AU690664B2 - Low dosage ranitidine compositions for the treatment of minor gastrointestinal disorders associated with excess acid secretion - Google Patents
Low dosage ranitidine compositions for the treatment of minor gastrointestinal disorders associated with excess acid secretion Download PDFInfo
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- AU690664B2 AU690664B2 AU21380/95A AU2138095A AU690664B2 AU 690664 B2 AU690664 B2 AU 690664B2 AU 21380/95 A AU21380/95 A AU 21380/95A AU 2138095 A AU2138095 A AU 2138095A AU 690664 B2 AU690664 B2 AU 690664B2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
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- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Description
WO 95/27486 PCT/EP95/01271 1 LOW DOSAGE RANITIDINE COMPOSITIONS FOR THE TREATMENT OF MINOR GASTROINTESTINAL DISORDERS ASSOCIATED WITH EXCESS ACID SECRETION The present invention relates to low dosage formulations containing the histamine Hz-receptor antagonist ranitidine and their use in the treatment of gastric disorders such as episodic heartburn.
Ranitidine, N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'methyl-2-nitro-1,1-ethenediamine, and its physiologically acceptable salts are described and claimed in British Patent Specification No. 1565966, and a particular crystalline form of ranitidine hydrochloride is described and claimed in British Patent Specification No. 2084580. In both these specifications there is reference to formulations for oral administration, which may take the form of for example tablets, capsules, granules, powders, solutions, syrups, suspensions, or tablets or lozenges for buccal administration. Oral administration constitutes a preferred route for administering ranitidine.
US Patent No. 5229137 describes the use of a combination of ranitidine and an antacid for the treatment of episodic heartburn. According to US 5229137, when H 2 -antagonists such as ranitidine are administered alone, relief from episodic heartburn is not experienced until some time after the medication is ingested. Specifically, when 150mg of ranitidine were administered to two patients suffering from episodic heartburn, relief was obtained 45 and minutes after ingestion. Therefore, according to US 5229137, an antacid needs to be administered with the H 2 -antagonist in order to obtain rapid relief. When the H 2 -antagonist is ranitidine, the doses used in the combination are between 100 and 150mg.
Compositions containing reduced doses of H 2 -antagonists are described in EP0193400 and W093/12779. EP0193400 describes a combination of an
H
2 -antagonist, such as ranitidine, and sodium polyacrylate for use in the treatment of gastritis or gastro-duodenal ulcers. According to EP0193400, the synergistic effect between the H2-antagonist and polyacryiate affords the possibility of the lower doses of H 2 -antagonist being used.
II II WO 95/27486 PCT/EP95/01271 2 W093/12779 describes the use of a combination of an H 2 -antagonist, including ranitidine, and an antacid in the treatment of gastric disorders, where the combination is buffered to confer a pH substantially equal to that of the pKa of the H2-antagonist and where the dose of the Hz-antagonist per unit dosage form is less than 25mg. The lower dose is said to be effective since the combination of active agents increases bioavailability of the H 2 -antagonist at the local stomach wall receptor site.
EP0492247 also describes a composition having a reduced dose of
H
2 .antagonist for the treatment of heartburn etc. Here the composition uses a combination of water-soluble H 2 -antagonist and an effervescent delivery system, such as an alkali metal bicarbonate and citric acid. The use of the effervescent delivery system is said to decrease the time for onset of action of the
H
2 .antagonist and increases its potency such that the formulation requires about twenty-five per cent of the H 2 -antagonist dosage currently prescribed for the treatment of active duodenal ulcer. In the case of ranitidine, the effervescent delivery system reduces the dosage from 150mg to less than about 37.5mg.
Dosage levels between 50 and 600mg, such as 150 and 300mg, of ranitidine when administered alone are conventionally regarded as conferring therapeutic benefit.
Surprisingly, it has now been found that very low doses of ranitidine, administered alone, are effective in the treatment of minor gastrointestinal disorders associated with excess acid secretion, such as episodic heartburn for example, and that relief from symptoms occurs within 30-45 minutes after ingestion. Duration of control of acid secretion is also advantageous with the dosage of the invention.
