OA10687A - Pharmaceutical formulations - Google Patents

Pharmaceutical formulations Download PDF

Info

Publication number
OA10687A
OA10687A OA9800058A OA9800058A OA10687A OA 10687 A OA10687 A OA 10687A OA 9800058 A OA9800058 A OA 9800058A OA 9800058 A OA9800058 A OA 9800058A OA 10687 A OA10687 A OA 10687A
Authority
OA
OAPI
Prior art keywords
formulation
weight
drug compound
range
active drug
Prior art date
Application number
OA9800058A
Inventor
Ross James Macrae
Janet Sarah Smith
Original Assignee
Pfizer Res & Dev
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Res & Dev filed Critical Pfizer Res & Dev
Publication of OA10687A publication Critical patent/OA10687A/en

Links

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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates

Landscapes

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

Abstract

The invention provides a controlled-release pharmaceutical formulation for oral administration consisting essentially of: an active drug compound; low molecular weight polyethylene oxide; hydroxypropylmethyl cellulose; tabletting excipients; and optionally one or more enteric polymers. Formulations according to the invention produce a constant rate of release of drug in in vitro models of the gastrointestinal tract.

Description

010687
Pharmaceutical formulations
This invention relates to controlled-release oral pharmaceutica! formulations. 5 Controlled-release oral pharmaceutical formulations are known. Their purpose is tomodify the rate of drug reiease, for example to produce a constant rate of release of adrug into the gastrointestinal tract of a patient, or to delay the reiease of a drug into thegastrointestinal tract of a patient (see ‘Sustained and Controlled Release Drug DeliverySystems’, pp 3-6, edited by J R Robinson, published by Marcel Dekker Inc). 10 US Patent N° 4,765,989 discloses an osmotic deiivery device for delivering inter alianifedipine or doxazosin. it has a perforated semipermeable wall enclosing a drugcomposition which includes an osmopolymer, and a pusher composition containing asecond osmopolymer. The performance of this prior art device is satisfactory, but it has 15 the disadvantage that it is very complicated, leading to high manufacturing costs. UK Patent Application 2,123,291 discioses a sustained release formulation of suloctidilwhich is a two-part tablet: a first part is a prompt-release portion and a second part is aslow-release portion, which must contain a surface-active agent to promote bio-erosion. 20 US Patent N° 5,393,765 discloses an erodibie pharmaceutical composition providing azéro order controlled release profile, comprising low viscosity hydroxypropylmethylcellulose. 2 5 According to the présent invention, there is provided a controlled-release pharmaceutical formulation for oral administration consisting essentially of: an active drug compound; lowmolecular weight polyethylene oxide; hydroxypropylmethyl cellulose; tabietting excipients;and optionally one or more enteric polymers. 3 0 Primariiy, “oral administration” means administration to the mouth followed by swailowing.
However, the formulations of the présent invention may also be administered buccally (i.e. placed behind the top lip and allowed to dissolve), and the term includes such formulations. 010687 “Consisting essentiaily of means that at least 95% by weight of the formulation is madeup of the listed components. At least 99% by weight of uncoated formulations, and thecores of coated formulations, are preferably made up of the listed components.
Polymerized ethylene oxide having a number average molecular weight less than 100,000 ’ is sometimes referred to as “polyethylene glycol”. However, for simplicity, the term “lowmolecular weight polyethylene oxide” is used to refer to polymerized ethylene oxide in thenumber average molecular weight range of interest, namely 15,000 to 750,000.
Tabletting excipients making up formulations according to the invention may be conven-tional tabletting excipients, for example dibasic calcium phosphate, lactose and -..magnésium stéarate.
There are three classes of drug compound which are particularly suitable for administra-tion in formulations according to the invention. The first class is weakly basic compounds.
Examples of this class include dipyridamole, noscapine, papaverine, doxazosin, sildenafiland prazosin. Doxazosin and its pharmaceutically acceptable salts are of particularinterest.
The second class are compounds having high solubility in aqueous media. Examples ofthis class include salbutamol, metoprolol, propanolol, aminophylline, isosorbide mono-and dinitrate, glyceryl trinitrate, verapamil, captopril, diltiazem, morphine, chlorpherii-ramine, promethazine, eletriptan, darifenacin and fluconazole.
