EP0862437A1 - Pharmaceutical formulations - Google Patents

Pharmaceutical formulations

Info

Publication number
EP0862437A1
EP0862437A1 EP96938215A EP96938215A EP0862437A1 EP 0862437 A1 EP0862437 A1 EP 0862437A1 EP 96938215 A EP96938215 A EP 96938215A EP 96938215 A EP96938215 A EP 96938215A EP 0862437 A1 EP0862437 A1 EP 0862437A1
Authority
EP
European Patent Office
Prior art keywords
formulation
molecular weight
polyethylene oxide
range
low molecular
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP96938215A
Other languages
German (de)
French (fr)
Inventor
Ross James Macrae
Janet Sarah Smith
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Ltd
Pfizer Research and Development Co NV SA
Original Assignee
Pfizer Ltd
Pfizer Research and Development Co NV SA
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 Ltd, Pfizer Research and Development Co NV SA filed Critical Pfizer Ltd
Publication of EP0862437A1 publication Critical patent/EP0862437A1/en
Withdrawn legal-status Critical Current

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

Definitions

  • This invention relates to controlled-release oral pharmaceutical formulations
  • Controlled-release oral pharmaceutical formulations are known Their purpose is to modify the rate of drug release, for example to produce a constant rate of release of a drug into the gastrointestinal tract of a patient, or to delay the release of a drug into the gastrointestinal tract of a patient (see 'Sustained and Controlled Release Drug Delivery Systems', pp 3-6, edited by J R Robinson, published by Marcel Dekker Inc)
  • US Patent N° 4,765,989 discloses an osmotic delivery device for delivering inter alia nifedipi ⁇ e or doxazosin It has a perforated semipermeable wall enclosing a drug composition which includes an osmopolymer, and a pusher composition containing a second osmopolymer
  • a drug composition which includes an osmopolymer
  • a pusher composition containing a second osmopolymer The performance of this prior art device is satisfactory, but it has the disadvantage that it is very complicated, leading to high manufacturing costs
  • UK Patent Application 2,123,291 discloses a sustained release formulation of suloctidil which is a two-part tablet a first part is a prompt-release portion and a second part is a slow-release portion, which must contain a surface-active agent to promote bio-erosion
  • US Patent N° 5,393,765 discloses an erodibie pharmaceutical composition providing a zero order controlled release profile, comprising low viscosity hydroxypropylmethyl cellulose
  • 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 of the present invention may also be administered buccally (i e placed behind the top lip and allowed to dissolve) and the term includes such formulations "Consisting essentially of means that at least 95% by weight of the formulation is made up of the listed components. At least 99% by weight of uncoated formulations, and the cores 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".
  • polyethylene glycol Polyethylene glycol
  • low molecular weight polyethylene oxide is used to refer to polymerized ethylene oxide in the number 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 magnesium stearate.
  • the first class is weakly basic compounds. Examples of this class include dipyridamole, noscapine, papaverine, doxazosin, sildenafil and prazosin. Doxazosin and its pharmaceutically acceptable salts are of particular interest.
  • the second class are compounds having high solubility in aqueous media.
  • this class include salbutamol, metoprolol, propanolol, aminophylline, isosorbide mono- and dinitrate, glyceryl trinitrate, verapamil, captopril, diltiazem, morphine, chlorpheni- ramine, promethazine, eletriptan, darifenacin and fluconazole.
  • the third class are compounds having low solubility in aqueous media.
  • Examples of this class include nifedipine, griseofulvin, carbamazepine, felodipine, nimodipine and megestrol.
  • solubility in aqueous media and “low solubility in aqueous media” will be understood by those skilled in the art. However, the former may be defined as a solubility
  • Formulations according to the invention have the advantage that they produce a constant rate of release of drugs that are weakly basic and/or have a high solubility in aqueous media in in vitro models of the gastrointestinal tract, and so are expected to produce a constant rate of release of the drug in the gastrointestinal tract of a patient.
  • the formulations of the invention have the advantage that they produce a delayed or pulsed release of the drug.
  • the formulations are very simple and so can be manufactured at a compara ⁇ tively low cost.
  • the hydroxypropylmethyl cellulose has a number average molecular weight in the range 80,000-250,000.
  • the hydroxypropylmethyl cellulose has a degree of methyl substitution in the range 19-30 %.
