CA2096962A1 - Composition containing antihistamine h2 receptor antagonists and bioadhesive material - Google Patents
Composition containing antihistamine h2 receptor antagonists and bioadhesive materialInfo
- Publication number
- CA2096962A1 CA2096962A1 CA002096962A CA2096962A CA2096962A1 CA 2096962 A1 CA2096962 A1 CA 2096962A1 CA 002096962 A CA002096962 A CA 002096962A CA 2096962 A CA2096962 A CA 2096962A CA 2096962 A1 CA2096962 A1 CA 2096962A1
- Authority
- CA
- Canada
- Prior art keywords
- histamine
- receptor antagonist
- treatment
- cimetidine
- gastric
- 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.)
- Abandoned
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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biophysics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
Buffered pharmaceutical compositions for the local treatment of gastric disorders comprising a histamine H2-receptor antagonist in intimate admixture with a bioadhesive material.
Description
W092/09286 ~ 0 96 9~? PCT/GB91/02063 Composition containing ant1h~stamine H2 receptor antagonists and b~oadhes~ve ~his inventlon relates to the treatment of gastric disorders and pharmaceutlcal compositions for use therein. More 5 particularly the lnvention relates to the local treatment o gastric disorders, especially acute gastric disorders such as acid indigestion, heartburn and gastritis, and gastric and peptic ulcer, usina orally administrable pharmaceutical compositions comprising a histamlne H2-receptor antagonist contained within a drug delivery system. Compositions for use in the invention are specifically adapted to provide local delivery across the stomach wall to the H~-receptor on _he ?a-ietal cell ~eceptor.
....
is~amine H2-recep~or ant2gonists, for example cimetidine, -anitidine, nizetidine and famotidine, reduce acid secretion by acting directly on the acid-secreting parietal cell located within the gastric gland of the stomach wall.
20 Although histamine H2-receptor antagonists are remarkably effec~ive in the treatment of many gastric disorders, in particular peptic and gastric ulcers, there exist certain patient groups which do not respond to treatment. In addition, the time lapse between dosing and onset of action, ~s limits the potential benefit of histamine H2-receptor antaaonists in the treatment of acute, self-limiting gastric disorders.
A significant propor~ion of gastric and peptic ulcer 30 patients, referred to as non-responders, do not respond to conventional histamine H2-receptor antagonist therapy.
(Walker et al.: Frequent non-response to histamine H2-receptor antagonists in cirrhotics; Gut, 30, 1105-9, 1989; and Brack A. et al.: Clinical failures with 35 cimetidine; Surgery, 88(3), 417-24.
W092/09286 ~ ~6 96~ PCT/GB91/02063
....
is~amine H2-recep~or ant2gonists, for example cimetidine, -anitidine, nizetidine and famotidine, reduce acid secretion by acting directly on the acid-secreting parietal cell located within the gastric gland of the stomach wall.
20 Although histamine H2-receptor antagonists are remarkably effec~ive in the treatment of many gastric disorders, in particular peptic and gastric ulcers, there exist certain patient groups which do not respond to treatment. In addition, the time lapse between dosing and onset of action, ~s limits the potential benefit of histamine H2-receptor antaaonists in the treatment of acute, self-limiting gastric disorders.
A significant propor~ion of gastric and peptic ulcer 30 patients, referred to as non-responders, do not respond to conventional histamine H2-receptor antagonist therapy.
(Walker et al.: Frequent non-response to histamine H2-receptor antagonists in cirrhotics; Gut, 30, 1105-9, 1989; and Brack A. et al.: Clinical failures with 35 cimetidine; Surgery, 88(3), 417-24.
W092/09286 ~ ~6 96~ PCT/GB91/02063
-2- ~ -In addition, the ~nown poor response to histamine H2-receptor antagonist treatment by hypersecreting patients, for e.Ya~ple critically ill, multiple trauma patients (Martin 5 L. et al.: Failure of cimetidine prophylaxis in the critically ill; Arch. Surg., 114, 492-6, 1979) or those wi~
Zollinger-Ellison syndrome (Stahile B.G. et al.: Failure or histamine H2-receptor antagonist therapy in Zollinger-Ellison syndrome; Am. J. Surg., 145, 17-23, 1983) 10 has led to the development of alternative treatments, notably the use of proton-pump inhibitors.
~istamine H2-receptor antagonists are o~ potential bener-t in the self-medlcation of acute, self-limiting gas.ric ~s disoràers such as hyperacidity. However, their slow onset of action is unlikely to meet the consumer requirement for rapid relief of symptoms.
Moreover, it will be appreciated that use of high dose 20 levels in an attempt to achieve rapid relief of symptoms is not appropriate for non-prescription use. Indeed, a reduction from the standard therapeutic dose would be desirable for self-medication.
2s Co-administration of histamine H2-receptor antagonists and other pharmaceutically active materials, including sucralfate and other antacids, has been investigated. The rationale for co-administration with antacid is that the antacid brings about rapid relief from the symptoms of 30 excess stomach acidity by neutralisation whereas the histamine H2-receptor antagonist acts independently by inhibiting secretion of acid from the parietal cell.
However, it is well known (Bodemar G. et al., Lancet, 1, 35 444-445, 1979; Mihaly G.W. et al., B.M.J., 285, 998 9, `1982;
Lin. J.H. et al., B.J. Clin. Pharmacol. 24, 551-3, 1987) w~ 92/09286 ~09~ PCT/GB91/0~063 _na~ when histamine H2-receptor an~agonists are co-administered with antacids, especially antacids with high acid-neutralising capacity, a substantial reduction in the plasma bioavailability of the histamine H2-receptor an~agonist is frequently observed. Histamine H2-receptor an.agonist - antacid combinations are therefore generally conrraindicated.
~ioadnesive materials have received considerable attention ~o as platforms for controlled drug delivery. They can be targetted to specific drug administration sites, prolong the -esidence time and ensure an optimal contact with the absorbina surface. Many different types of bioadhesive ~a_e-ials, both natural and synthetic, can be used in the :- ces~gn o. controlled drug delivery systems.
'' :' Sucralfate is a basic aluminium sulphate sucrose complex having ulcer healing and buffering properties. According to ~he literature, sucralfate has been shown to act by forming 20 a bioadhesive gel structure which is believed to provide a local protective barrier. It has been reported that su-_alfate does not interfere with the absorption of his~amine H2-receptor antagonists. Clinical studies have incicated a combination therapy to be of potential benefi-. -~s : -:
EP-A-O 286 781 (Heumann Pharma) relates to pharmaceutical preparations with cytoprotective effect on the gastrointestinal tract containing a combination of a his~amine H2-receptor antagonist and an antacid substance 30 which is able to give functional cytoprotection. Sucralfate - is identified as an example of the antacid substance. It is àescribed as giving functional cytoprotection but having a comparatively low acid-netutralising effect.
':
W O 92/09286 2~9~9~j~ PC~r/G B91/02063 EP-A-0 403 048 (Warner-Lambert~, published on December 19, 1990, describes medicated composltions comprising sucralfate and a therapeutically effective amount of a medicament which is a) substantially water insoluble, or b) a mixture of a 5 water-soluble medicament and a release-delaying material which on admixture forms a substantially water-insoluble medicament. In a preferred embodiment, the medicament is selected from the group consisting of inter alia antacids and anti-ulcer medicaments. Compositions comprising 0 sucralfate plus antacid and sucralfate plus an anti-ulcer medicament are described as cytoprotective compositions, useful in the treatment of peptic ulcers by forming an ulcer-adherent protective gel barrier.
EP~ O 193 400 (Reckitt and Colman) describes pharmaceutica~
compositions comprising mixtures of a histamine H2-receptor antagonist and sodium polyacrylate in the weight ratio 10 :
1 to 1 : 10. The compositions are described for use in the treatment of gastritis or of gastro-duodenal ulcers. The 20 compositi~ns may include an antacid. Use of antacid is described as resulting in a reduction in the viscosity of the liquid compositions, thereby providing some degree of viscosity control in the design of readily pourable liquid preparatlons .
2s US 4,615,697 (Robinson) discloses a controlled release composition comprising an effective amount of a treating agent, which may be a medicamen~, and a bioadhesive materlal which is a water-swellable and water-insoluble, fibrous, 30 cross-linked càrboxy-functional polymer. The controlled release compositions are described as adhering to the skin or to mucous meMbranes in the presence of water. Cimetidine is listed as an example of a medicament.