The third class are compounds having low solubility in aqueous media. Examples of thisclass include nifedipine, griseofulvin, carbamazepine, felodipine, nimodipine andmegestrol.
The terms “high solubility in aqueous media’’ and “low solubility in aqueous media” will beunderstood by those skilled in the art. However, the former may be defined as a solubility>1mg/ml in water, and the latter may be defined as a solubility <1mg/ml in water.
It will be apparent to those skilled in the art that some compounds may fall into more than one of the above classes, for example certain compounds may be weakly basic and hâve a high solubility in aqueous media. 010687
Formulations according to the invention hâve the advantage that they produce a constant rate of release of drugs that are weakly basic and/or hâve a high solubility in aqueous media in in vitro models of the gastrointestinal tract, and so are expected to produce a 5 constant rate of release of the drug in the gastrointestinal tract of a patient. When thedrug to be administered has a low solubility in aqueous media, the formulations of theinvention hâve the advantage that they produce a delayed or pulsed release of the drug.However, the formulations are very simple and so can be manufactured at a compara-tively low cost. 10
Preferably, the hydroxypropylmethyl cellulose has a number average molecular weight inthe range 80,000-250,000. Preferably, the hydroxypropylmethyl cellulose has a degree ofmethyl substitution in the range 19-30 %. Preferably, the hydroxypropylmethyl cellulosehas a degree of hydroxy substitution in the range 4-12 %. A number of hydroxypropylme- 15 thyl cellulose polymers are available commercially under the brand name Methocel®, andsome of those suitable for use in formulations according to the invention are given in thetable below:
Methocel® grade Number average MW Degree ofmethylsubstitution Degree ofhydroxysubstitution Nominalviscosity of a2% aqueous solution USP désignation K4M 89000 19-24% 4-12% 4000cps 2208 K15M 125000 U U 15000cps U K100M 215000 tf U 100000cps H E4M 93000 28-30% 7-12% 4000cps 2910 E10M 113000 U U 10000cps u F4M 90000 27-30% 4-7.5% 4000cps 2906 20 Methocel® K4M has characteristics of particular interest.
Preferably, the low molecular weight polyethylene oxide has a number average molecularweight in the range 20,000 to 500,000, more preferably 100,000-300,000. Polyethyleneoxide with a number average molecular weight above 100,000 is a powder, which makes 25 it easier to handle than lower molecular weight polyethylene oxide, which has a lower meiting point. For example, polyethylene oxide with a number average molecular weight of 6000 has a meiting point of 60-63°C. 010687
It will be apparent to those skiiled in the art that the polyethylene oxide may consist ofmolécules of different Chain lengths, but that the average Chain length gives a molecuiarweight in the range stated. The same applies to the hydroxypropylmethyl cellulose.
Formulations according to the invention may contain an enteric poiymer admixed with theother components of the formulation. In addition or alternatively, formulations accordingto the invention are preferably provided with a coating of an enteric poiymer. Entericpolymers that may be mentioned are phthalate dérivatives (including cellulose acetatephthalate, polyvinyiacetate phthalate and hydroxypropylmethyl cellulose phthalate),polyacrylic acid dérivatives (including methacrylic acid copolymer), and vinyl acetate andcrotonic acid copolymers. Methacrylic acid copolymer is of particular interest.
Preferably, the formulation contains up to 50% by weight of active drug compound, forexample 1-20%.
It is preferred that the formulations of the invention contain 5-30% by weight of lowmolecuiar weight polyethylene oxide, for example 8-10%.
Preferably, the formulations of the invention contain 10-60% by weight of hydroxypropyl-methyl cellulose, for example 25-35%.
Formulations having enteric poiymer admixed with the other components of the formula-tion preferably hâve 10-40% by weight of admixed enteric poiymer, for example 25-35%.
In formulations according to the présent invention, it is preferred that the mass ratio of lowmolecuiar weight polyethylene oxide:hydroxypropylmethyl cellulose is in the range 2:1-1:5.
In formulations according to the présent invention containing admixed enteric poiymer, itis preferred that the mass ratio of (low molecuiar weight polyethylene ox-ide+hydroxypropylmethyl ceilulose):admixed enteric poiymer is in the range 1:2-6:1, morepreferably 1:2-2:1. Preferably, the enteric coating (where présent) makes up 2-15% byweight of the formulation, more preferably 5-10% by weight of the formulation. 010687