-Thus-the present inventlon prodes an oral phfrmaeutial-c;Tj ,.A as a tablet, comprising ranitidine, or a physiologi p able salt thereof, as the sole active ingredient, charat in that the dose of ranitidine per unit dosage form isb e and 30mg, such as 25mg, expressed as the weight II ;i~-e WO 95/27486 PCT/EP95/01271 3 -Aording to a furrhe, ffln.e present invention plFWurevides-a-s ta comprising ranitidine, or a physiologically acceptabe-set tereof, as the sole active ingredient, characterised in ose of ranitidine per unit dosage form is between 10an mg, such as 25mg, expressed as the weight of free se.
According to anfthw- aspect the present invention/provided a method of treating minor gastrointestinal disorders associated with excess acid secretion which comprises administering to a patient in need of such, an oral pharmaceutical composition which consists essentially of ranitidine, or a physiologically acceptable salt thereof, as the sole active ingredient characterised in that the dose of ranitidine per unit dosage form is between and 30mg, such as 25mg, expressed as the weight of free base, toge ~r w.o pgwwacelic.\[[d acceptabke- caCia(TC or tAue-4.
It will be understood that the compositions according to the invention are substantially free from antacids, a polyacrylate or an effervescent delivery system.
Raritidine may be employed in the tablets according to the invention in the form of either its free base or a physiologically acceptable salt. Such salts include salts with inorganic or organic acids such as the hydrochloride, hydrobromide, sulphate, acetate, maleate, succinate, citrate, tartrate, fumarate and ascorbate salts. A particularly preferred salt of ranitidine is the hydrochloride.
Ranitidine may be employed in the tablets according to the invention in conventional form or coated or encapsulated forms of ranitidine may be used.
Suitable coated and encapsulated forms are described in, for example, EP538034, EP523847, W092/21328, EP473431, EP459695, EP 103, CA2068366 and US5084278. Ranitidine resin adsorbates as described in UK2218333 may also be incorporated into the tablets according to the present invention.
Preferably ranitidine and its salts are used in conventional form.
I
WO 95/27486 PCT/EP95/01271 4 The amount of ranitidine, preferably in the form of a physiologically acceptable salt, particularly ranitidine hydrochloride, in the composition according to the invention is -pwfeab in the range of 10 to 30mg per dosage unit (for example per tablet), e.g. 25mg, expressed as the weight of free base.
The unit dose (for example contained in one tablet according to the invention) may be administered up to, for example, 12 times a day depending upon the nature and severity of the conditions being treated, and the age and weight of the patient. Thus, for example, in the treatment of minor gastrointestinal disorders associated with excess acid secretion such as, for example, acid indigestion, over-indulgence of food or drink alcoholic beverages), acid stomach, sour stomach, waterbrash/regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn, gastritis and dyspepsia, a 10-30mg dose of ranitidine, e.g. a 25mg dose, expressed as the weight of free base, may be administered up to 12 times a day, for example 6 times a day, as and when required.
The pharmaceutical compositions according to the invention may also contain other excipients conventional to the art such as fillers, binders, disintegrants, lubricants and dessicants. Suitable excipients are well-known to those skilled in the art.
Suitable binders include methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, alginic acid, ethylcellulose, acacia, gelatin, pregelatinised starch, sucrose syrup, polyvinylpyrrolidone (povidone) and guar gum.
Suitable lubricants include magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oils, glyceryl palmitostearate, glyceryl behenate, sodium benzoate, sodium lauryl sulphate, magnesium lauryl sulphate, mineral oil, talc and mixtures thereof.
Magnesium stearate is a preferred lubricant.
Suitable dessicants include silica gel.
-e WO 95/27486 PCT/EP95/01271 Suitable fillers include microcrysalline cellulose. Suitable disintegrants include croscarmellose sodium.
Suitable chewable tablets are described in our co-pending PCT Application No.
PCT/EP93/02763. Chewable tablets specifically disclosed in this co-pending application are not included within the scope of the present invention.
Such chewable tablets comprise ranitidine, or a physiologically acceptable salt thereof, a chewable base selected from sucrose, glucose, lactose, maltose, or a mixture thereof, a flavouring and, optionally an intense sweetener.
The chewable tablets may be prepared using the conventional stages of mixing, granulation, drying, blending, compression and packing.
Suitable swahw tablet cores may be prepared in a conventional manner, for example in a similar manner to that described in British Patent Specification No.
