since the peak serum concentrations are lower and less active drug is administered to the patient on a daily basis.

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