~S Current treatments using histamine H2-receptor antagonists act systemically, i.e. the histamine H2--receptor antagonist W O 92/09286 - X ~ PC~r/G B91/02063 is dellvered to the parietal cell receptor from the blood.
International Patent Application No. pcT/Gs9l/oo953 describes oral treatment of gastric dlsorders using a 5 histamine H2-receptor antagonist in combination with an antacid to promote local dellvery of the histamine H2-receptor antagonist to the receptor of the parietal cell wall. The increase in stomach wall receptor site bioavailability of the histamine H~-receptor antagonist 0 increases the capacity of the histamine H2-receptor antagonist to reduce acid secretion compared with that of histamine H2-receptor antagonist alone.
The increase in acid-secretion reducing capacity is -5 described as being advantageous in the treatment of ulcer patients, in particular hypersecreting patients, in the treatment of those patients diagnosed as non-responders, and also to reduce the onset-phase of single-dose, self-medication for acute gastric disorders, for example gastric 20 orders due to hyperacidity.
It has now been found that an intimate mixture comprising 2 histamine H2-receptor antagonist with a bioadhesive material, for example sucralfate, buffered at or around the 2s pKa of the histamine H2-receptor antagonist, provides an effective therapy for gastric disorders, mediated through local delivery of the histamine H2-receptor antagonist directly into the parietal cell receptor of the stomach wall.
Accordingly, the present invention pro~ides the use of an orally administrable pharmaceutical composition comprising a histamine H2-receptor antagonist and a bioadhesive material, for the manufacture of a medicament for the treatment of 35 gastric disorders, characterised in that the composition is 'ormulated as an intimate mixture whereby the bioadhesive material and the histamine H2-receptor antagonist form, ln situ, a bioadhesive complex, locally targeting the histamine H2-receptor antagonist to the stomach wall; and the composition is optimally buffexed to confer a pH
5 substantially equal to that of the pKa of the histamine H2-receptor antagonist.
The lnvention also provides a method of treatment of gast= _ disorders comprising administering to a sufferer an 0 effective amount of a locally acting pharmaceutical composition comprising an intimate mixture of a histamine H2-receptor antagonisc and a bioadhesive material forming ln situ a bioadhesive complex; and a buffering component to confer a pH substantially equal to that of the pKa of the :5 histamine H2-receptor antagonist.
In a further aspect, the invention provides a locally acting pharmaceutical composition for use in the treatment of gastric disorders which comprises an intimate mixture of a ~o histamine H2-receptor antagonist and a bioadhesive material, and a buffering component to confer a pH substantially equal to that of the pKa of the histamine H2-receptor antagonist.
Bioadhesive materials for use in compositions of the presen ~5 invention include materials, both natural and synthetic, which are capable of adhering to biological surfaces such as mucus membranes. Examples of bioadhesive materials include natural gums and plant extracts and synthetic materials such as sucralfate, cellulose derivatives, acrylic acid and 30 methacrylic acid derivatives, for example cross-linked acrylic and methacrylic acid copolymers available under the Trade Names CAREOPOL and POLYCARBOPHIL.
Compositions for use in the invention are optimally buffered 3s by the use of a buffering component which is suitably an antacid having equilibrium pH, acid neutralising capacity wo g2/09286 ~9~96~ PCT/GB91/02063 and gastric residence time values which provide a pH pro~ile with time conferring a local pH level substantially equal to that of the pKa of the histamine H2-receptor antagonist.
5 It will be appreciated that when the bioadhesive material is sucralfate which has buffering properties, it may function as the buffering component of the pharmaceutical composition.
o This approach of locally delivering H2-receptor antagonists via the stomach mucosa is of particular benefit in the self-medication of acute, self-limiting gastric disorders such as hyperacidity. It is understood that H2-RA therapy fails in Zollinger-Ellison syndrome due to low levels of th~ drug at :~ the H2-receptor of the parietal cells. ~ocal delivery according to the invention which increases the concentration -~
of drug at the H2-receptors of the parietal cell and renders the histamine H2-receptor antagonist effective at low dosage levels, is regarded as of particular benefi~ in the ~o treatment of these disorders.
~istamine H2-receptor antagonists for use in compositions of the invention include cimetidine, ranitidine and famotidine, preferably cimetidine and ranitidine, and especially 5 cimeditine. pKa values for known histamine-H2-receptor antagonists are readily available from pharmacological publications.
Similarly, the above-mentioned parameters for a suitable 30 buffering component are readily available to those skilled in the art. Suitable buffering agents for use in ;
compositions of the invention include aluminium hydroxide, magnesium hydroxide, aluminium hydroxide-magnesium carbonate - co-dried gel, magnesium carbonate, magnesium oxide, 35 magnesium aluminium silicate, magnesium trisilicate, sodium ~:C959ti~092/09286 PCT/GB91/02063 bicarbonate, calcium carbonate, bismuth carbonate, alkali metal salts of citric, tartaric, benzoic, sorbic and phosphoric acid, and combinations thereof.
5 Further suitable antacids may be selected by pharmacokinetic analysis of the acid-secretion reducing capacity of a selected histamine H2-receptor antagonist using a pharmaco~inetic model based upon a modified, stan~ard two-compartment model. with the introduction of further lO compartments to separately describe the stomach and the intestine, and with transport between the tissue compartment, representing the parietal cell tissue receptor compartment, and the stomach lumen, the model may be used to describe pharmacokinetics for a selected histamine , H2-receptor antagonist. The model demonstrates the reduction in local bioavailability of the histamine H2-receptor antagonist at the parietal cell tissue receptor compartment as a function of gastric excretion and the increase in local bioavailability in the parietal cell 20 tissue xeceptor compartment as a function of local, gastric absorption, and their dependence on gastric pH. Gastric pH
levels are influenced by antacid. Thus, by inserting known values for equilibrium pH, acid neutralising capacity and gastric residence time, the suitability of any given antacid may be determined.
Conventional histamine H2-receptor antagonist therapies act systemically and drug is distributed to all parts of the body via the bloodstream. Hence, it will be appreciated 30 that non-target body tissues are exposed to drug. An advantage of a locally targeted drug delivery system is that low doses may be used and thus pharmacologically relevant doses are not achieved in non-target tissues.
35 Excretion of histamine H2-receptor antagonist into the stomach lumen from the parietal cell tissue receptor causes a reduction in local bioavailability of the antagonist -W092/09286 ~ ~ 9~9 ~ PCT/GB91/~2063 whilst gastric absorption of histamine H2-receptor antagonist into the parietal cell tissue receptor causes an increase in local bioavailability of the antagonist. An advantageous feature of the invention is the potential for s using reduced dose levels of histamine H2-receptor antagonist brought about by buffering the histamine H2-receptor antagonist in the gastric environment, effectively reducing antagonist excre~ion into the stomach lumen, increasing absorption from the stomach lumen, and increasing the residence time of the histamine H2-receptor antagonist in the gastric environment by forming a bioadhesive complex.
The dose level of histamine H2-receptor antagonist may be : selected according to the potency of the antagonist on a weight basis and according to the severity of the condition.
For example where the histamine H2-receptor antagonist is cimetidine or ranitidine it may be present in an amount from about l mg to 800 mg per dosage form, typically from about 5 20 mg to 50 mg for example 5, 10, IS, 20 or 25 mg.
'.:
It will be further appreciated that treatment with the present compositions provides a more rapid onset of action which renders them particularly suitable for the treatment 2s of acute gastritis.
A further aspect of the invention is that the amount of antacid present in any given composition is independent of the dose of histamine H2-receptor antagonis~.
The bioadhesive material, for example sucralfate, may be present in an amount from about 100 mg to 1500 mg per dosage form, typically from about 800 mg to 1200 mg, for example `
1000 mg.
:
W092/09286 ~09~6~ PCT/GB9l/02063 These dosage levels encompass compositions where sucralfate serves as the buffering component and which do not include a further buffering agent.
5 Where a compositlon includes a bioadhesive material which has no buffering capacity or, in addition to sucralfate includes a further buffering agent, the level of buffer is optimally chosen to confer a pH substantially equal to that of the pKa of the histamine H2-receptor antagonist.
It is a feature of the buffering component that it serves a dual role. In one aspect, in the accepted mode of action of antacids, lt brings about relief from the symptoms of excess stomach acidity by neutralisation. In a second aspect, and more importantly, it serves to act as an appropriate buffered vehicle to enhance the absorption of the histamine H2-receptor antagonist. The dose of buffering agent may be selected to achleve both effects.