According to another aspect of the invention, there is provided the use of low molecularweight polyethylene oxide in an oral controlled-release pharmaceutical formulation,having a hydroxypropylmethyl cellulose matrix, to enhance the érosion of the matrix aftera predetermined period of time following administration of the formulation to a patient.Typically, the predetermined period of time is 6 hours. In this way, a constant rate of drugrelease can be achieved in the gastrointestinal tract of a patient despite the varyingconditions which exist along its iength.
By varying the proportion of polyethylene oxide in the formulation it is possible to controlthe onset of enhancement of matrix érosion and so the onset of increased drug releasefollowing administration of the formulation to a patient.
According to a yet further aspect of the invention, there is provided a process for theproduction of a pharmaceutical formulation as defined in claim 1, which comprises mixing:an active drug compound; low molecular weight polyethylene oxide; hydroxypropylmethylcellulose; tabletting excipients; and optionally one or more enteric polymère; followed bypressing into tablets.
The drug release properties of formulations according to the présent invention may bemeasured in a model of the gastrointestinal tract such as Apparatus 1 of USP 22, page1578, Method 1 (baskets).
The invention is iilustrated by the following examples with référencé to the accompanyingdrawings, in which:
Figure 1 shows the percentage of drug compound released v time from formulationsaccording to the invention [as prepared in Examples 1(a) and 1(b)] in comparison with acontrol [as prepared in Example 6] using simple dissolution testing; and
Figure 2 shows the percentage of drug compound released v time from a formulationaccording to the invention [as prepared in Exampie 2(a)] using dissolution testing with firstan acidic and then a neutral dissolution medium.
Example 1
Sustained release formulations of doxazosin mesvlate (a)
Ingrédient| mg/tablet 010687 6
Doxazosin mesylate3 3.636 Poiyethyleneoxide 100,000 MW° 9.000 Polyethyleneoxide 200,000 MW0 9.000 Hydroxypropylmethylcellulose0 60.000 Dibasic calcium phosphateé 58.182 Lactose' 58.182 Magnésium stéarate 2.000 Total 200.000 a équivalent to 3mg doxazosin based on a theoretical activity of 82.5%b as Polyox® WSR N 10 c as Polyox® WSR N 80
5 d as Methocel® K4M e as anhydrous f as lactose fast flo
Ail of the ingrédients except the magnésium stéarate were blended together in a Turbula10 blender for 10 minutes. The mixture was then screened using a 30 mesh (500μιτι apertures) screen and reblended for a further 10 minutes. Then the magnésium stéaratewas screened through a 30 mesh (500pm apertures) screen and added to the mixturebefore blending for a further 5 minutes. The blend was then subjected to compression ona tabletting machine using 8mm round normal convex tooling to make the required 15 number of tablets of 200 mg mass. (b)
Ingrédient mg/tablet Doxazosin mesylate3 4.876 Polyethyleneoxide 100,000 MW6 20.000 Polyethyleneoxide 200,000 MW° 20.000 Hydroxypropylmethylcellulose3 60.000 Dibasic calcium phosphate3 46.562 Lactose' 46.562 Magnésium stéarate 2.000 Total 200.000 a équivalent to 4mg doxazosin based on a theoretical activity of 82.5%20 b as Polyox® WSR N 10 c as Polyox® WSR N 80
d as Methocel® K4M e as anhydrous f as lactose fast flo 200mg tablets were prepared by the method of (a). Ί (c) 010687
Ingrédient mg/tablet Doxazosin mesylateà 4.876 Polyethyleneoxide 100,000 MW° 30.000 Polyethyleneoxide 200,000 MW^ 30.000 Hydroxypropylmethylcellulose0 60.000 Dibasic calcium phosphate® 36.562 Lactose' 36.562 Magnésium stéarate 2.000 Total 200.000 a équivalent to 4mg doxazosin based on a theoretical activity of 82.5%b as Polyox® WSR N 10 5 c as Polyox® WSR N 80
d as Methocel® K4M e as anhydrous f as lactose fast flo 10 200mg tablets were prepared by the method of (a).
Example 2
Sustained release formulations of doxazosin mesvlate containing an enteric oolymér (a) ingrédient mg/tablet Doxazosin mesylate3 3.636 Polyethyleneoxide 100,000 MW° 9.000 Polyethyleneoxide 200,000 MW0 9.000 Hydroxypropylmethylcellulose® 60.000 Methacrylic acid copolymer type® C 60.000 Dibasic calcium phosphate* 28.182 Lactose9 28.182 Magnésium stéarate 2.000 Total 200.000 15 a équivalent to 3mg doxazosin based on a theoretical activity of 82.5%b as Polyox® WSR N 10 c as Polyox® WSR N 80
d as Methocel® K4M 20 e as Eudragit® L 100 55 f as anhydrous g as lactose fast flo 200mg tablets were prepared by the method of Example 1 (a). 25 (b) 010687 8