  • the hydroxypropylmethyl cellulose has a degree of hydroxy substitution in the range 4-12 %.
  • a number of hydroxypropylme- thyl cellulose polymers are available commercially under the brand name Methocel®, and some of those suitable for use in formulations according to the invention are given in the table below:
  • Methocel® K4M has characteristics of particular interest.
  • the low molecular weight polyethylene oxide has a number average molecular weight in the range 20,000 to 500,000, more preferably 100,000-300,000.
  • Polyethylene oxide with a number average molecular weight above 100,000 is a powder, which makes it easier to handle than lower molecular weight polyethylene oxide, which has a lower melting point.
  • polyethylene oxide with a number average molecular weight of 6000 has a melting point of 60-63°C It will be apparent to those skilled in the art that the polyethylene oxide may consist of molecules of different chain lengths, but that the average chain length gives a molecular weight in the range stated. The same applies to the hydroxypropylmethyl cellulose.
  • Formulations according to the invention may contain an enteric polymer admixed with the other components of the formulation.
  • formulations according to the invention are preferably provided with a coating of an enteric polymer.
  • Enteric polymers that may be mentioned are phthalate derivatives (including cellulose acetate phthalate, polyvinyiacetate phthalate and hydroxypropylmethyl cellulose phthalate), polyacrylic acid derivatives (including methacrylic acid copolymer), and vinyl acetate and crotonic acid copolymers. Methacrylic acid copolymer is of particular interest.
  • the formulation contains up to 50% by weight of active drug compound, for example 1-20%.
  • formulations of the invention contain 5-30% by weight of low molecular weight polyethylene oxide, for example 8-10%.
  • the formulations of the invention contain 10-60% by weight of hydroxypropyl- methyl cellulose, for example 25-35%.
  • Formulations having enteric polymer admixed with the other components of the formula ⁇ tion preferably have 10-40% by weight of admixed enteric polymer, for example 25-35%.
  • the mass ratio of low molecular weight polyethylene oxide:hydroxypropylmethyl cellulose is in the range 2:1- 1 :5.
  • the mass ratio of (low molecular weight polyethylene ox- ide+hydroxypropylmethyl cellulose):admixed enteric polymer is in the range 1 :2-6: 1 , more preferably 1 :2-2:1.
  • the enteric coating (where present) makes up 2-15% by weight of the formulation, more preferably 5-10% by weight of the formulation.
  • the use of low molecular weight polyethylene oxide in an oral controlled-release pharmaceutical formulation having a hydroxypropylmethyl cellulose matrix, to enhance the erosion of the matrix after a predetermined period of time following administration of the formulation to a patient
  • the predetermined period of time is 6 hours In this way, a constant rate of drug release can be achieved in the gastrointestinal tract of a patient despite the varying conditions which exist along its length
  • a process for the production of a pharmaceutical formulation as defined in claim 1 which comprises mixing an active drug compound, low molecular weight polyethylene oxide, hydroxypropylmethyl cellulose, tabletting excipients, and optionally one or more enteric polymers, followed by pressing into tablets
  • formulations according to the present invention may be measured in a model of the gastrointestinal tract such as Apparatus 1 of USP 22, page
  • Figure 1 shows the percentage of drug compound released v time from formulations according to the invention [as prepared in Examples 1 (a) and 1 (b)] in comparison with a control [as prepared in Example 6] using simple dissolution testing
  • Figure 2 shows the percentage of drug compound released v time from a formulation according to the invention [as prepared in Example 2(a)] using dissolution testing with first an acidic and then a neutral dissolution medium
  • Methacrylic acid copolymer type C a 6 500
  • Example 5 Sustained release formulations of fluconazole (suitable for buccal administration.
  • Example 1 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 rotation speed of the baskets was 100 rpm
  • the drug compound released was detected by UV spectroscopy at a wavelength of 246 nm
  • the percentage of drug compound released v time for each tablet type is shown in Figure 1
  • Example 2(a) The tablets of Example 2(a) were dissolved using Apparatus 1 of USP 22, page 1578, Method 1 (baskets)
  • the rotation speed of the baskets was 200 rpm, and the drug compound released was detected by UV spectros- copy at a wavelength of 246 nm
  • the percentage of drug compound released v time is shown in Figure 2