20 A suitable dose range for magnesium hydroxide is from about 150 mg to 3000 mg, for example from about 300 mg to 1500 mg, such as from about 300 mg to 600 mg.
A suitable dose range for aluminium hydroxide is from about 2s 180 mg to 3600 mg, for example from about 360 mg to 1800 mg, - such as from 360 to 720 mg.
A suitable dose range for sodium bicarbonate is from about 400mg to 8,000mg for example from about 800 mg to 4000mg, 30 such as from about 800mg to 1600mg~
Compositions for use in the present invention may also ~ -contain pharmaceutically acceptable carriers. Compositions W O 92/09286 Z C~ 9 ~ . PC~r/~ B91/02063 may be formulated for oral administration in solid or liquid -form, for example as tablets, capsules, powders, suspensions or dispersions. Compositions may thus be formulated by admixture with pharmaceutically acceptable vehicles -additionally containing, as desired, pharmaceutically acceptable adjuvants including inter alia thickeners, preservatlves, and colouring and flavouring agents.
It will be appreciated that certain pharmaceutical ~0 compositions for use in the present invention are novel and as such form a further aspect of the invention.
The following Examples illustrate the invention.
' ':
~he examples include sucralfate as the bioadhesive material but are not limited thereto. Any material having bioadhesive properties, either a natural or synthetic material, may be incorporated into compositions for use in the invention.
2~ ' , ,.
WO 92/09286 ~09~,~9fi? PCI/GB91/02063 -12-- !
Example 1 Entrapment of Cimetidine in Sucralfate 5 Cimetidine solutions were made up at pH 2.5 at concentrations in the range 0-200mg/ml. To 50ml of each cimetidine solution was added sucralfate (2g). 1 M HCl was added until a good paste was formed.
lO Results mq!ml Cimetidine Nature of Paste Nature of supernatant 0 good clear good clear ~s lO0 good clear 125 good clear lS0 poor cloudy suspension 200 no paste cloudy suspension 20 The results show that concentrations of cimetidine below 150 mg/ml are most favourable for entrapment. At concentratlons above 150 mg/ml paste integrity is affected.
Exam~le 2 2s Cimetidine Entra~ment and Release from Sucralfate The level of entrapment of cimetidine in sucralfate and the release of the entrapped cimetidine into solutlion as a ~0 function of time was determined.
W092/09286 ~9~9~ PCT/GB91/02063 The levels of cimetldine studled were 0, 25, 50, 75, 100 and 125 mg/ml in a 50 ml volume.
Method s A preweighed amount of clmetidlne was added to O.1 M
hydrochloric acid (30ml). The solution was mixed using a magnetic stirrer.
o A pH probe was inserted into the solution and lM
hydrochloric acid was added until a clear solution (pH 2.5) -was obtained. The volume was made up to 50ml. A 200 ~1 sample was removed.
, :
Sucralfate (2g ex Katsura) was added with stirring and allowed to disperse. 1 M HCl was added in 200 ~1 aliquots until paste formation occurred. Stirring was continued until the supernatant was clear. A 200 ~1 sample of supernatant was removed.
The supernatant was poured off leaving the cimetidine/sucralfate paste. -O.lM HCl (50ml) was added, the mixture swirled for 10 seconds and a 200 ~1 sample removed. A further 50ml sample of 0.1 M HCl was added. A 200 ~1 sample was removed. A ;
third 50ml sample of O.lM HCl (pH 1.5j was added. The resulting mixture was placed on an orbital shaker (GFL.3017) at 3/4 maximum speed.
200~1 aliquots were removed after 1, 5, 15, 30 and 45 mins.
and after 1, 1.5, 2, 2.5, 3, 3.5 and 4 hours.
At the end of the experiment 5M HCl (5ml) was added to 35 dissolve the sucralfate. This final solution was diluted W O 92/09286 ~C~ 9 ~i 9 ~ PC~r/GB91/OtO63 -14- f:
and the total final level of sucralfate was determined.
Each of the 200~1 samples removed throughout the experment was assayed as follows:
a 50~ sample was transferred to a vial and 1.95 ~1. 0.1 M
HCl was added. Further dilutions with distilled water were made as necessary. Optical density at 218mm was determined versus a distilled water blank.
Cimetidine Release (Corrected data) ..
Time Cimetidine concentrations (mg/ml) 5 Point _ (Mins) 0 25 50 75 100 125 . . _ 01 0.0 0.05 0.06 0.187 0.507 0.680 05 0.0 0.086 0.166 0.249 0.609 0.945 2015 0.0 0.138 0.314 0.549 0.966 1~734 0.0 0.193 0.519 0.738 1.364 2.120 q5 0.0 0.237 0.645 0.948 1.691 2.488 0.0 0.274 0.743 1.107 1.942 2.828 0.0 0.323 0.855 1.43 2.337 3.494 25120 0.0 0.363 0.935 1.665 2.615 3.868 150 0.0 0.382 1.039 1.969 2.865 4.220 180 0.0 0.406 1.13 2.176 3.203 4.448 210 0.0 0.438 1.162 2.285 3.419 4.596 240 0.0 0.439 1.185 3.012 3 438 4.497 30 _ W092/Og286 PCT/~B91/02063 : 20~962 Cimetidine Entrapment . ~.
Total Total % of total 5 CimeditineCimeditineCimetidine added (mg/ml)added in paste entrapped 0.0 o,o _ 251175.5 59.35 5.05 :' :0 50 2399.0 121.45 5.06 3497.0 166.0 4.75 100 4613.0 225.75 4.89 125 5207.5 263.75 5.06 . :.
At each cimetldine concentration, approximately 5% by weight of the available cimetidine is entrapped in sucralfate.
Visual o~servations indicated that the integrity of the paste was interfered with at cimetidine concentrations in 20 excess of 75mg/ml. Agitation caused pieces of the paste mass to break off.
The release data indicates that release from sucralfate is a diffusional process.
~5 Exam~le 3 The Effect of pH on Cimetidine release from Sucralfate Pastes The rate of cimetidine release from sucralfate as a function of pH was determined at pH values 1.5, 3.0, 4.5, 6.0 and 7.5. The experiment was carried out using a cimetidine concentration of 50 mg/ml and lg sucralfate.
~5 .
. .
W092/09286 ~9~9fi~ ; ` . PCT/GB91/02063 Theoretical pH Value 1.5 3.0 4.5 6.0 7.5 _ Total 1.079 1.082 1.117 l.lOS 1.045 Cimetldine (mg):
Experimental pH: 1.69 3.23 4.64 6.12 7.54 o (initlal) Experimental pH: 3.21 3.17 q.S7 6.18 7.66 (Shrs) 15 The following table shows the release data as a function of % of total clmetidine entrapped within the sucralfate paste.
_ .' Time 20 Points pH Value (Mins) 1.5 3.0 4.5 6.0 7.5 . ...
01 6.95 6.65 5.28 9.41 6.32 OS 12.6 l9.S0 14.50 11.31 6.96 ~slS 21.87 31.89 23.63 15.48 11.20 32.16 37.15 27.48 19.91 15.98 42.08 42.79 29.45 25.16 21.44 51.62 44.82 32.86 28.69 26.69 68.39 50.09 39.21 34.93 35.8~
30120 83.5 57.02 ~1.99 40.0 45.26 150 94.16 61.28 46.46 47.87 54.74 180 104.54 65.25 48.97 52.04 63.83 210 111.21 68.69 52.28 56.29 72.63 240 119.55 70.06 54.43 60 27 81.24 W092/09286 ~ 0 ~ 9~ PCT/GB91/02063 The results show the greatest release of cimetidine from the paste exposed to the pH of 1.5. As the pH increases, the amount of cimetidine released decreases up to pH 4.5. Above this pH, the level of release lncreases again.
_xamDle 4 Powde~ Formulations o The ingredients are dry blended under conditions of controlled temperature and humidity using conventional equipment.
~xample 5 - 6 :s Tablet Formulations The active antacid ingredients are granulated or spray dried in a conventional manner. The granule, the histamine 20 H2-receptor antagonist and the bioadhesive material are blended along with conventional tabletting aids, fillers and palatability aids and the blend is tabletted on a conventional machine.