2084580 which is incorporated herein by reference. Thus, for example the required quantities of ranitidine or its salt, a lubricant, such as magnesium stearate and optionally a pharmaceutically acceptable disintegrant, such as croscarmellose sodium, are mixed and compressed into tablet cores.
Swallow tablets are conventionally film-coated according to conventional procedures either by aqueous or organic techniques. A preferred film coat is described in British Patent specification No. 2218336 which is incorporated herein by reference.
The fo!lowing are illustrations of non-limiting examples of the pharmaceutical compositions according to the invention. Opaspray white K-1-7000 is a suspension of titanium dioxide and hydroxypropyl cellulose in industrial methylated spirits. Opadry Yellow Y S-1-12606 is a mixture of hydroxypropyl methylcellulose 2910, titanium dioxide, triacetin and iron oxide yellow. Both Opaspray and Opadry are the tradenames of Colorcon Inc., West Point, Philadelphia, USA.
WO 95/27486 WO 9527486PCT/EP95101271 6 Reference Example I Chewable Tablet Ingredient mg/tablet Ranitidine HCI 28.0 Sucrose 2268.0 Aspartame 37.5 Povidone 50.0 Peppermint Flavour 41.5 Silica Gel 50.0 Magnesium Stear&ate 25.0 Isopropyl Alcohol qs not present in final product Example 2 Swallow Tablet Tablet Core mg/tablet Ranitidine HCI 28.0 Microcrystal line Cellulose 263.75 Croscarmellose Sodium Type A 6.00 Magnesium Stearate 2.25 Target compression weight 300mg Film Coat w/w Unit amounts (mg/tablet)* Methylhydroxypropyl Cellulose 4.0 11.3 Opaspray White K-I1-7000 3.3 4.7 Isopropyl Alcohol 26.3 qs Dichloromethane 66.4 qs I WO 95/27486 PCT/EP95/01271 7 The amount of film coat applied per tablet may be less than that stated, depending on the efficiency of the process.
Not present in the final product.
Example 3 Swallow Tablet Tablet Core Unit Amounts (mg/tablet) Ranitidine HCI 28.000 Microcrystalline Cellulose 120.875 Magnesium Stearate 1.125 Total Compression Weight 150.00 Film Coat Opadry Yellow YS-1-12606 6.75 Purified Water 42.34 Removed during processing Clinical Studies !n double-blind placebo controlled studies tc evaluate the efficacy of ranitidine (administered as the hydrochloride) in the treatment of episodic heartburn ii ,the general population, both the chewable tablets of Example 1 and the swallow tablets of Example 2 were effective within 30-45 minutes of administration.
-8- Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
*0 00 6 o
Claims (3)
1. A method of treating minor gastrointestinal disorders associated with excess acid secretion which comprises administering to a patient in need of such treatment a single unit dose of an oral pharmaceutical composition comprising ranitidine, or a physiologically acceptable salt thereof, as the sole active ingredient, characterised in that the dose of ranitidine per unit dosage form is between 10 and 30 mg, expressed as the weight of free base, together with a pharmaceutically acceptable carrier or diluent.