Ingrédient mg/tablet Doxazosin mesylate3 4.876 Polyethyleneoxide 100,000 MW° 20.000 Polyethyleneoxide 200,000 MW0 20.000 Hydroxypropylmethylcellulosea 60.000 Methacrylic acid copolymer type Ce 60.000 Dibasic calcium phosphate' 16.562 Lactose9 16.562 Magnésium stéarate Γ2.000 Total 200.000 a équivalent to 4mg doxazosin based on a theoretical activity of 82.5%b as Polyox® WSR N 10 c as Polyox® WSR N 80
5 d as Methocel® K4M e as Eudragit® L 100 55 f as anhydrous g as lactose fast flo 10 200mg tablets were prepared by the method of Example 1 (a).
Example 3
Sustained release formulations of doxazosin mesvlate having an enteric coat (a)
Ingrédient mg/unit Doxazosin mesylate tablets fromExample 1 (a) 200.000 Methacrylic acid copolymer type Ca 6.500 Triethyl citrate 0.650 Talc 3.250 Sodium hydroxide 0.090 Purified WaterD (41.510) Total 210.490 a as Eudragit® L100-55 b Lost during processing and does not appear in the final product
Ail of the ingrédients except the tablets were mixed together until the methacrylic acid20 copolymer had dispersed. This mixture was then appiied to the tablets by spraying to give a coating of the rèquired weight using conventional means. (b)
Ingrédient mg/unit Doxazosin mesylate tablets fromExample 2(a) 200.000 010687 9
Methacrylic acid copolymer type Ca 6.500 Triethyl citrate 0.650 Talc 3.250 Sodium hydroxide 0.090 Purified Water0 (41.510) Total 210.490 a as Eudragit® L 100-55 b Lost during Processing and does not appear in the final product 5 The tablets were coated by the method of (a). (c)
Ingrédient mg/unit Doxazosin mesylate tablets fromExample 2(a) 200.000 Methacrylic acid copolymer type Aa 3.985 Methacrylic acid copolymer type BD 3.985 Triethyl citrate 3.984 Ammonia solution0 0.058 Water content of ammonia solution0 (0.172) Talc 3.988 Purified Water0 (55.554) Total 216.000 a as Eudragit® L 100 10 b as Eudragit® S 100 c As ammonia solution sp.gr.0.91 (25% NH3). The aqueous component of thissolution is lost during Processing. d Lost during Processing and does not appear in the final product 15 The tablets were coated by the method of (a).
Example 4
Sustained release formulation of darifenacin hvdrobromide ingrédient mg/tablet Darifenacin hydrobromide 35.714 Poiyethyleneoxide 100,000 MW° 20.000 Polyethyleneoxide 200,000 MW° 20.000 Hydroxypropylmethylcellulose0 60.000 Lactose® 62.286 Magnésium stéarate ï 2.000 Total 200.000 20 010687 10 a équivalent to 30mg darifenacin based on a theoretical activity of 84.0%b as Polyox® WSR N 10 c as Polyox® WSR N 80
d as Methocel® K4M e as anhydrous 200mg tablets were prepared by the method of Example 1(a).
Example 5
Sustained release formulations of fluconazole (suitable for buccal administration) (a)
Ingrédient mg/tablet Fluconazole 20.000 Polyethyleneoxide 100,000 MW3 10.000 Polyethyleneoxide 200,000 MW° 10.000 Hydroxypropylmethylcellulosec 30.000 Lactose0 29.000 Magnésium stéarate 1.000 Total 100.000 a as Polyox® WSR N 10 b as Polyox® WSR N 80
c as Methocel® K4M d as lactose fastflo 100mg tablets were prepared by the method of Example 1(a). (b)
Ingrédient mg/tablet Fluconazole 10.000 Polyethyleneoxide 100,000 MWa 7.500 Hydroxypropylmethylcellulose0 22.500 Dibasic calcium phosphatee 34.250 Magnésium stéarate 0.750 Total 75.000 a as Polyox® WSR N 10
b as Methocel® K4M c as anhydrous 100mg tablets were prepared by the method of Example 1(a).
Examole 6 (Comparative)
Sustained release formulation of doxazosin mesvlate not containing polvethyleneoxide 01068? 11
Ingrédient mg/tablet Doxazosin mesylate3 3.636 Hydroxypropylmethylcelluloseb 60.000 Dibasic calcium phosphate6 67.182 Lactose0 67.182 Magnésium stéarate 2.000 Total 200.000
a équivalent to 3mg doxazosin based on a theoretical activity of 82.5%b as Methocel® K4M 5 c as anhydrous d as lactose fast flo 200mg tablets were prepared by the method of Example 1 (a). 10 Example 7
Dissolution analysis
The tablets of Examples 1(a), 1(b) and 6 were dissolved using Apparatus 1 of USP 22,page 1578, Method 1 (baskets). The dissolution fluid was 900ml of water at 37°C, the 15 rotation speed of the baskets was 100 rpm, and the drug compound released wasdetected by UV spectroscopy at a wavelength of 246 nm. The percentage of drugcompound released vtime for each tablet type is shown in Figure 1.
The tablets of Example 2(a) were dissolved using Apparatus 1 of USP 22, page 1578, 20 Method 1 (baskets). The dissolution fluid was 900ml of acidic medium [1M HCl, 100ml;NaCI, 70.2g; water, to 10 litres; pH=2] at 37°C for 2 hours, which was then replaced withneutral pH medium [KH2PO4, 8.7g; KCI, 47.4g; NaCI, 20.3g; 1M NaOH, 52ml; water, to 10litres] which was used for the remainder of the experiment. The rotation speed of thebaskets was 200 rpm, and the drug compound released was detected by UV spectros- 2 5 copy at a wavelength of 246 nm. The percentage of drug compound released v time isshown in Figure 2.

Claims (25)

1. A controiled-release pharmaceutical formulation for oral administration consisting i essentially of: an active drug compound; low moiecular weight polyethyiene oxide; j hydroxypropylmethyl cellulose; tabletting excipients; and optionally one or more entericpolymers.
2. A formulation as claimed in claim 1, wherein the active drug compound is weaklybasic.
3. A formulation as claimed in claim 1 or claim 2, wherein the active drug compound isdoxazosin, or a pharmaceutically acceptable sait thereof.
4. A formulation as claimed in claim 1, wherein the active drug compound has a high 'Osolubility in aqueous media.
5. A formulation as claimed in claim 1, wherein the active drug compound has a lowsolubility in aqueous media.
6. A formulation as claimed in any one of the preceding claims, wherein the hy-droxypropylmethyl cellulose has a number average moiecular weight in the range 80,000-250,000.
7. A formulation as claimed in any one of the preceding claims, wherein the hy-droxypropylmethyl cellulose has a degree of methyl substitution in the range 19-30 %.
8. A formulation as claimed in any one of the preceding claims, wherein the hy-droxypropylmethyl cellulose has a degree of hydroxy substitution in the range 4-12 %.
9. A formulation as claimed in any one of the preceding claims, wherein the polyethyl-ene oxide has a number average moiecular weight in the range 20,000-500,000.
10. A formulation as claimed in claim 9, wherein the polyethyiene oxide has a numberaverage moleculan/veight in the range 100,000-300,000.
11. A formulation as claimed in any one of the preceding claims, wherein an entericpolymer is admixed with the other components of the formulation.
12. A formulation as claimed in any one of the preceding claims, which has a coatingcontaining an enteric polymer.
12 01068? Claims:
13. A formulation as claimed in claim 11 or claim 12, wherein the enteric polymer ismethacrylic acid copolÿmer.
14. A formulation as claimed in any one of the preceding claims, which contains up to50% by weight of active drug compound.
15. A formulation as claimed in any one of the preceding claims, which contains 5-30%by weight of low moiecular weight polyethyiene oxide. 13 010687
16. A formulation as claimed in any one of the preceding daims, which contains 10-60%by weight of hydroxypropylmethyl cellulose.
17. A formulation as claimed in any one of the preceding daims, which contains 10-40%by weight of enteric polymer by weight admixed with the other components of the 5 formulation.
18. A formulation as claimed in any one of the preceding daims, wherein the mass ratioof low molecular weight polyethylene oxide:hydroxypropylmethyl cellulose is in the range2:1-1:5.
19. A formulation as claimed in any one of daims 11-18, wherein the mass ratio of (low 10 molecular weight polyethylene oxide+hydroxypropylmethyl cellulose): admixed enteric polymer is in the range 1:2-6:1.
20. A formulation as claimed in daim 19, wherein the mass ratio of (low molecularweight polyethylene oxide+hydroxypropylmethyl cellulose): admixed enteric polymer is inthe range 1:2-2:1. 15
21. A formulation as claimed in any one of daims 12-20, wherein the enteric coating makes up 2-15% by weight of the formulation.
22. A formulation as claimed in daim 21, wherein the enteric coating makes up 5-10%by weight of the formulation.
23. The use of low molecular weight polyethylene oxide in an oral controlled-release 20 pharmaceutical formulation, having a hydroxypropylmethyl cellulose matrix, to enhance the érosion of the matrix after a predetermined period of time following administration ofthe formulation to a patient.
24. The use as claimed in daim 23, wherein the predetermined period of time is 6hours.
25 25. A process for the production of a pharmaceutical formulation as defined in daim 1, which comprises mixing: an active drug compound; low molecular weight polyethyleneoxide; hydroxypropylmethyl cellulose; tabletting excipients; and optionally one or moreenteric poiymers; followed by pressing into tablets.
OA9800058A 1995-11-21 1998-05-19 Pharmaceutical formulations OA10687A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GBGB9523752.5A GB9523752D0 (en) 1995-11-21 1995-11-21 Pharmaceutical formulations

Publications (1)

Publication Number Publication Date
OA10687A true OA10687A (en) 2002-11-27

Family

ID=10784188

Family Applications (1)

Application Number Title Priority Date Filing Date
OA9800058A OA10687A (en) 1995-11-21 1998-05-19 Pharmaceutical formulations

Country Status (29)

Country Link
EP (1) EP0862437A1 (en)
JP (1) JPH10513481A (en)
KR (1) KR19990071505A (en)
CN (1) CN1215993A (en)
AP (1) AP718A (en)
AR (1) AR004335A1 (en)
AU (1) AU709560B2 (en)
BG (1) BG102438A (en)
BR (1) BR9611626A (en)
CA (1) CA2232715A1 (en)
CO (1) CO4480020A1 (en)
CZ (1) CZ155498A3 (en)
GB (1) GB9523752D0 (en)
HR (1) HRP960554A2 (en)
HU (1) HUP9903734A3 (en)
IS (1) IS4706A (en)
MA (1) MA26410A1 (en)
MX (1) MX9804008A (en)
NO (1) NO982302L (en)
NZ (1) NZ322053A (en)
OA (1) OA10687A (en)
PE (1) PE22898A1 (en)
PL (1) PL326981A1 (en)
SK (1) SK63098A3 (en)
TN (1) TNSN96141A1 (en)
TR (1) TR199800902T2 (en)
WO (1) WO1997018814A1 (en)
YU (1) YU62096A (en)
ZA (1) ZA969722B (en)