~S Example 7 Liquid SusDensions Aluminium hydroxide and magnesium hydroxide are received as 30 commercially available suspensions. These active suspensions are added to a premix of thickeners. The - resulting mixture is then blended with the histamine H2-receptor antagonist, the bioadhesive material and preservatives and flavours as appropriate.
2(~9~g~ 1 8 WO 92/09286 __ - PCI/GB91/02063 ~ o -o _ ___ -o ,_ o o o ~ _ _ _--o o ,,~ o o -o- o _ o __ O _ O N N N O _ o . ~ O l O O O _ O ~'''.' ol I_ o o I ,,,~ o ~:) _ ,r~ ,., ~ ~ O I l O Ln l l ~ O
O O _ O ,_~ ~7 ._ ._ _ O
IY; Ir~ O l ~_I l r- l l O
3a ~ ~
~ O l l l O _ l U~ ~'',',.
~I O l O l O l l ~ .
_ O O O _ --O ''','~
C ~ C C ~11 ~r1 U U h ~ . . ~ .
~r ~ ~ ~ m v ~ ~5 v~ E
~ ~ ~ ~ J O .~ .~ ~ ~0 cn f~ ~ ~
E~ ~ o E ~: E a JJ s~ ~ . ~ _, :
~:d ~ ~ ,~ ~ ~ O ~ E~ ~ O ~
,.
2(~9ti~ .
WO 92/09286 __ _ PCI/GB91/02063 ( . N O O . _ o O _ o O
N O O ~ _ _ __ N __ N ~:
~ O O O O N O O
N O ~1 l l l O N ~ (~J
~1 ~1 __ _ _ O O O N O O
O O O O O U-) ~1 t~l N O l l N l l O ~_1 N
. __ _ O O O O N O O
a~ o o o o u-~ ~ N
~ O l ~ l l l ~ ~t N
_ O _ _ O O O _ O O
:~ O O O O L0 .--1 N
~ O ~1 l l ll C~O ~J N
O ~1 ~-I O ___ O O _ O O
E-~ ~_ O N r r o ~ ~ N
O _ _ o __ ___ N _ ~ ~D O ~ O O O O ~ O` O
~1 O l l l O O l O Ll'~ ~1 N
O _ _ _ _ N
~ Ln O O O O O o ~ O O
~ O ~ l l 1~) Ir) l ~ Ir) ,_1 N
O l 't f'~ /~
_ O O O O O O ~ O O
O N Lr~ Ir) O Ir) ~' N
o l o l ~_ r l ~ N
O O O O O O (~J O O
~ O l ~--1 l O O l O (:~1 ~ N
. ~1 ~
O _ _ _ . . _ . O O O O O O ~I O O
(~I O r-l O O O Il') ~1 N
~ o ~ l l r r l ~ ~
_ _ ~ ~ . _ _ :' ,, ._, a~ a~ ~
. X X C h E~ .
Z ~ ~ ~ ~ ,~
c: a) a~ O a) :~ :T~ h h v~ ~1 u~ O C C C E~ E C ) ~ h C E C
a) ~1:1 ,_J .,.1 .,~1 .,1 C v~ :~ S :5 O u~ E~
_~ ~'4 JJ IJ ~ _~ a) ~ t~ ~ o ~ a Q 3 h O .,1 O E ~: ~ h C ::~ -,~ C
E~ E U E~ C E~ ~ ~ ~ 0 ._~ n~ ::~ 01 _1 1~1 O ~ .,_1 1~ 1~1 ,_1 (~5 t~l JJ t) _l O ~a ~ . .
X ~ __ tr~ __ C_~ _ H _ _ . , ' :
.
WO 92/09286 ~09~9~i~ PCr/GB91/02063 2 o ~ ~--N _ _ N . .
t ~
C ~ o o o o o ..
~,: I N O l l N O N N
~ --O O O O O
C!~ N O l ~1 l O O 1-') H O ~ N N N
ZN O ---- N N N
Z_ o __ N O O N
Y t~l O l O ~ ~1 O O O O O _ ,',, ~ O l ~ l O O ~\l N O ~ O ~ ~
__ O ~ . .
N O O l l O O N . ~
-1 .-1 ~1 _ = e z; o 3 o J- C C C Q E ~J c ;
D q~ ~ ~ ~ m ~ a) o o a) _, ~ .,, .,, ~ ~ v~ r~ ~ .
.~ ~ ~ ~ ~ o o - ~
. E Ll 0 ~ o ._~ c ~,1 h --1 .
~E~ ~ ~ _0 C ~4 ~ 0~_ ~a ,~
~ . , .
' ' ' :
W O 92/09286 - PC~r/G B91/02063 ;~9~96 _ . _ _ _ o o u~ u~ O O Lr) O n ~r O N r I_ o o . ~ ~r ~ o l l l ~ ~ o o ~r .
;i~l_ o o _ o o _ o _ o--- a~
O ~ o l ~ l o o I_ o . ~ C ~
Z r7 O l ~ ~ c~ O ~ ~ . `.
_ ___ -o o o o o U~ o U~
:~ ~ o o n Ll~ L~ o . ~ ~ ~ .
~ o l l l _ ~ r- o ~r .
C .
~ . . ~0 ~X C o ~
O h h O V ... ~ . .
Q~5 V) :>~:~ h ~1 a) ~1 ~: 3:: ~ ~ O ~ ~ , o a) ~ aJ ~ ~ u? .,, u~ ,_ :
.~ ~ C C C E E.,~ v h .,1 1 -,~ ~ ~ ~ _~
-~1 ,~ O ~ ~ C
.,., ~.~ ~n1:: E ~ ~ ~ a~
~ 11~ J_) ~ ~ a),~ 3 _1C) O .Y h E h a) ._~ O C E.,~ Q u):~ ~ O _~
~ o E C E ~ ~ ~ h a)~J ,~ J
O :~ .,~ 1~ ~1~ ~1 O O ~1 ~1 C 1~1 k. U) t.) C~ tL~ ~ ~ ~ U~ U~ _ E~ _ :
t-a X
L~ : ' :
- ' ':
- , ! I
Zollinger-Ellison syndrome (Stahile B.G. et al.: Failure or histamine H2-receptor antagonist therapy in Zollinger-Ellison syndrome; Am. J. Surg., 145, 17-23, 1983) 10 has led to the development of alternative treatments, notably the use of proton-pump inhibitors.
~istamine H2-receptor antagonists are o~ potential bener-t in the self-medlcation of acute, self-limiting gas.ric ~s disoràers such as hyperacidity. However, their slow onset of action is unlikely to meet the consumer requirement for rapid relief of symptoms.
Moreover, it will be appreciated that use of high dose 20 levels in an attempt to achieve rapid relief of symptoms is not appropriate for non-prescription use. Indeed, a reduction from the standard therapeutic dose would be desirable for self-medication.
2s Co-administration of histamine H2-receptor antagonists and other pharmaceutically active materials, including sucralfate and other antacids, has been investigated. The rationale for co-administration with antacid is that the antacid brings about rapid relief from the symptoms of 30 excess stomach acidity by neutralisation whereas the histamine H2-receptor antagonist acts independently by inhibiting secretion of acid from the parietal cell.
However, it is well known (Bodemar G. et al., Lancet, 1, 35 444-445, 1979; Mihaly G.W. et al., B.M.J., 285, 998 9, `1982;
Lin. J.H. et al., B.J. Clin. Pharmacol. 24, 551-3, 1987) w~ 92/09286 ~09~ PCT/GB91/0~063 _na~ when histamine H2-receptor an~agonists are co-administered with antacids, especially antacids with high acid-neutralising capacity, a substantial reduction in the plasma bioavailability of the histamine H2-receptor an~agonist is frequently observed. Histamine H2-receptor an.agonist - antacid combinations are therefore generally conrraindicated.
~ioadnesive materials have received considerable attention ~o as platforms for controlled drug delivery. They can be targetted to specific drug administration sites, prolong the -esidence time and ensure an optimal contact with the absorbina surface. Many different types of bioadhesive ~a_e-ials, both natural and synthetic, can be used in the :- ces~gn o. controlled drug delivery systems.