2. A method as claimed in claim 1, wherein the dose of ranitidine per dosage unit is mg expressed as the weight of free base. its hydrochloride salt. 0
4. A method as claimed in any one of claims 1 to 3, wherein the composition is in the form of a tablet. 0** S 20 5. A method as claimed in claim 4, wherein the tablet is in the form of a swallow tablet. 0 DATED this 23rd day of February 1998 Glaxo Group Limited by DAVIES COLLISON CAVE Patent Attorneys for the Applicants I- INTERNATIONAL SEARCH REPORT Intrns .1 Appllcation No PCT/EP 95/01271 A. CLASSIFICATION OF SUBJECT MATTER IPC 6 A61K31/34 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classificaton system followed by classification symbols) IPC 6 A61K Documentation searched other than minimum documentation to the extent that such documents are included in the fields !iarched Electronic data base consulted during the international search (name of data base and, where practical, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document, with indication, where appropnate, of the relevalit passages Relevant to claim No. X 66TH ANNUAL MEETING OF THE JAPANESE 1,3-7 PHARMACOLOGICAL SOCIETY, YOKOHAMA, JAPAN, MARCH 24-27, 1993.;& JPN J PHARMACOL,, VOL. 61, SUPPL. 1, PAGE(S) 318P, 1993. UCHIDA E et al 'EFFECT OF LOW-DOSE RANITIDINE ON GASTRIC ACIDITY AFTER TETRAGASTRIN ADMINISTRATION IN HEALTHY YOUNG VOLUNTEERS' Y see abstract 2 X ALIMENT PHARMACOL THER (ENGLAND), AUG 1,3-7 1993, VOL. 7, NO. 4, PAGE(S) 417-22, Koss MA et al 'Anti-secretory effects and pharmacokinetics of low dose ranitidine.' Y ,ee the whole document 2 j Further documents are listed in the continuation of box C. Patent family members are listed in annex. SSpecial categories of cited documents: later document published after the intemational filing date or priority date and not in conflict with the application but A' document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention earlier document but published on or after the international document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to "Ldocument which may throw doubts on priority claim(s) or involve an inventive step when the document is taken alone which is cted to establish the publication date of another Y' document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu. other means ments, such combination being obvious to a person skilled documenr pb!tt'itd prior to the international filing date but in the art. later than the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the intemational search report June 1995 04. 07. Name and mailing address of the ISA Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 l'L 2280 HV Rijswijk Tel. (+31.70) 3402040, Tx. 31 651 epo n, Stierman B Fax: 31-70) 340-3016 Form PCT/ISA/210 (second sheet) (July 1991) page 1 of 2 INTERNATIONAL SEARCH REPORT Intern, .1 Application No PCT/EP 95/01271 C(Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Categor citation of document, with indication, where appropniatc, of the relevant passag. j levant to claim NO, 91ST ANNUAL MEETING OF THE AMERICAN GASTROENTEROLOGICAL ASSOCIATION AND DIGESTIVE DISEASE WEEK, SAN ANTONIO, TEXAS, USA, MAY 12-18, 1990.;& GASTROENTEROLOGY,, VOL. 98, NO. 5 PART 2, PAGE(S) A71, 1990. KOSS M A et al 'CAN LOW DOSE RANITIDINE EFFECTIVELY INHIBIT MEAL-STIMULATED GASTRIC ACID SECRETION' see abstract WO,A,92 09286 (BEECHAM GROUP PLC) 11 June 1992 see the whole document WO,A,93 12779 (SMITH-KLINE BEECHAM PLC) 8 July 1993 cited in the application see the whole document EP,A,O 492 247 (MILES INC.) 1 July 1992 cited in the application see the whole document 1, 3-7 2 2 1-7 1-7 1-7 Form PCT'/ISAi,210 (continugan of tcend sheet) Pull' 1992) page 2 of 2 I_ INTERNATIONAL SEARCH REPORT In itonal application No, PCT/EP 95/ 01271 Box I Observations where certain claims were found unsearchable (Continuation of item I of first sheet) This international a arch report has not been established in respect of certain claims under irticle 17(2)(a) for the following reasons: 1. Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely: Remark: Although claim 6 is directed to a method of treatment of the human/ animal body, the search has been carried out and based on the alleged effects of the compound/composition. 