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  • 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

Pharmaceutical formulations
This invention relates to controlled-release oral pharmaceutical formulations
Controlled-release oral pharmaceutical formulations are known Their purpose is to modify the rate of drug release, for example to produce a constant rate of release of a drug into the gastrointestinal tract of a patient, or to delay the release of a drug into the gastrointestinal tract of a patient (see 'Sustained and Controlled Release Drug Delivery Systems', pp 3-6, edited by J R Robinson, published by Marcel Dekker Inc)
US Patent N° 4,765,989 discloses an osmotic delivery device for delivering inter alia nifedipiπe or doxazosin It has a perforated semipermeable wall enclosing a drug composition which includes an osmopolymer, and a pusher composition containing a second osmopolymer The performance of this prior art device is satisfactory, but it has the disadvantage that it is very complicated, leading to high manufacturing costs
UK Patent Application 2,123,291 discloses a sustained release formulation of suloctidil which is a two-part tablet a first part is a prompt-release portion and a second part is a slow-release portion, which must contain a surface-active agent to promote bio-erosion
US Patent N° 5,393,765 discloses an erodibie pharmaceutical composition providing a zero order controlled release profile, comprising low viscosity hydroxypropylmethyl cellulose
According to the present invention, there is provided 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
Primarily 'oral administration ' means administration to the mouth followed by swallowing
However, the formulations of the present invention may also be administered buccally (i e placed behind the top lip and allowed to dissolve) and the term includes such formulations "Consisting essentially of means that at least 95% by weight of the formulation is made up of the listed components. At least 99% by weight of uncoated formulations, and the cores 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 "low molecular weight polyethylene oxide" is used to refer to polymerized ethylene oxide in the number 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 magnesium stearate.
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, sildenafil and prazosin. Doxazosin and its pharmaceutically acceptable salts are of particular interest.
The second class are compounds having high solubility in aqueous media. Examples of this class include salbutamol, metoprolol, propanolol, aminophylline, isosorbide mono- and dinitrate, glyceryl trinitrate, verapamil, captopril, diltiazem, morphine, chlorpheni- ramine, promethazine, eletriptan, darifenacin and fluconazole.
The third class are compounds having low solubility in aqueous media. Examples of this class include nifedipine, griseofulvin, carbamazepine, felodipine, nimodipine and megestrol.
The terms "high solubility in aqueous media" and "low solubility in aqueous media" will be understood by those skilled in the art. However, the former may be defined as a solubility
>1 mg/ml in water, and the latter may be defined as a solubility <1 mg/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 have a high solubility in aqueous media. Formulations according to the invention have the advantage that they produce a constant rate of release of drugs that are weakly basic and/or have a high solubility in aqueous media in in vitro models of the gastrointestinal tract, and so are expected to produce a constant rate of release of the drug in the gastrointestinal tract of a patient. When the drug to be administered has a low solubility in aqueous media, the formulations of the invention have 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.
Preferably, the hydroxypropylmethyl cellulose has a number average molecular weight in the range 80,000-250,000. Preferably, the hydroxypropylmethyl cellulose has a degree of methyl substitution in the range 19-30 %. Preferably, the hydroxypropylmethyl cellulose has a degree of hydroxy substitution in the range 4-12 %. A number of hydroxypropylme- thyl cellulose polymers are available commercially under the brand name Methocel®, and some of those suitable for use in formulations according to the invention are given in the table below:
Methocel® K4M has characteristics of particular interest.
Preferably, the low molecular weight polyethylene oxide has a number average molecular weight in the range 20,000 to 500,000, more preferably 100,000-300,000. Polyethylene oxide with a number average molecular weight above 100,000 is a powder, which makes it easier to handle than lower molecular weight polyethylene oxide, which has a lower melting point. For example, polyethylene oxide with a number average molecular weight of 6000 has a melting point of 60-63°C It will be apparent to those skilled in the art that the polyethylene oxide may consist of molecules of different chain lengths, but that the average chain length gives a molecular weight in the range stated. The same applies to the hydroxypropylmethyl cellulose.