'' :' Sucralfate is a basic aluminium sulphate sucrose complex having ulcer healing and buffering properties. According to ~he literature, sucralfate has been shown to act by forming 20 a bioadhesive gel structure which is believed to provide a local protective barrier. It has been reported that su-_alfate does not interfere with the absorption of his~amine H2-receptor antagonists. Clinical studies have incicated a combination therapy to be of potential benefi-. -~s : -:
EP-A-O 286 781 (Heumann Pharma) relates to pharmaceutical preparations with cytoprotective effect on the gastrointestinal tract containing a combination of a his~amine H2-receptor antagonist and an antacid substance 30 which is able to give functional cytoprotection. Sucralfate - is identified as an example of the antacid substance. It is àescribed as giving functional cytoprotection but having a comparatively low acid-netutralising effect.
':
W O 92/09286 2~9~9~j~ PC~r/G B91/02063 EP-A-0 403 048 (Warner-Lambert~, published on December 19, 1990, describes medicated composltions comprising sucralfate and a therapeutically effective amount of a medicament which is a) substantially water insoluble, or b) a mixture of a 5 water-soluble medicament and a release-delaying material which on admixture forms a substantially water-insoluble medicament. In a preferred embodiment, the medicament is selected from the group consisting of inter alia antacids and anti-ulcer medicaments. Compositions comprising 0 sucralfate plus antacid and sucralfate plus an anti-ulcer medicament are described as cytoprotective compositions, useful in the treatment of peptic ulcers by forming an ulcer-adherent protective gel barrier.
EP~ O 193 400 (Reckitt and Colman) describes pharmaceutica~
compositions comprising mixtures of a histamine H2-receptor antagonist and sodium polyacrylate in the weight ratio 10 :
1 to 1 : 10. The compositions are described for use in the treatment of gastritis or of gastro-duodenal ulcers. The 20 compositi~ns may include an antacid. Use of antacid is described as resulting in a reduction in the viscosity of the liquid compositions, thereby providing some degree of viscosity control in the design of readily pourable liquid preparatlons .
2s US 4,615,697 (Robinson) discloses a controlled release composition comprising an effective amount of a treating agent, which may be a medicamen~, and a bioadhesive materlal which is a water-swellable and water-insoluble, fibrous, 30 cross-linked càrboxy-functional polymer. The controlled release compositions are described as adhering to the skin or to mucous meMbranes in the presence of water. Cimetidine is listed as an example of a medicament.
~S Current treatments using histamine H2-receptor antagonists act systemically, i.e. the histamine H2--receptor antagonist W O 92/09286 - X ~ PC~r/G B91/02063 is dellvered to the parietal cell receptor from the blood.
International Patent Application No. pcT/Gs9l/oo953 describes oral treatment of gastric dlsorders using a 5 histamine H2-receptor antagonist in combination with an antacid to promote local dellvery of the histamine H2-receptor antagonist to the receptor of the parietal cell wall. The increase in stomach wall receptor site bioavailability of the histamine H~-receptor antagonist 0 increases the capacity of the histamine H2-receptor antagonist to reduce acid secretion compared with that of histamine H2-receptor antagonist alone.
The increase in acid-secretion reducing capacity is -5 described as being advantageous in the treatment of ulcer patients, in particular hypersecreting patients, in the treatment of those patients diagnosed as non-responders, and also to reduce the onset-phase of single-dose, self-medication for acute gastric disorders, for example gastric 20 orders due to hyperacidity.
It has now been found that an intimate mixture comprising 2 histamine H2-receptor antagonist with a bioadhesive material, for example sucralfate, buffered at or around the 2s pKa of the histamine H2-receptor antagonist, provides an effective therapy for gastric disorders, mediated through local delivery of the histamine H2-receptor antagonist directly into the parietal cell receptor of the stomach wall.
Accordingly, the present invention pro~ides the use of an orally administrable pharmaceutical composition comprising a histamine H2-receptor antagonist and a bioadhesive material, for the manufacture of a medicament for the treatment of 35 gastric disorders, characterised in that the composition is 'ormulated as an intimate mixture whereby the bioadhesive material and the histamine H2-receptor antagonist form, ln situ, a bioadhesive complex, locally targeting the histamine H2-receptor antagonist to the stomach wall; and the composition is optimally buffexed to confer a pH
5 substantially equal to that of the pKa of the histamine H2-receptor antagonist.
The lnvention also provides a method of treatment of gast= _ disorders comprising administering to a sufferer an 0 effective amount of a locally acting pharmaceutical composition comprising an intimate mixture of a histamine H2-receptor antagonisc and a bioadhesive material forming ln situ a bioadhesive complex; and a buffering component to confer a pH substantially equal to that of the pKa of the :5 histamine H2-receptor antagonist.
In a further aspect, the invention provides a locally acting pharmaceutical composition for use in the treatment of gastric disorders which comprises an intimate mixture of a ~o histamine H2-receptor antagonist and a bioadhesive material, and a buffering component to confer a pH substantially equal to that of the pKa of the histamine H2-receptor antagonist.
Bioadhesive materials for use in compositions of the presen ~5 invention include materials, both natural and synthetic, which are capable of adhering to biological surfaces such as mucus membranes. Examples of bioadhesive materials include natural gums and plant extracts and synthetic materials such as sucralfate, cellulose derivatives, acrylic acid and 30 methacrylic acid derivatives, for example cross-linked acrylic and methacrylic acid copolymers available under the Trade Names CAREOPOL and POLYCARBOPHIL.
Compositions for use in the invention are optimally buffered 3s by the use of a buffering component which is suitably an antacid having equilibrium pH, acid neutralising capacity wo g2/09286 ~9~96~ PCT/GB91/02063 and gastric residence time values which provide a pH pro~ile with time conferring a local pH level substantially equal to that of the pKa of the histamine H2-receptor antagonist.
5 It will be appreciated that when the bioadhesive material is sucralfate which has buffering properties, it may function as the buffering component of the pharmaceutical composition.
o This approach of locally delivering H2-receptor antagonists via the stomach mucosa is of particular benefit in the self-medication of acute, self-limiting gastric disorders such as hyperacidity. It is understood that H2-RA therapy fails in Zollinger-Ellison syndrome due to low levels of th~ drug at :~ the H2-receptor of the parietal cells. ~ocal delivery according to the invention which increases the concentration -~
of drug at the H2-receptors of the parietal cell and renders the histamine H2-receptor antagonist effective at low dosage levels, is regarded as of particular benefi~ in the ~o treatment of these disorders.
~istamine H2-receptor antagonists for use in compositions of the invention include cimetidine, ranitidine and famotidine, preferably cimetidine and ranitidine, and especially 5 cimeditine. pKa values for known histamine-H2-receptor antagonists are readily available from pharmacological publications.
Similarly, the above-mentioned parameters for a suitable 30 buffering component are readily available to those skilled in the art. Suitable buffering agents for use in ;
compositions of the invention include aluminium hydroxide, magnesium hydroxide, aluminium hydroxide-magnesium carbonate - co-dried gel, magnesium carbonate, magnesium oxide, 35 magnesium aluminium silicate, magnesium trisilicate, sodium ~:C959ti~092/09286 PCT/GB91/02063 bicarbonate, calcium carbonate, bismuth carbonate, alkali metal salts of citric, tartaric, benzoic, sorbic and phosphoric acid, and combinations thereof.
5 Further suitable antacids may be selected by pharmacokinetic analysis of the acid-secretion reducing capacity of a selected histamine H2-receptor antagonist using a pharmaco~inetic model based upon a modified, stan~ard two-compartment model. with the introduction of further lO compartments to separately describe the stomach and the intestine, and with transport between the tissue compartment, representing the parietal cell tissue receptor compartment, and the stomach lumen, the model may be used to describe pharmacokinetics for a selected histamine , H2-receptor antagonist. The model demonstrates the reduction in local bioavailability of the histamine H2-receptor antagonist at the parietal cell tissue receptor compartment as a function of gastric excretion and the increase in local bioavailability in the parietal cell 20 tissue xeceptor compartment as a function of local, gastric absorption, and their dependence on gastric pH. Gastric pH
levels are influenced by antacid. Thus, by inserting known values for equilibrium pH, acid neutralising capacity and gastric residence time, the suitability of any given antacid may be determined.
Conventional histamine H2-receptor antagonist therapies act systemically and drug is distributed to all parts of the body via the bloodstream. Hence, it will be appreciated 30 that non-target body tissues are exposed to drug. An advantage of a locally targeted drug delivery system is that low doses may be used and thus pharmacologically relevant doses are not achieved in non-target tissues.
35 Excretion of histamine H2-receptor antagonist into the stomach lumen from the parietal cell tissue receptor causes a reduction in local bioavailability of the antagonist -W092/09286 ~ ~ 9~9 ~ PCT/GB91/~2063 whilst gastric absorption of histamine H2-receptor antagonist into the parietal cell tissue receptor causes an increase in local bioavailability of the antagonist. An advantageous feature of the invention is the potential for s using reduced dose levels of histamine H2-receptor antagonist brought about by buffering the histamine H2-receptor antagonist in the gastric environment, effectively reducing antagonist excre~ion into the stomach lumen, increasing absorption from the stomach lumen, and increasing the residence time of the histamine H2-receptor antagonist in the gastric environment by forming a bioadhesive complex.
The dose level of histamine H2-receptor antagonist may be : selected according to the potency of the antagonist on a weight basis and according to the severity of the condition.
For example where the histamine H2-receptor antagonist is cimetidine or ranitidine it may be present in an amount from about l mg to 800 mg per dosage form, typically from about 5 20 mg to 50 mg for example 5, 10, IS, 20 or 25 mg.
'.:
It will be further appreciated that treatment with the present compositions provides a more rapid onset of action which renders them particularly suitable for the treatment 2s of acute gastritis.
A further aspect of the invention is that the amount of antacid present in any given composition is independent of the dose of histamine H2-receptor antagonis~.
The bioadhesive material, for example sucralfate, may be present in an amount from about 100 mg to 1500 mg per dosage form, typically from about 800 mg to 1200 mg, for example `
1000 mg.
:
W092/09286 ~09~6~ PCT/GB9l/02063 These dosage levels encompass compositions where sucralfate serves as the buffering component and which do not include a further buffering agent.
5 Where a compositlon includes a bioadhesive material which has no buffering capacity or, in addition to sucralfate includes a further buffering agent, the level of buffer is optimally chosen to confer a pH substantially equal to that of the pKa of the histamine H2-receptor antagonist.
It is a feature of the buffering component that it serves a dual role. In one aspect, in the accepted mode of action of antacids, lt brings about relief from the symptoms of excess stomach acidity by neutralisation. In a second aspect, and more importantly, it serves to act as an appropriate buffered vehicle to enhance the absorption of the histamine H2-receptor antagonist. The dose of buffering agent may be selected to achleve both effects.
20 A suitable dose range for magnesium hydroxide is from about 150 mg to 3000 mg, for example from about 300 mg to 1500 mg, such as from about 300 mg to 600 mg.
A suitable dose range for aluminium hydroxide is from about 2s 180 mg to 3600 mg, for example from about 360 mg to 1800 mg, - such as from 360 to 720 mg.
A suitable dose range for sodium bicarbonate is from about 400mg to 8,000mg for example from about 800 mg to 4000mg, 30 such as from about 800mg to 1600mg~
Compositions for use in the present invention may also ~ -contain pharmaceutically acceptable carriers. Compositions W O 92/09286 Z C~ 9 ~ . PC~r/~ B91/02063 may be formulated for oral administration in solid or liquid -form, for example as tablets, capsules, powders, suspensions or dispersions. Compositions may thus be formulated by admixture with pharmaceutically acceptable vehicles -additionally containing, as desired, pharmaceutically acceptable adjuvants including inter alia thickeners, preservatlves, and colouring and flavouring agents.
It will be appreciated that certain pharmaceutical ~0 compositions for use in the present invention are novel and as such form a further aspect of the invention.
The following Examples illustrate the invention.
' ':
~he examples include sucralfate as the bioadhesive material but are not limited thereto. Any material having bioadhesive properties, either a natural or synthetic material, may be incorporated into compositions for use in the invention.
2~ ' , ,.
WO 92/09286 ~09~,~9fi? PCI/GB91/02063 -12-- !
Example 1 Entrapment of Cimetidine in Sucralfate 5 Cimetidine solutions were made up at pH 2.5 at concentrations in the range 0-200mg/ml. To 50ml of each cimetidine solution was added sucralfate (2g). 1 M HCl was added until a good paste was formed.
lO Results mq!ml Cimetidine Nature of Paste Nature of supernatant 0 good clear good clear ~s lO0 good clear 125 good clear lS0 poor cloudy suspension 200 no paste cloudy suspension 20 The results show that concentrations of cimetidine below 150 mg/ml are most favourable for entrapment. At concentratlons above 150 mg/ml paste integrity is affected.
Exam~le 2 2s Cimetidine Entra~ment and Release from Sucralfate The level of entrapment of cimetidine in sucralfate and the release of the entrapped cimetidine into solutlion as a ~0 function of time was determined.
W092/09286 ~9~9~ PCT/GB91/02063 The levels of cimetldine studled were 0, 25, 50, 75, 100 and 125 mg/ml in a 50 ml volume.
Method s A preweighed amount of clmetidlne was added to O.1 M
hydrochloric acid (30ml). The solution was mixed using a magnetic stirrer.
o A pH probe was inserted into the solution and lM
hydrochloric acid was added until a clear solution (pH 2.5) -was obtained. The volume was made up to 50ml. A 200 ~1 sample was removed.
, :
Sucralfate (2g ex Katsura) was added with stirring and allowed to disperse. 1 M HCl was added in 200 ~1 aliquots until paste formation occurred. Stirring was continued until the supernatant was clear. A 200 ~1 sample of supernatant was removed.
The supernatant was poured off leaving the cimetidine/sucralfate paste. -O.lM HCl (50ml) was added, the mixture swirled for 10 seconds and a 200 ~1 sample removed. A further 50ml sample of 0.1 M HCl was added. A 200 ~1 sample was removed. A ;
third 50ml sample of O.lM HCl (pH 1.5j was added. The resulting mixture was placed on an orbital shaker (GFL.3017) at 3/4 maximum speed.
200~1 aliquots were removed after 1, 5, 15, 30 and 45 mins.
and after 1, 1.5, 2, 2.5, 3, 3.5 and 4 hours.
At the end of the experiment 5M HCl (5ml) was added to 35 dissolve the sucralfate. This final solution was diluted W O 92/09286 ~C~ 9 ~i 9 ~ PC~r/GB91/OtO63 -14- f:
and the total final level of sucralfate was determined.
Each of the 200~1 samples removed throughout the experment was assayed as follows:
a 50~ sample was transferred to a vial and 1.95 ~1. 0.1 M
HCl was added. Further dilutions with distilled water were made as necessary. Optical density at 218mm was determined versus a distilled water blank.
Cimetidine Release (Corrected data) ..
Time Cimetidine concentrations (mg/ml) 5 Point _ (Mins) 0 25 50 75 100 125 . . _ 01 0.0 0.05 0.06 0.187 0.507 0.680 05 0.0 0.086 0.166 0.249 0.609 0.945 2015 0.0 0.138 0.314 0.549 0.966 1~734 0.0 0.193 0.519 0.738 1.364 2.120 q5 0.0 0.237 0.645 0.948 1.691 2.488 0.0 0.274 0.743 1.107 1.942 2.828 0.0 0.323 0.855 1.43 2.337 3.494 25120 0.0 0.363 0.935 1.665 2.615 3.868 150 0.0 0.382 1.039 1.969 2.865 4.220 180 0.0 0.406 1.13 2.176 3.203 4.448 210 0.0 0.438 1.162 2.285 3.419 4.596 240 0.0 0.439 1.185 3.012 3 438 4.497 30 _ W092/Og286 PCT/~B91/02063 : 20~962 Cimetidine Entrapment . ~.
Total Total % of total 5 CimeditineCimeditineCimetidine added (mg/ml)added in paste entrapped 0.0 o,o _ 251175.5 59.35 5.05 :' :0 50 2399.0 121.45 5.06 3497.0 166.0 4.75 100 4613.0 225.75 4.89 125 5207.5 263.75 5.06 . :.
At each cimetldine concentration, approximately 5% by weight of the available cimetidine is entrapped in sucralfate.
Visual o~servations indicated that the integrity of the paste was interfered with at cimetidine concentrations in 20 excess of 75mg/ml. Agitation caused pieces of the paste mass to break off.
The release data indicates that release from sucralfate is a diffusional process.
~5 Exam~le 3 The Effect of pH on Cimetidine release from Sucralfate Pastes The rate of cimetidine release from sucralfate as a function of pH was determined at pH values 1.5, 3.0, 4.5, 6.0 and 7.5. The experiment was carried out using a cimetidine concentration of 50 mg/ml and lg sucralfate.
~5 .
. .
W092/09286 ~9~9fi~ ; ` . PCT/GB91/02063 Theoretical pH Value 1.5 3.0 4.5 6.0 7.5 _ Total 1.079 1.082 1.117 l.lOS 1.045 Cimetldine (mg):
Experimental pH: 1.69 3.23 4.64 6.12 7.54 o (initlal) Experimental pH: 3.21 3.17 q.S7 6.18 7.66 (Shrs) 15 The following table shows the release data as a function of % of total clmetidine entrapped within the sucralfate paste.
_ .' Time 20 Points pH Value (Mins) 1.5 3.0 4.5 6.0 7.5 . ...
01 6.95 6.65 5.28 9.41 6.32 OS 12.6 l9.S0 14.50 11.31 6.96 ~slS 21.87 31.89 23.63 15.48 11.20 32.16 37.15 27.48 19.91 15.98 42.08 42.79 29.45 25.16 21.44 51.62 44.82 32.86 28.69 26.69 68.39 50.09 39.21 34.93 35.8~
30120 83.5 57.02 ~1.99 40.0 45.26 150 94.16 61.28 46.46 47.87 54.74 180 104.54 65.25 48.97 52.04 63.83 210 111.21 68.69 52.28 56.29 72.63 240 119.55 70.06 54.43 60 27 81.24 W092/09286 ~ 0 ~ 9~ PCT/GB91/02063 The results show the greatest release of cimetidine from the paste exposed to the pH of 1.5. As the pH increases, the amount of cimetidine released decreases up to pH 4.5. Above this pH, the level of release lncreases again.
_xamDle 4 Powde~ Formulations o The ingredients are dry blended under conditions of controlled temperature and humidity using conventional equipment.
~xample 5 - 6 :s Tablet Formulations The active antacid ingredients are granulated or spray dried in a conventional manner. The granule, the histamine 20 H2-receptor antagonist and the bioadhesive material are blended along with conventional tabletting aids, fillers and palatability aids and the blend is tabletted on a conventional machine.
~S Example 7 Liquid SusDensions Aluminium hydroxide and magnesium hydroxide are received as 30 commercially available suspensions. These active suspensions are added to a premix of thickeners. The - resulting mixture is then blended with the histamine H2-receptor antagonist, the bioadhesive material and preservatives and flavours as appropriate.
2(~9~g~ 1 8 WO 92/09286 __ - PCI/GB91/02063 ~ o -o _ ___ -o ,_ o o o ~ _ _ _--o o ,,~ o o -o- o _ o __ O _ O N N N O _ o . ~ O l O O O _ O ~'''.' ol I_ o o I ,,,~ o ~:) _ ,r~ ,., ~ ~ O I l O Ln l l ~ O
O O _ O ,_~ ~7 ._ ._ _ O
IY; Ir~ O l ~_I l r- l l O
3a ~ ~
~ O l l l O _ l U~ ~'',',.
~I O l O l O l l ~ .
_ O O O _ --O ''','~
C ~ C C ~11 ~r1 U U h ~ . . ~ .
~r ~ ~ ~ m v ~ ~5 v~ E
~ ~ ~ ~ J O .~ .~ ~ ~0 cn f~ ~ ~
E~ ~ o E ~: E a JJ s~ ~ . ~ _, :
~:d ~ ~ ,~ ~ ~ O ~ E~ ~ O ~
,.
2(~9ti~ .
WO 92/09286 __ _ PCI/GB91/02063 ( . N O O . _ o O _ o O
N O O ~ _ _ __ N __ N ~:
~ O O O O N O O
N O ~1 l l l O N ~ (~J
~1 ~1 __ _ _ O O O N O O
O O O O O U-) ~1 t~l N O l l N l l O ~_1 N
. __ _ O O O O N O O
a~ o o o o u-~ ~ N
~ O l ~ l l l ~ ~t N
_ O _ _ O O O _ O O
:~ O O O O L0 .--1 N
~ O ~1 l l ll C~O ~J N
O ~1 ~-I O ___ O O _ O O
E-~ ~_ O N r r o ~ ~ N
O _ _ o __ ___ N _ ~ ~D O ~ O O O O ~ O` O
~1 O l l l O O l O Ll'~ ~1 N
O _ _ _ _ N
~ Ln O O O O O o ~ O O
~ O ~ l l 1~) Ir) l ~ Ir) ,_1 N
O l 't f'~ /~
_ O O O O O O ~ O O
O N Lr~ Ir) O Ir) ~' N
o l o l ~_ r l ~ N
O O O O O O (~J O O
~ O l ~--1 l O O l O (:~1 ~ N
. ~1 ~
O _ _ _ . . _ . O O O O O O ~I O O
(~I O r-l O O O Il') ~1 N
~ o ~ l l r r l ~ ~
_ _ ~ ~ . _ _ :' ,, ._, a~ a~ ~
. X X C h E~ .
Z ~ ~ ~ ~ ,~
c: a) a~ O a) :~ :T~ h h v~ ~1 u~ O C C C E~ E C ) ~ h C E C
a) ~1:1 ,_J .,.1 .,~1 .,1 C v~ :~ S :5 O u~ E~
_~ ~'4 JJ IJ ~ _~ a) ~ t~ ~ o ~ a Q 3 h O .,1 O E ~: ~ h C ::~ -,~ C
E~ E U E~ C E~ ~ ~ ~ 0 ._~ n~ ::~ 01 _1 1~1 O ~ .,_1 1~ 1~1 ,_1 (~5 t~l JJ t) _l O ~a ~ . .
X ~ __ tr~ __ C_~ _ H _ _ . , ' :
.
WO 92/09286 ~09~9~i~ PCr/GB91/02063 2 o ~ ~--N _ _ N . .
t ~
C ~ o o o o o ..
~,: I N O l l N O N N
~ --O O O O O
C!~ N O l ~1 l O O 1-') H O ~ N N N
ZN O ---- N N N
Z_ o __ N O O N
Y t~l O l O ~ ~1 O O O O O _ ,',, ~ O l ~ l O O ~\l N O ~ O ~ ~
__ O ~ . .
N O O l l O O N . ~
-1 .-1 ~1 _ = e z; o 3 o J- C C C Q E ~J c ;
D q~ ~ ~ ~ m ~ a) o o a) _, ~ .,, .,, ~ ~ v~ r~ ~ .
.~ ~ ~ ~ ~ o o - ~
. E Ll 0 ~ o ._~ c ~,1 h --1 .
~E~ ~ ~ _0 C ~4 ~ 0~_ ~a ,~
~ . , .
' ' ' :
W O 92/09286 - PC~r/G B91/02063 ;~9~96 _ . _ _ _ o o u~ u~ O O Lr) O n ~r O N r I_ o o . ~ ~r ~ o l l l ~ ~ o o ~r .
;i~l_ o o _ o o _ o _ o--- a~
O ~ o l ~ l o o I_ o . ~ C ~
Z r7 O l ~ ~ c~ O ~ ~ . `.
_ ___ -o o o o o U~ o U~
:~ ~ o o n Ll~ L~ o . ~ ~ ~ .
~ o l l l _ ~ r- o ~r .
C .
~ . . ~0 ~X C o ~
O h h O V ... ~ . .
Q~5 V) :>~:~ h ~1 a) ~1 ~: 3:: ~ ~ O ~ ~ , o a) ~ aJ ~ ~ u? .,, u~ ,_ :
.~ ~ C C C E E.,~ v h .,1 1 -,~ ~ ~ ~ _~
-~1 ,~ O ~ ~ C
.,., ~.~ ~n1:: E ~ ~ ~ a~
~ 11~ J_) ~ ~ a),~ 3 _1C) O .Y h E h a) ._~ O C E.,~ Q u):~ ~ O _~
~ o E C E ~ ~ ~ h a)~J ,~ J
O :~ .,~ 1~ ~1~ ~1 O O ~1 ~1 C 1~1 k. U) t.) C~ tL~ ~ ~ ~ U~ U~ _ E~ _ :
t-a X
L~ : ' :
- ' ':
- , ! I
Claims (13)
1. The use of an orally administrable pharmaceutical composition comprising a histamine H2-receptor antagonist and a bioadhesive material for the manufacture of a medicament for the treatment of gastric disorders, characterised in that the composition is formulated as an intimate mixture whereby the bioadhesive material and the histamine H2-receptor antagonist form, in-situ, a bioadhesive complex, locally targeting the histamine H2-receptor antagonist to the stomach wall; and the composition is optimally buffered to confer a pH substantially equal to that of the pKa of the histamine H2-receptor antagonist, whereby local levels of the histamine H2-receptor antagonist at the parietal cell receptor are increased.
2. Use as claimed in claim 1 characterised in that the composition is optimally buffered with a buffering component which is an antacid having equilibrium pH, acid neutralising capacity and gastric residence time values which provide a pH profile with time conferring a local pH level substantially equal to that of the pKa of the histamine H2-receptor antagonist.
3. Use as claimed in claim 1 or 2 for the treatment of gastric disorders in ulcer patients.
4. Use as claimed in claim 3 for the treatment of patients who do not respond to conventional histamine H2-receptor antagonist therapy.
5. Use as claimed in claim 3 for the treatment of acid hypersecreting patients.
6. Use as claimed in claim 1 or 2 for the single-dose treatment of acute gastric disorders.
7. Use as claimed in any preceding claim whereby the histamine H2-receptor antagonist is cimetidine, ranitidine, or famotidine.
8. Use as claimed in claim 7 whereby the histamine H2-receptor antagonist is cimetidine.
9. Use as claimed in claim 8 whereby the dose level or cimetidine is from 1 to 800mg per dosage form.
10. Use as claimed in claim 9 whereby the dose level of cimetidine is from 5 to 50mg per dosage form.
11. Use as claimed in any preceding claim whereby the composition is buffered with aluminium hydroxide, magnesium hydroxide, aluminium hydroxide-magnesium carbonate co-dried gel, magnesium carbonate, magnesium oxide, magnesium trisilicate, sodium bicarbonate, calcium carbonate, bismuth carbonate, magnesium aluminium silicate, alkali metal salts of citric, tartaric, benzoic, sorbic or phosphoric acid, or combinations of any of the aforementioned antacids.
12. A method of treatment of gastric disorders comprising orally administering to a sufferer an effective amount of a pharmaceutical composition comprising an intimate mixture or a histamine H2-receptor antagonist and a bioadhesive material, and a buffering component wherein the equilibrium pH, the acid neutralising capacity and the gastric residence time values confer a pH level substantially equal to that of the pKa of the histamine H2-receptor antagonist.
13. A pharmaceutical composition for use in the treatment of gastric disorders comprising an intimate mixture of a histamine H2-receptor antagonist and a bioadhesive material, and a buffering component wherein the equilibrium pH, the acid neutralising capacity and the gastric residence time values confer a pH level substantially equal to that of the pKa of the histamine H2-receptor antagonist.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9025710.6 | 1990-11-27 | ||
| GB909025710A GB9025710D0 (en) | 1990-11-27 | 1990-11-27 | Novel treatment |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2096962A1 true CA2096962A1 (en) | 1992-05-28 |
Family
ID=10686017
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002096962A Abandoned CA2096962A1 (en) | 1990-11-27 | 1991-11-21 | Composition containing antihistamine h2 receptor antagonists and bioadhesive material |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0559812A1 (en) |
| JP (1) | JPH06502855A (en) |
| AU (1) | AU659422B2 (en) |
| CA (1) | CA2096962A1 (en) |
| GB (1) | GB9025710D0 (en) |
| IE (1) | IE914091A1 (en) |
| PL (1) | PL168421B1 (en) |
| WO (1) | WO1992009286A1 (en) |
| ZA (1) | ZA919290B (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4139883A1 (en) * | 1991-11-29 | 1993-06-03 | Michael Prof Dr Dittgen | Prodn. of bio-adhesive medicament, e.g. oral or vaginal tablet - comprises mixing drug with swellable, bio-adhesive polymer, dispersant and opt. binder |
| WO1995001784A1 (en) * | 1993-07-06 | 1995-01-19 | Merck & Co., Inc. | H2 antagonist-sucralfate-antiflatulent combinations |
| WO1995010274A1 (en) * | 1993-10-14 | 1995-04-20 | F.H. Faulding & Co. Limited | Aqueous pharmaceutical composition |
| GB9407235D0 (en) * | 1994-04-12 | 1994-06-08 | Glaxo Group Ltd | Pharmaceutical compositions |
| US5593696A (en) * | 1994-11-21 | 1997-01-14 | Mcneil-Ppc, Inc. | Stabilized composition of famotidine and sucralfate for treatment of gastrointestinal disorders |
| KR19980703526A (en) * | 1995-04-03 | 1998-11-05 | 나가야마오사무 | Sucralate-containing formulation composition |
| WO1997028823A1 (en) * | 1996-02-08 | 1997-08-14 | Chugai Seiyaku Kabushiki Kaisha | Method of using antacid agent and pharmaceutical preparation containing antacid agent |
| WO1999049872A1 (en) * | 1998-04-01 | 1999-10-07 | Chugai Seiyaku Kabushiki Kaisha | Preventives for alcoholic gastritis |
| US6319513B1 (en) | 1998-08-24 | 2001-11-20 | The Procter & Gamble Company | Oral liquid mucoadhesive compounds |
| WO2023218480A1 (en) * | 2022-05-09 | 2023-11-16 | Syri Research Private Limited | Liquid oral formulation of famotidine or pharmaceutically acceptable salt thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3710462A1 (en) * | 1987-03-30 | 1988-10-13 | Heumann Pharma Gmbh & Co | PHARMACEUTICAL PREPARATION FOR THE TREATMENT OF DISEASES OF THE gastrointestinal tract |
| US4975281A (en) * | 1989-01-30 | 1990-12-04 | E. R. Squibb & Sons, Inc. | Anti-ulcer composition |
| EP0403048A3 (en) * | 1989-06-14 | 1991-01-30 | Warner-Lambert Company | Medicated compositions containing sucralfate and processes for their production |
-
1990
- 1990-11-27 GB GB909025710A patent/GB9025710D0/en active Pending
-
1991
- 1991-11-21 WO PCT/GB1991/002063 patent/WO1992009286A1/en not_active Application Discontinuation
- 1991-11-21 AU AU89098/91A patent/AU659422B2/en not_active Ceased
- 1991-11-21 EP EP92902524A patent/EP0559812A1/en not_active Withdrawn
- 1991-11-21 PL PL91299319A patent/PL168421B1/en unknown
- 1991-11-21 JP JP4500445A patent/JPH06502855A/en active Pending
- 1991-11-21 CA CA002096962A patent/CA2096962A1/en not_active Abandoned
- 1991-11-25 ZA ZA919290A patent/ZA919290B/en unknown
- 1991-11-25 IE IE409191A patent/IE914091A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1992009286A1 (en) | 1992-06-11 |
| GB9025710D0 (en) | 1991-01-09 |
| AU659422B2 (en) | 1995-05-18 |
| IE914091A1 (en) | 1992-06-03 |
| ZA919290B (en) | 1992-09-30 |
| EP0559812A1 (en) | 1993-09-15 |
| PL168421B1 (en) | 1996-02-29 |
| JPH06502855A (en) | 1994-03-31 |
| AU8909891A (en) | 1992-06-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5629026A (en) | Compositions containing histamine-H2-receptor antagonists at low dosage | |
| AU752214B2 (en) | Flash-melt oral dose formulations | |
| AU627298B2 (en) | Pharmaceutical formulation | |
| CA2074215C (en) | Improved oral dosing formulations of dideoxy purine nucleosides | |
| AU620866B2 (en) | Pharmaceutical compositions | |
| US5275823A (en) | Pharmaceutical compositions | |
| JPH05112445A (en) | Transfer system that hastens initiation of action and increases latent characteristics | |
| HU211236A9 (en) | Antacide compositions with prolonged gastric residence time | |
| EP1807068B1 (en) | Composition comprising acetaminophen, caffeine and aspirin together with an alkiline agent fr enhanced absorption | |
| AU659422B2 (en) | Composition containing antihistamine H2 receptor antagonists and bioadhesive material | |
| EP0533770A1 (en) | Novel treatment | |
| AU4082793A (en) | Compositions based on histamine h2-receptor antagonists and cationic exchangers complexes | |
| WO1996008238A1 (en) | Use of paracellular absorption enhancers such as glucose for enhaincing the absorption of histamine h2-antagonists | |
| EP0715520B1 (en) | Use of a suspension based on sucralphate gel as antacid | |
| CN1140996A (en) | Ranitidine and calcium carbonate pharmaceutical combination product |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |