CA2481739A1 - Sustained release of guaifenesin combination drugs - Google Patents

Sustained release of guaifenesin combination drugs Download PDF

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Publication number
CA2481739A1
CA2481739A1 CA002481739A CA2481739A CA2481739A1 CA 2481739 A1 CA2481739 A1 CA 2481739A1 CA 002481739 A CA002481739 A CA 002481739A CA 2481739 A CA2481739 A CA 2481739A CA 2481739 A1 CA2481739 A1 CA 2481739A1
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CA
Canada
Prior art keywords
guaifenesin
delivery system
drug delivery
max
unit dose
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Granted
Application number
CA002481739A
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French (fr)
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CA2481739C (en
Inventor
Robert D. Davis
Ralph W. Blume
Donald Jeffrey Keyser
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RB Health US LLC
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Individual
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Priority claimed from US10/121,706 external-priority patent/US6955821B2/en
Priority claimed from US10/406,557 external-priority patent/US7838032B2/en
Priority claimed from US10/406,574 external-priority patent/US7985420B2/en
Application filed by Individual filed Critical Individual
Publication of CA2481739A1 publication Critical patent/CA2481739A1/en
Application granted granted Critical
Publication of CA2481739C publication Critical patent/CA2481739C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P11/10—Expectorants

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Otolaryngology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a novel pharmaceutical modified release formulation of guaifenesin and optionally a second drug which is preferably selected fro m dextromethorphan and pseudoephedrine. The formulation may comprise a hydrophilic polymer, preferably a hydroxypropyl methylcellulose, and a water~insoluble polymer, preferably an acrylic resin, in a ratio range of about one-to-one (1:1) to about nine-to-one (9:1), more preferably a range o f about three-to-two (3:2) to about six-to-one (6:1), and most preferably in a range of about two-to-one (2:1) to about four-to-one (4:1) by weight. This formulation capable of providing therapeutically effective bioavailability o f guaifenesin for at least twelve hours after dosing in a human subject. The invention also relates to a modified release product which has two portions: a first portion having an immediate release formulation of guaifenesin and a second portion having a sustained release formulation of guaifenesin, wherei n one or both portions further comprises dextromethorphan. The modified releas e product has a maximum guaifenesin serum concentration equivalent to that of an immediate release guaifenesin tablet, and is capable of providing therapeutically effective bioavailability of guaifenesin for at least twelve hours after dosing in a human subject.

Claims (54)