Formulations according to the invention may contain an enteric polymer admixed with the other components of the formulation. In addition or altematively, formulations according to the invention are preferably provided with a coating of an enteric polymer. Enteric polymers that may be mentioned are phthalate derivatives (including cellulose acetate phthalate, polyvinyiacetate phthalate and hydroxypropylmethyl cellulose phthalate), polyacrylic acid derivatives (including methacrylic acid copolymer), and vinyl acetate and crotonic acid copolymers. Methacrylic acid copolymer is of particular interest.
Preferably, the formulation contains up to 50% by weight of active drug compound, for example 1-20%.
It is preferred that the formulations of the invention contain 5-30% by weight of low molecular 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 polymer admixed with the other components of the formula¬ tion preferably have 10-40% by weight of admixed enteric polymer, for example 25-35%.
In formulations according to the present invention, it is preferred that the mass ratio of low molecular weight polyethylene oxide:hydroxypropylmethyl cellulose is in the range 2:1- 1 :5.
In formulations according to the present invention containing admixed enteric polymer, it is preferred that the mass ratio of (low molecular weight polyethylene ox- ide+hydroxypropylmethyl cellulose):admixed enteric polymer is in the range 1 :2-6: 1 , more preferably 1 :2-2:1. Preferably, the enteric coating (where present) makes up 2-15% by weight of the formulation, more preferably 5-10% by weight of the formulation. According to another aspect of the invention, there is provided the use of low molecular weight polyethylene oxide in an oral controlled-release pharmaceutical formulation, having a hydroxypropylmethyl cellulose matrix, to enhance the erosion of the matrix after a 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 drug release can be achieved in the gastrointestinal tract of a patient despite the varying conditions which exist along its length
By varying the proportion of polyethylene oxide in the formulation it is possible to control the onset of enhancement of matπx erosion and so the onset of increased drug release following administration of the formulation to a patient
According to a yet further aspect of the invention, there is provided a process for the production of a pharmaceutical formulation as defined in claim 1 , which comprises mixing an active drug compound, low molecular weight polyethylene oxide, hydroxypropylmethyl cellulose, tabletting excipients, and optionally one or more enteric polymers, followed by pressing into tablets
The drug release properties of formulations according to the present invention may be measured in a model of the gastrointestinal tract such as Apparatus 1 of USP 22, page
1578, Method 1 (baskets)
The invention is illustrated by the following examples with reference to the accompanying drawings, in which Figure 1 shows the percentage of drug compound released v time from formulations according to the invention [as prepared in Examples 1 (a) and 1 (b)] in comparison with a control [as prepared in Example 6] using simple dissolution testing, and Figure 2 shows the percentage of drug compound released v time from a formulation according to the invention [as prepared in Example 2(a)] using dissolution testing with first an acidic and then a neutral dissolution medium
Example 1
Sustained release formulations of doxazosin mesylate
(a)
Ingredient I mg/tablet Doxazosin mesylate3 3.636
Polyethyleneoxide 100,000 MW° 9.000
Polyethyleneoxide 200,000 MW° 9.000
Hydroxypropylmethylcellulose0 60.000
Dibasic calcium phosphate6 58.182
Lactose' 58.182
Magnesium stearate 2.000
Total 200.000
a equivalent 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 e as anhydrous f as lactose fast flo
All of the ingredients except the magnesium stearate were blended together in a Turbula blender for 10 minutes. The mixture was then screened using a 30 mesh (500μm apertures) screen and reblended for a further 10 minutes. Then the magnesium stearate was screened through a 30 mesh (500μm apertures) screen and added to the mixture before blending for a further 5 minutes. The blend was then subjected to compression on a tabletting machine using 8mm round normal convex tooling to make the required number of tablets of 200 mg mass.
(b)
Ingredient mg/tablet
Doxazosin mesylate3 4.876
Polyethyleneoxide 100,000 MW° 20.000
Polyethyleneoxide 200,000 MW° 20.000
Hydroxypropylmethylcellulose0 60.000
Dibasic calcium phosphate6 46.562
Lactose1 46.562
Magnesium stearate 2.000
Total 200.000 a equivalent to 4mg 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 e as anhydrous f as lactose fast flo
200mg tablets were prepared by the method of (a). (c)
Ingredient mg/tablet
Doxazosin mesylate3 4.876
Polyethyleneoxide 100,000 MW° 30.000
Polyethyleneoxide 200,000 MW° 30 000
Hydroxypropylmethylcellulose0 60.000
Dibasic calcium phosphate6 36.562
Lactose' 36.562
Magnesium stearate 2.000
Total 200.000
a equivalent to 4mg 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 e as anhydrous f as lactose fast flo
200mg tablets were prepared by the method of (a)
Example 2
Sustained release formulations of doxazosin mesylate containing an enteric polymer
(a)
Ingredient mg/tablet
Doxazosin mesylate3 3.636
Polyethyleneoxide 100,000 MW° 9.000
Polyethyleneoxide 200,000 MW° 9.000
Hydroxypropylmethylcellulose0 60 000
Methacrylic acid copolymer type6 C 60.000
Dibasic calcium phosphate' 28.182
Lactose9 28.182
Magnesium stearate 2.000
Total 200.000 a equivalent 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 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)
(b) Ingredient mg/tablet
Doxazosin mesylate3 4 876
Polyethyleneoxide 100,000 MW° 20 000
Polyethyleneoxide 200,000 MW° 20 000
Hydroxypropylmethylcellulose0 60 000
Methacrylic acid copolymer type Ce 60 000
Dibasic calcium phosphate' 16 562
Lactose9 16 562
Magnesium stearate 2 000
Total 200 000 a equivalent to 4mg 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 e as Eudragιt® L 100 55 f as anhydrous g as lactose fast flo
200mg tablets were prepared by the method of Example 1 (a)
Example 3
Sustained release formulations of doxazosin mesylate having an enteric coat
(a)
Ingredient mg/unit
Doxazosin mesylate tablets from 200 000 Example 1 (a)
Methacrylic acid copolymer type Ca 6 500
Triethyl citrate 0 650
Talc 3 250
Sodium hydroxide 0 090
Purified Water" (41 510)
Total 210 490
a as Eudragit® L 100-55 b Lost during processing and does not appear in the final product
Al! of the ingredients except the tablets were mixed together until the methacrylic acid copolymer had dispersed This mixture was then applied to the tablets by spraying to give a coating of the required weight using conventional means
(b)
Ingredient mg/unit
Doxazosin mesylate tablets from 200 000 Example 2(a) 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
The tablets were coated by the method of (a)
(c)
Ingredient mg/unit
Doxazosin mesylate tablets from 200 000 Example 2(a)
Methacrylic acid copolymer type A3 3.985
Methacrylic acid copolymer type B° 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 b as Eudragit® S 100 c As ammonia solution sp gr 0 91 (25% NH3) The aqueous component of this solution is lost during processing d Lost during processing and does not appear in the final product
The tablets were coated by the method of (a)
Example 4
Sustained release formulation of danfenacin hydrobromide
Ingredient mg/tablet
Danfenacin hydrobromide 35 714
Polyethyleneoxide 100,000 MW" 20 000
Polyethyleneoxide 200 000 MW" 20 000
Hydroxypropylmethylcellulose0 60 000
Lactose6 62 286
Magnesium stearate 2 000
Total 200 000 a equivalent 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)
Ingredient mg/tablet
Fluconazole 20.000
Polyethyleneoxide 100,000 MW3 10.000
Polyethyleneoxide 200,000 MW° 10.000
Hydroxypropylmethylcellulose0 30.000
Lactose0 29.000
Magnesium stearate 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)
Ingredient mg/tablet
Fluconazole 10.000
Polyethyleneoxide 100,000 MWa 7.500
Hydroxypropylmethylcellulose0 22.500
Dibasic calcium phosphate0 34.250
Magnesium stearate 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)
Example 6 (Comparative)
Sustained release formulation of doxazosin mesylate not containing polyethyleneoxide ingredient mg/tablet
Doxazosin mesylate3 3 636
Hydroxypropylmethylcellulose0 60.000
Dibasic calcium phosphate0 67.182
Lactose0 67 182
Magnesium stearate 2 000
Total 200.000
a equivalent to 3mg doxazosin based on a theoretical activity of 82 5% b as Methocel® K4M c as anhydrous d as lactose fast flo
200mg tablets were prepared by the method of Example 1 (a).
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 rotation speed of the baskets was 100 rpm, and the drug compound released was detected by UV spectroscopy at a wavelength of 246 nm The percentage of drug compound released v time 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, Method 1 (baskets) The dissolution fluid was 900mi of acidic medium [1 M HCl, 100ml, NaCl, 70 2g, water, to 10 litres, pH=2] at 37°C for 2 hours, which was then replaced with neutral pH medium [KH2P04, 8 7g, KCI, 47.4g, NaCl, 20.3g, 1 M NaOH, 52ml, water, to 10 litres] which was used for the remainder of the experiment The rotation speed of the baskets was 200 rpm, and the drug compound released was detected by UV spectros- copy at a wavelength of 246 nm The percentage of drug compound released v time is shown in Figure 2

Claims

Claims:
1. 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.
2. A formulation as claimed in claim 1 , wherein the active drug compound is weakly basic.
3. A formulation as claimed in claim 1 or claim 2, wherein the active drug compound is doxazosin, or a pharmaceutically acceptable salt thereof.
4. A formulation as claimed in claim 1 , wherein the active drug compound has a high solubility in aqueous media.
5. A formulation as claimed in claim 1 , wherein the active drug compound has a low solubility in aqueous media.
6. A formulation as claimed in any one of the preceding claims, wherein the hy¬ droxypropylmethyl cellulose has a number average molecular 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 molecular weight in the range 20,000-500,000.
10. A formulation as claimed in claim 9, wherein the polyethylene oxide has a number average molecular weight in the range 100,000-300,000.
11. A formulation as claimed in any one of the preceding claims, wherein an enteric polymer is admixed with the other components of the formulation.
12. A formulation as claimed in any one of the preceding claims, which has a coating containing an enteric polymer 13 A formulation as claimed in claim 1 1 or claim 12, wherein the enteric polymer is methacrylic acid copolymer.
14 A formulation as claimed in any one of the preceding claims, which contains up to 50% 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 molecular weight polyethylene oxide 16 A formulation as claimed in any one of the preceding claims, which contains 10-60% by weight of hydroxypropylmethyl cellulose
17 A formulation as claimed in any one of the preceding claims, which contains 10-40% by weight of enteric polymer by weight admixed with the other components of the formulation
18 A formulation as claimed in any one of the preceding claims, wherein the mass ratio of low molecular weight polyethylene oxide hydroxypropylmethyl cellulose is in the range 2 1-1 5
19 A formulation as claimed in any one of claims 1 1-18, wherein the mass ratio of (low molecular weight polyethylene oxide+hydroxypropylmethyl cellulose) admixed enteric polymer is in the range 1 2-6 1
20 A formulation as claimed in claim 19, wherein the mass ratio of (low molecular weight polyethylene oxide+hydroxypropylmethyl cellulose) admixed enteric polymer is in the range 1 2-2 1 21 A formulation as claimed in any one of claims 12-20, wherein the enteric coating makes up 2-15% by weight of the formulation
22 A formulation as claimed in claim 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 pharmaceutical formulation, having a hydroxypropylmethyl cellulose matrix, to enhance the erosion of the matrix after a predetermined period of time following administration of the formulation to a patient
24 The use as claimed in claim 23, wherein the predetermined period of time is 6 hours 25 A process for the production of a pharmaceutical formulation as defined in claim 1 , which comprises mixing an active drug compound, low molecular weight polyethylene oxide hydroxypropylmethyl cellulose tabletting excipients and optionally one or more enteric polymers, followed by pressing into tablets
EP96938215A 1995-11-21 1996-11-11 Pharmaceutical formulations Withdrawn EP0862437A1 (en)

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GBGB9523752.5A GB9523752D0 (en) 1995-11-21 1995-11-21 Pharmaceutical formulations
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HUP9903734A3 (en) 2000-04-28
MX9804008A (en) 1998-09-30
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AP9600883A0 (en) 1997-01-31
AR004335A1 (en) 1998-11-04
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CA2232715A1 (en) 1997-05-29
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BG102438A (en) 1999-01-29
NO982302D0 (en) 1998-05-20
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AU7572196A (en) 1997-06-11
AU709560B2 (en) 1999-09-02
CN1215993A (en) 1999-05-05
OA10687A (en) 2002-11-27
ZA969722B (en) 1998-05-20
JPH10513481A (en) 1998-12-22
IS4706A (en) 1998-03-31
MA26410A1 (en) 2004-12-20
KR19990071505A (en) 1999-09-27
CO4480020A1 (en) 1997-07-09
PL326981A1 (en) 1998-11-09
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