Families Citing this family (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ504487A (en) * 1997-12-16 2002-11-26 Pfizer Prod Inc Combination of alpha-adrenergic antagonists and cGMP elevators for the treatment of impotence
BR9908911A (en) 1998-03-19 2001-10-02 Bristol Myers Squibb Co Biphasic system and distribution process by controlled release of high solubility pharmaceutical substances
GT199900061A (en) * 1998-05-15 2000-10-14 Pfizer PHARMACEUTICAL FORMULATIONS.
EP0987020A1 (en) * 1998-09-04 2000-03-22 Pharma Pass LLC Metoprolol composition and processes for manufacturing the same
EP0974343B1 (en) * 1998-07-22 2004-09-29 Pharma Pass II LLC Process for manufacturing a solid metoprolol composition
CO5140079A1 (en) * 1998-10-14 2002-03-22 Novartis Ag PHARMACEUTICAL COMPOSITION OF SUSTAINED LIBERATION AND METHOD TO RELEASE A PHARMACEUTICALLY ACTIVE AGENT FROM SUSTAINED LIBERATION AND METHOD TO RELEASE A PHARMACEUTICALLY ACTIVE AGENT
UA67802C2 (en) * 1998-10-23 2004-07-15 Пфайзер Рісьоч Енд Дівелепмент Компані, Н.В./С.А. CONTROLLED-RELEASE FORMULATIONS FOR ORAL ADMINISTRATION CONTAINING cGMP PDE-5 INHIBITOR (VARIANTS), METHOD FOR ITS PREPARATION AND METHOD FOR TREATING ERECTILE DYSFUNCTION
US20030059467A1 (en) * 2001-09-14 2003-03-27 Pawan Seth Pharmaceutical composition comprising doxasozin
TWI312285B (en) 2001-10-25 2009-07-21 Depomed Inc Methods of treatment using a gastric retained gabapentin dosage
US6723340B2 (en) 2001-10-25 2004-04-20 Depomed, Inc. Optimal polymer mixtures for gastric retentive tablets
US7612112B2 (en) 2001-10-25 2009-11-03 Depomed, Inc. Methods of treatment using a gastric retained gabapentin dosage
US8329217B2 (en) 2001-11-06 2012-12-11 Osmotica Kereskedelmi Es Szolgaltato Kft Dual controlled release dosage form
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
WO2005037247A2 (en) * 2003-10-17 2005-04-28 Ranbaxy Laboratories Limited Oral matrix formulations of doxazosin
US20050255157A1 (en) * 2004-05-11 2005-11-17 Glenmark Pharmaceuticals Limited Sustained release, mucoadhesive vaginal pharmaceutical compositions
KR100574554B1 (en) * 2004-05-28 2006-04-27 한미약품 주식회사 Sustained release composition for oral administration of niacin
DE102004054054A1 (en) 2004-11-05 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines
KR100679111B1 (en) * 2004-11-20 2007-02-07 대우약품공업주식회사 A sustained release tablet comprising doxazosin
CA2619035A1 (en) * 2005-08-22 2007-03-01 Novartis Ag Pharmaceutical compositions
US20090176882A1 (en) 2008-12-09 2009-07-09 Depomed, Inc. Gastric retentive gabapentin dosage forms and methods for using same
AU2007242984B2 (en) 2006-04-26 2012-11-08 Supernus Pharmaceuticals Inc. Controlled released preparations of oxcarbazepine having sigmoidal release profile
PE20110235A1 (en) 2006-05-04 2011-04-14 Boehringer Ingelheim Int PHARMACEUTICAL COMBINATIONS INCLUDING LINAGLIPTIN AND METMORPHINE
EP1852108A1 (en) 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG DPP IV inhibitor formulations
CA2810522A1 (en) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Polymorphs
CN100396282C (en) * 2006-07-25 2008-06-25 山东省医药工业研究所 Slow released doxazosin mesilate capsule and its prepn process
SA07280459B1 (en) 2006-08-25 2011-07-20 بيورديو فارما إل. بي. Tamper Resistant Oral Pharmaceutical Dosage Forms Comprising an Opioid Analgesic
US8372432B2 (en) 2008-03-11 2013-02-12 Depomed, Inc. Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic
WO2009114648A1 (en) 2008-03-11 2009-09-17 Depomed Inc. Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic
PE20091730A1 (en) 2008-04-03 2009-12-10 Boehringer Ingelheim Int FORMULATIONS INVOLVING A DPP4 INHIBITOR
KR20190016601A (en) 2008-08-06 2019-02-18 베링거 인겔하임 인터내셔날 게엠베하 Treatment for diabetes in patients inappropriate for metformin therapy
US20200155558A1 (en) 2018-11-20 2020-05-21 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug
KR101004205B1 (en) * 2008-12-17 2010-12-24 동아제약주식회사 The controlled released pharmaceutical compsitions of udenafil for sustained release property
PL2395983T3 (en) 2009-02-13 2020-09-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprisng a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof
US8828953B2 (en) 2009-04-20 2014-09-09 NaZura BioHealth, Inc. Chemosensory receptor ligand-based therapies
US9901551B2 (en) 2009-04-20 2018-02-27 Ambra Bioscience Llc Chemosensory receptor ligand-based therapies
BRPI1013856A2 (en) 2009-04-20 2016-04-05 Elcelyx Therapeutics Inc chemosensitive receptor ligand-based therapies
KR102668834B1 (en) 2009-11-27 2024-05-24 베링거 인겔하임 인터내셔날 게엠베하 Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin
US20110150989A1 (en) * 2009-12-22 2011-06-23 Mallinkckrodt Inc. Methods of Producing Stabilized Solid Dosage Pharmaceutical Compositions Containing Morphinans
US9198861B2 (en) 2009-12-22 2015-12-01 Mallinckrodt Llc Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans
CN102946875A (en) 2010-05-05 2013-02-27 贝林格尔.英格海姆国际有限公司 Combination therapy
JP6042330B2 (en) 2010-07-09 2016-12-14 ビーエイチヴィ ファーマ、インコーポレイテッド Combined immediate / delayed delivery system for short half-life drugs including remogliflozin
KR20140114736A (en) 2010-10-19 2014-09-29 엘셀릭스 테라퓨틱스 인코포레이티드 Chemosensory receptor ligand-based therapies
AR083878A1 (en) 2010-11-15 2013-03-27 Boehringer Ingelheim Int VASOPROTECTORA AND CARDIOPROTECTORA ANTIDIABETIC THERAPY, LINAGLIPTINA, TREATMENT METHOD
WO2012094636A2 (en) 2011-01-07 2012-07-12 Elcelyx Therapeutics, Inc. Chemosensory receptor ligand-based therapies
CN102058555A (en) * 2011-01-13 2011-05-18 北京汇诚瑞祥医药技术有限公司 Doxazosin controlled release tablet
UY33937A (en) 2011-03-07 2012-09-28 Boehringer Ingelheim Int PHARMACEUTICAL COMPOSITIONS CONTAINING DPP-4 AND / OR SGLT-2 AND METFORMIN INHIBITORS
CN102188431A (en) * 2011-05-09 2011-09-21 浙江九旭药业有限公司 Doxazosin mesylate sustained-release tablets and preparation method thereof
US8858963B1 (en) 2011-05-17 2014-10-14 Mallinckrodt Llc Tamper resistant composition comprising hydrocodone and acetaminophen for rapid onset and extended duration of analgesia
US8741885B1 (en) 2011-05-17 2014-06-03 Mallinckrodt Llc Gastric retentive extended release pharmaceutical compositions
US8658631B1 (en) 2011-05-17 2014-02-25 Mallinckrodt Llc Combination composition comprising oxycodone and acetaminophen for rapid onset and extended duration of analgesia
US20130143867A1 (en) 2011-12-02 2013-06-06 Sychroneuron Inc. Acamprosate formulations, methods of using the same, and combinations comprising the same
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
WO2013158928A2 (en) 2012-04-18 2013-10-24 Elcelyx Therapeutics, Inc. Chemosensory receptor ligand-based therapies
EP3685839A1 (en) 2012-05-14 2020-07-29 Boehringer Ingelheim International GmbH Linagliptin for use in the treatment of albuminuria and kidney related diseases
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
CN105431144A (en) 2013-06-05 2016-03-23 思康脑侒股份有限公司 Acamprosate formulations, methods of using the same, and combinations comprising the same
ES2950384T3 (en) 2014-02-28 2023-10-09 Boehringer Ingelheim Int Medical use of a DPP-4 inhibitor
CN105616378A (en) * 2014-10-31 2016-06-01 康普药业股份有限公司 Fluconazole capsule and preparation method therefor
MX2018015089A (en) 2016-06-10 2019-05-13 Boehringer Ingelheim Int Combinations of linagliptin and metformin.

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1198386B (en) * 1982-07-06 1988-12-21 Lepetit Spa A PROTRACTED RELEASE PRODUCT CONTAINING SULOCTIDYL
US4765989A (en) * 1983-05-11 1988-08-23 Alza Corporation Osmotic device for administering certain drugs
US4837111A (en) * 1988-03-21 1989-06-06 Alza Corporation Dosage form for dispensing drug for human therapy
IL92966A (en) * 1989-01-12 1995-07-31 Pfizer Dispensing devices powered by hydrogel
PT98374A (en) * 1990-07-23 1994-01-31 Alza Corp OSMOTIC DEVICE FOR NICOTINE SYSTEMIC ADMINISTRATION AND NICOTINE BASED PROCESS

Also Published As

Publication number Publication date
BR9611626A (en) 1999-06-01
JPH10513481A (en) 1998-12-22
CZ155498A3 (en) 1999-03-17
IS4706A (en) 1998-03-31
CN1215993A (en) 1999-05-05
WO1997018814A1 (en) 1997-05-29
GB9523752D0 (en) 1996-01-24
MA26410A1 (en) 2004-12-20
PL326981A1 (en) 1998-11-09
AU709560B2 (en) 1999-09-02
HUP9903734A3 (en) 2000-04-28
KR19990071505A (en) 1999-09-27
AR004335A1 (en) 1998-11-04
TR199800902T2 (en) 1998-09-21
AU7572196A (en) 1997-06-11
TNSN96141A1 (en) 2005-03-15
SK63098A3 (en) 1999-05-07
NO982302L (en) 1998-07-17
ZA969722B (en) 1998-05-20
NO982302D0 (en) 1998-05-20
HUP9903734A2 (en) 2000-03-28
HRP960554A2 (en) 1998-02-28
BG102438A (en) 1999-01-29
EP0862437A1 (en) 1998-09-09
CA2232715A1 (en) 1997-05-29
AP9600883A0 (en) 1997-01-31
NZ322053A (en) 1999-11-29
MX9804008A (en) 1998-09-30
YU62096A (en) 1999-03-04
PE22898A1 (en) 1998-05-07
CO4480020A1 (en) 1997-07-09
AP718A (en) 1999-01-06

Similar Documents

Publication Publication Date Title
AU709560B2 (en) Pharmaceutical formulations
DE60121857T2 (en) Drug composition with delayed release of active ingredient
JP5420590B2 (en) pH independent extended release pharmaceutical composition
KR101858797B1 (en) Pharmaceutical compositions comprising hydromorphone and naloxone
US20090196923A1 (en) Controlled release formulation comprising anti-epileptic drugs
US11291660B2 (en) Method of treating heart failure with preserved ejection fraction by administering milrinone
BG107372A (en) Sustained-release preparations of quinolone antibiotics and method for preparation thereof
JP2009513622A (en) Pharmaceutical formulation of losartan
WO2004058229A1 (en) Modified release formulations of selective serotonin re-uptake inhibitors
US20060210623A1 (en) Sustained release delivery of isradipine
US20060147530A1 (en) Sustained release compositions containing alfuzosin
EP2503996A2 (en) Controlled release pharmaceutical compositions of galantamine
EP1317925B1 (en) Microgranules of Ursodeoxycholic acid
JP5826456B2 (en) Controlled release formulation comprising an uncoated discrete unit and an extended release matrix
WO2009087663A2 (en) Oral controlled release coated tablet
US20030035834A1 (en) Sustained release verapamil pharmaceutical composition free of food effect and a method for alleviating food effect in drug release
US20080206338A1 (en) Controlled release formulations of an alpha-adrenergic receptor antagonist
EP1680078A2 (en) Oral matrix formulations of doxazosin
NZ732954B2 (en) Method of Treating Heart Failure with Preserved Ejection Fraction with 5-(Pyridinyl)-2(1H)-pyridinone Compounds
RU98111607A (en) PHARMACEUTICAL FINISHED FORMS
JP2707023C (en)