1. A drug delivery system in which a unit dose form comprises a sustained release portion comprising guaifenesin, and optionally a second drug and a release-delaying matrix comprising a hydrophilic polymer and a water-insoluble polymer; an immediate release portion comprising guaifenesin;
wherein the guaifenesin is bioavailable at a therapeutically effective level for at least twelve hours following a single dose.
2. The drug delivery system of claim 1, wherein said optional drug is selected from dextromethorphan and pseudoephedrine.
3. The drug delivery system of claim 2, wherein said optional drug is only in the sustained release portion.
4. The drug delivery system of claim 2, wherein said optional drug is only in the immediate release portion.
5. The drug delivery system of claim 2, wherein said optional drug is in both the immediate release portion and the sustained release portion.
6. The system of claim 2, wherein the release-delaying matrix comprises hydrophilic polymer and water-insoluble polymer in a weight ratio selected from 1:1 to about 9:1, 3:2 to about 6:1, and 2:1 to about 4:1.
7. The system of claim 2, wherein the total amount of guaifenesin is between 500 mg and 1300 mg.
8. The drug delivery system of claim 7, wherein the total quantity of guaifenesin in said unit dose form is from about 600 mg to about 1200 mg.
9. The system of claim 8, wherein said unit dose form has a C max for guaifenesin that is bioequivalent to the FDA-specified C max for an immediate guaifenesin release tablet of one-third the dose strength.
10. The system of claim 9, wherein said unit dose form contains 1200 mg of guaifenesin.
11. The system of claim 10, wherein the C max for guaifenesin is selected from between 1,000 ng/mL and 3,750 ng/mL, 1,200 ng/mL and 3,500 ng/mL, 1,350 ng/mL and 3,000 ng/mL, and 1450 ng/mL and 2,750 ng/mL.
12. The system of claim 9, wherein said unit dose form contains 600 mg of guaifenesin.
13. The system of claim 12, wherein the C max for guaifenesin is selected from between 320 ng/mL and 1875 ng/mL, 400 ng/mL and 1500 ng/mL, 500 ng/mL and 1375 ng/mL, and 625 ng/mL and 1250 ng/mL.
14. The system of claim 8, wherein said therapeutically effective level is measured according to C max.
15. The system of claim 14, wherein the unit dose form has a C max for guaifenesin that is bioequivalent to the FDA-specified C max for an immediate release guaifenesin tablet containing 400 mg of guaifenesin.
16. The system of claim 14, wherein the C max for guaifenesin is selected from between 35 ng/mL and 75 ng/mL, 40 ng/mL and 70 ng/mL, 45 ng/mL and 65 ng/mL, and 50 ng/mL and 60 ng/mL.
17. The system of claim 8, wherein said therapeutically effective level is measured according to AUC inf.
18. The system of claim 17, wherein said unit dose form contains 1200 mg of guaifenesin.
19. The system of claim 18, wherein the AUC inf for guaifenesin is selected from between 4,000 hr-ng/mL and 12,500 hr-ng/mL, 5,000 hr-ng/mL and 10,000 hr-ng/mL, 5,500 hr-ng/mL and 9,500 hr-ng/mL, and 6,000 hr-ng/mL and 9,000 hr-ng/mL.
20. The system of claim 8, where said unit dose form contains 600 mg of guaifenesin.
21. The system of claim 20, wherein the AUC inf for guaifenesin is selected from between 2,000 hr-ng/mL and 6,250 hr-ng/mL, 2,500 hr-ng/mL and 5,000 hr-ng/mL, 2,250 hr-ng/mL and 4,750 hr-ng/mL, and 3,000 hr-ng/mL and 4,500 hr-ng/mL.
22. The drug delivery system of claim 2, wherein the immediate release portion further comprises microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.
23. The drug delivery system of claim 2, wherein the ratio of the total quantity of guaifenesin to the dextromethorphan is from about 1:1 to about 30:1 by weight.
24. The drug delivery system of claim 2, wherein the ratio of the total quantity of guaifenesin to the dextromethorphan is from about 8:1 to about 12:1 by weight.
25. The drug delivery system of claim 2, wherein the ratio of the total quantity of guaifenesin to the pseudoephedrine is from about 1:1 to about 30:1 by weight.
26. The drug delivery system of claim 2, wherein the ratio of the total quantity of guaifenesin to the pseudoephedrine is from about 8:1 to about 12:1 by weight.
27. The drug delivery system of claim 1, wherein the ratio of the immediate release quantity of guaifenesin to the sustained release quantity of guaifenesin is about 1:1 to about 1:15 by weight.
28. The drug delivery system of claim 1, wherein the ratio of the immediate release quantity of guaifenesin to the sustained release quantity of guaifenesin is from about 2:3 to about 1:11.
29. The drug delivery system of claim 1, wherein at least about 60% of the guaifenesin particles used to make the unit dose form have a particle size in the range of from about 150 µm to 2.0 mm.
30. The drug delivery system of claim 1, wherein a unit dose form has a C max for guaifenesin of at least about 1900 ng/ml and an AUC inf for guaifenesin of at least 7000 hr-ng/ml.
31. The drug delivery system of claim 1, wherein a unit dose form has a C max for guaifenesin of at least 1000 ng/ml and an AUC inf for guaifenesin of at least 3500 hr-ng/ml.
32. The drug delivery system of claim 1, wherein a unit dose form has a half life of at least 3 hours as determined by serum analysis.
33. The drug delivery system of claim 1, wherein the sustained release portion comprises about 75% to about 95% by weight of guaifenesin, from about 1%

to about 15% of dextromethorphan, from about 0.5% to about 10% of the hydrophilic polymer, and about 0.5% to about 2.5% water-insoluble polymer by weight.
34. The drug delivery system of claim 1, wherein the unit dose form comprises immediate release and sustained release portions each comprise abutting substantially planar layers which form a bi-layer tablet.
35. The drug delivery system of claim 1, wherein the dextromethorphan is bioavailable at therapeutically effective level for at least twelve hours following a single dose.
36. The drug delivery system of claim 1, wherein the sustained release portion comprises from about 75% to 80% by weight of guaifenesin, from about 5%
to about 10% by weight of dextromethorphan, from about 3% to about 6% of the hydroxypropyl cellulose, and from about 1% to about 1.5% by weight of an acrylic resin.
37. The drug delivery system of claim 1, wherein a unit dose form has a C max for guaifenesin from about 1600 to 2500 ng/ml and an AUC inf for guaifenesin of about 5600 to 8750 hr-ng/ml.
38. The drug delivery system of claim 1, wherein a unit dose form has a C max for guaifenesin of about 800 to 1250 ng/ml and an AUC inf for guaifenesin of about 2800 to 4375 hr-ng/ml.
39. The drug delivery system of claim 1, wherein the unit dose form comprises a capsule that contains discrete or associated immediate release and sustained release portions.
40. The drug delivery system of claim 7, which is approximately equally effective when administered to a patient on an empty or full stomach.
41. The drug delivery system of claim 7, wherein said unit dose form has the guaifenesin serum concentration profile of Figure 10.
42. A drug product comprising an immediate release portion comprising a guaifenesin and optionally a second drug wherein guaifenesin becomes bioavailable in the subject's stomach; and a sustained release portion comprising guaifenesin and a second drug wherein the ratio of the immediate release guaifenesin to the sustained release guaifenesin is about 1:1 to about 1:15, the product provides a guaifenesin C max in a human subject equivalent to the C max obtained when the first of three doses of a FDA-specified immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period, and the product provides a therapeutically effective bioavailable guaifenesin for at least twelve hours after a single dose in a human subject according to serum analysis.
43. The drug product of claim 42, wherein the second drug is selected from dextromethorphan and pseudoephedrine.
44. The drug product according to claim 43, wherein the immediate release and sustained release portions each comprise abutting substantially planar layers which form a bi-layer tablet.
45. The drug product according to claim 43, wherein the sustained release portion is coated by a layer of the immediate release portion.
46. The drug product according to claim 43, wherein the product comprises a capsule containing immediate release and sustained release portions.
47. A method of treating a subject in need of temporary relief from bronchial mucus accumulation comprising administering to said subject a therapeutically effective amount of one drug delivery system according to claim 2.
48. The method according to claim 47, wherein the drug delivery system is administered orally.
49. A method of treating a subject in need of temporary relief from bronchial mucus and coughing comprising administering to said subject a therapeutically effective amount of a modified release drug product comprising guaifenesin and dextromethorphan in an immediate release formulation wherein the guaifenesin becomes bioavailable in the subject's stomach; and a sustained release portion comprising a guaifenesin, dextromethorphan and a release-delaying matrix, wherein the release-delaying matrix comprises a hydrophilic polymer and a water-insoluble polymer in a weight ratio of hydrophilic polymer to water-insoluble polymer from about 1:1 to about 9:1, wherein the guaifenesin has a C max in a human subject equivalent to the C max obtained when the first of three doses of a FDA-specified immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period, and releases therapeutically effective bioavailable guaifenesin dose for at least twelve hours after a single dose in a human subject according to serum analysis.
50. A method of treating a subject in need of temporary relief from bronchial mucus and nasal congestion comprising administering to said subject a therapeutically effective amount of a modified release drug product comprising guaifenesin in an immediate release formulation wherein the guaifenesin becomes bioavailable in the subject's stomach; and a sustained release portion comprising a guaifenesin, pseudoephedrine and a release-delaying matrix, wherein the release-delaying matrix comprises a hydrophilic polymer and a water-insoluble polymer in a weight ratio of hydrophilic polymer to water-insoluble polymer from about 1:1 to about 9:1, wherein the guaifenesin has a C max in a human subject equivalent to the C max obtained when the first of three doses of a FDA-specified immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period, and releases therapeutically effective bioavailable guaifenesin dose for at least twelve hours after a single dose in a human subject according to serum analysis.
51. A drug delivery system comprising a sustained release portion comprising guaifenesin, dextromethorphan and a release-delaying matrix comprising a hydrophilic polymer and a water-insoluble polymer; and an immediate release portion comprising guaifenesin and dextromethorphan; wherein the guaifenesin is bioavailable at a therapeutically effective level for at least twelve hours according to serum analysis following a single dose and wherein a unit dose form demonstrates a C max in a human subject above 640 ng/ml with a T max within .8 hours and maintains a C min above 80 ng/ml for a period of 12 or more hours.
52. A drug delivery system comprising a sustained release portion comprising guaifenesin, pseudoephedrine and a release-delaying matrix comprising a hydrophilic polymer and a water-insoluble polymer; and an immediate release portion comprising guaifenesin; wherein the guaifenesin is bioavailable at a therapeutically effective level for at least twelve hours according to serum analysis following a single dose and wherein a unit dose form demonstrates a C max in a human subject above 640 ng/ml with a T max within .8 hours and maintains a C min above 80 ng/ml for a period of 12 or more hours.
53. A drug delivery system in which a unit dose form comprises a sustained release portion comprising guaifenesin, pseudoephedrine and a release-delaying matrix comprising a hydrophilic polymer and a water-insoluble polymer; an immediate release portion comprising guaifenesin; wherein the guaifenesin is bioavailable at a therapeutically effective level for at least twelve hours following a single dose.
54. A drug delivery system in which a unit dose form comprises a sustained release portion comprising guaifenesin, dextromethorphan and a release-delaying matrix comprising a hydrophilic polymer and a water-insoluble polymer; an immediate release portion comprising guaifenesin and dextromethorphan; wherein the guaifenesin is bioavailable at a therapeutically effective level for at least twelve hours following a single dose.
CA2481739A 2002-04-15 2003-04-15 Sustained release of guaifenesin combination drugs Expired - Lifetime CA2481739C (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US10/121,706 US6955821B2 (en) 2000-04-28 2002-04-15 Sustained release formulations of guaifenesin and additional drug ingredients
US10/121,706 2002-04-15
US10/406,557 US7838032B2 (en) 2000-04-28 2003-04-04 Sustained release of guaifenesin
US10/406,557 2003-04-04
US10/406,574 US7985420B2 (en) 2000-04-28 2003-04-04 Sustained release of guaifenesin combination drugs
US10/406,574 2003-04-04
PCT/US2003/011500 WO2003088952A1 (en) 2002-04-15 2003-04-15 Sustained release of guaifenesin combination drugs

Publications (2)

Publication Number Publication Date
CA2481739A1 true CA2481739A1 (en) 2003-10-30
CA2481739C CA2481739C (en) 2012-10-02

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CA2481739A Expired - Lifetime CA2481739C (en) 2002-04-15 2003-04-15 Sustained release of guaifenesin combination drugs

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EP (1) EP1503739A4 (en)
JP (1) JP5466346B2 (en)
CN (1) CN1655766B (en)
AU (1) AU2003237807B2 (en)
CA (1) CA2481739C (en)
EA (1) EA007156B1 (en)
IL (1) IL164438A0 (en)
MX (1) MXPA04010225A (en)
WO (1) WO2003088952A1 (en)
ZA (1) ZA200409171B (en)

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EP4036088B1 (en) 2010-03-10 2024-04-03 Incyte Holdings Corporation Piperidin-4-yl azetidine derivatives as jak1 inhibitors
US9339478B2 (en) 2011-02-04 2016-05-17 Reckitt Benckiser Llc Pharmaceutical formulation
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IL291391B (en) 2012-11-15 2022-11-01 Incyte Holdings Corp Sustained-release dosage forms of ruxolitinib
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Publication number Publication date
EA200401369A1 (en) 2005-06-30
IL164438A0 (en) 2005-12-18
EP1503739A4 (en) 2006-06-21
EP1503739A1 (en) 2005-02-09
CN1655766A (en) 2005-08-17
MXPA04010225A (en) 2005-07-05
JP2005528402A (en) 2005-09-22
ZA200409171B (en) 2005-07-27
EA007156B1 (en) 2006-08-25
CA2481739C (en) 2012-10-02
WO2003088952A1 (en) 2003-10-30
AU2003237807A1 (en) 2003-11-03
AU2003237807B2 (en) 2008-10-23
CN1655766B (en) 2012-05-30
JP5466346B2 (en) 2014-04-09

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