2. Claims Nos.: because they relate to parts of the inttrnationl application that do not comply with the prescribed requirements to such an extent that no meaningful interrntiokal seurch can be carried out, specifically: 3. O Claims Nos.: because they are dependent claims and-are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This Interna.onal Searching Authority found multiple inventions in this international application, as follows: 1. As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims. 2. D As all searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment of any additional fee. 3. As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.: 4. O No required rdditiona! search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: Remark on Protest SThe additional search fees were accompanied by the applicant's protest D No protest accompanied the payment of additional search fees. Form PCT/ISA/210 (continuation of first sheet (July 1992) Form PTISA/210 (continuation of fist sheet (July 1992) ~h ~e IIC P -L~ %NURJNATIONAL SE~ARCH ILEPORWV Int~mi .1 AppIe4stin NO Inor~Iaon on pAt'h'ly r~iumbef~hts P CT/EP 95/01271 Patent document Publication Patent family Pulcadwi cie nsach report date membev(s)I date WO-A-9209286 11-06-92 AU-B- 659422 18-05-95 AU-A- 8909891 25-06-92 CA-A- 2096962 28-05-92 EP-A- 0559812 15-09-93 JP-T- 6502855 31-03-94 WO-A-9312779 08-07-93 AU-B- 3166293 28-07-93 CA-A- 2126231 08-07-93 EP-A- 0617617 05-10-94 JP-T- 7502527 16-03-95 EP-A-0492247 01-07-92 AU-A- 8989391 25-06-92 CA-A- 2055661 22-06-92 JP-A- 5039219 19-02-93 Form PCT/ISA/210 (patent family annex) (July 1992)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9407235 | 1994-04-12 | ||
GB9407235A GB9407235D0 (en) | 1994-04-12 | 1994-04-12 | Pharmaceutical compositions |
PCT/EP1995/001271 WO1995027486A1 (en) | 1994-04-12 | 1995-04-10 | Low dosage ranitidine compositions for the treatment of minor gastrointestinal disorders associated with excess acid secretion |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2138095A AU2138095A (en) | 1995-10-30 |
AU690664B2 true AU690664B2 (en) | 1998-04-30 |
Family
ID=10753423
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU21380/95A Ceased AU690664B2 (en) | 1994-04-12 | 1995-04-10 | Low dosage ranitidine compositions for the treatment of minor gastrointestinal disorders associated with excess acid secretion |
Country Status (11)
Country | Link |
---|---|
EP (1) | EP0755251A1 (en) |
JP (1) | JPH10502331A (en) |
KR (1) | KR970702034A (en) |
CN (1) | CN1146150A (en) |
AU (1) | AU690664B2 (en) |
BR (1) | BR9507312A (en) |
CA (1) | CA2187651A1 (en) |
GB (1) | GB9407235D0 (en) |
NZ (1) | NZ283354A (en) |
WO (1) | WO1995027486A1 (en) |
ZA (1) | ZA952931B (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992009286A1 (en) * | 1990-11-27 | 1992-06-11 | Beecham Group Plc | Composition containing antihistamine h2 receptor antagonists and bioadhesive material |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2055661A1 (en) * | 1990-12-21 | 1992-06-22 | Manley A. Paulos | Treatment of upset stomach associated with heartburn, sour stomach or acid indigestion with an effervescent h2 blocker formulation |
GB9127150D0 (en) * | 1991-12-20 | 1992-02-19 | Smithkline Beecham Plc | Novel treatment |
-
1994
- 1994-04-12 GB GB9407235A patent/GB9407235D0/en active Pending
-
1995
- 1995-04-10 CN CN95192537A patent/CN1146150A/en active Pending
- 1995-04-10 AU AU21380/95A patent/AU690664B2/en not_active Ceased
- 1995-04-10 EP EP95914346A patent/EP0755251A1/en not_active Withdrawn
- 1995-04-10 BR BR9507312A patent/BR9507312A/en unknown
- 1995-04-10 JP JP7526068A patent/JPH10502331A/en active Pending
- 1995-04-10 NZ NZ283354A patent/NZ283354A/en unknown
- 1995-04-10 WO PCT/EP1995/001271 patent/WO1995027486A1/en not_active Application Discontinuation
- 1995-04-10 CA CA002187651A patent/CA2187651A1/en not_active Abandoned
- 1995-04-10 ZA ZA952931A patent/ZA952931B/en unknown
-
1996
- 1996-10-11 KR KR1019960705716A patent/KR970702034A/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992009286A1 (en) * | 1990-11-27 | 1992-06-11 | Beecham Group Plc | Composition containing antihistamine h2 receptor antagonists and bioadhesive material |
Also Published As
Publication number | Publication date |
---|---|
BR9507312A (en) | 1997-10-07 |
NZ283354A (en) | 1998-08-26 |
WO1995027486A1 (en) | 1995-10-19 |
AU2138095A (en) | 1995-10-30 |
EP0755251A1 (en) | 1997-01-29 |
CA2187651A1 (en) | 1995-10-19 |
JPH10502331A (en) | 1998-03-03 |
KR970702034A (en) | 1997-05-13 |
ZA952931B (en) | 1996-01-05 |
GB9407235D0 (en) | 1994-06-08 |
MX9604553A (en) | 1997-11-29 |
CN1146150A (en) | 1997-03-26 |
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MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |