CA1229552A - Cimetidine compositions - Google Patents
Cimetidine compositionsInfo
- Publication number
- CA1229552A CA1229552A CA000458468A CA458468A CA1229552A CA 1229552 A CA1229552 A CA 1229552A CA 000458468 A CA000458468 A CA 000458468A CA 458468 A CA458468 A CA 458468A CA 1229552 A CA1229552 A CA 1229552A
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- Prior art keywords
- cimetidine
- tablet composition
- composition according
- mixed
- disintegrant
- Prior art date
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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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
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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)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A B S T R A C T
A pharmaceutical tablet composition is disclosed which contains from about 84 to about 98.25% w/w of cimetidine as the active ingredient, about 1% w/w or greater of a binder, about 0.25% w/w or greater of a disintegrant and from about 0.5 to 1.5% w/w of a lubricant, permitting a patient-compliance-enhancing reduction in size of particular merit in the case of high strength cimetidine tablet compositions and providing for ingestion of a lower quantum of excipient on the part of the subject being treated and lower production costs due to the reduction in excipient w/w percentage.
A pharmaceutical tablet composition is disclosed which contains from about 84 to about 98.25% w/w of cimetidine as the active ingredient, about 1% w/w or greater of a binder, about 0.25% w/w or greater of a disintegrant and from about 0.5 to 1.5% w/w of a lubricant, permitting a patient-compliance-enhancing reduction in size of particular merit in the case of high strength cimetidine tablet compositions and providing for ingestion of a lower quantum of excipient on the part of the subject being treated and lower production costs due to the reduction in excipient w/w percentage.
Description
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The present invention relates to pharmaceutical compositions for oral administration an din particular, to tablets which contain as their active ingredient cimetidine.
The compound known by common name as cimetidine, described as an amorphous off-white powder, has the chemical formula N-cyano-N'-methyl-N"-(2-((4-methyl-5-imidazolyl)-methylthio)ethyl)guanidine and the structural formula:
NON
H3C cH2scH2cH2NHcNHcH3 HO N
Cimetidine has been found to inhibit competitively the action of histamine at the histamine Ho receptor and is useful for mammalian treatment where the inhibition of gastric acid secretion is desired such as duodenal and non-malignant gastric ulcer and other conditions associated with gastric acid secretion. The efficacy of cimetidine in the treatment of duodenal ulcer has been confirmed by numerically well-docu-minted studies.
Initially, a large variety of dally doses ranging from 800 my. to 2000 my. have been shown to be effective (see Brogdenj R.N. et at., Doug 15: 93 (1978)). Although in all-Nikolai studies, cimetidine has been used in dosages us to 2400 my. per diem in divided doses, the usual dosage of cimetidine recommended for the treatment in human subjects of acute duo-dental ulcer is 1200 my. per diem in four divided doses of 300 my. each given with meals and at bedtime. Following cimetidine-induced ulcer healing, a daily maintenance regimen of 400 my.
at bedtime for 6 to 12 months is recommended.
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To these ends, cime-tidine is available from a number of manufacturers in a variety of dosage forms and strengths including tablets which contain 200, 300, 400 and 600 my. of cimetidine as active ingredient. These tablets generally contain about 67 to 76 % w/w of cimetidine and about 24 to 33 % w/w of pharmaceutically acceptable excip-tents such as granulating agents and aids, disintegrants, lit-tens and lubricants. Cimetidine tablets are generally film-coated using conventional coating solutions and film-coating methods for the purpose of masking the bitter taste of cimetidine and attaining better elegance. A dye or dyes is usually added to the tablet composition or, in the case of a film-coated tablet, to the film-coating solution to provide for color in the finished cimetidine tablet.
It is standard practice to manufacture cimetidine tablets using a wet granulation process, as the physical net-use of the material together with the high content of active ingredient in the composition render tabulating by direct compression undesirable. In a standard wet granulation pro-cuss, the cimetidine is mixed with intra-granular excipients such as fillers and disintegrants. The filler in this case may act as an aid to granulation, controlling wet mass consistency and doughtiness. The disintegrants act as granule disintegrants. This mix is blended with one or more binders in aqueous or non-aqueous solution until grant elation is achieved; that is, wet massing to form partial agglomeration. The binders may be added out of solution to the dry mix of cimetidine and intragranular So xcipients. Granulation is then achieved by wetting the dry mass with a granulating solvent until granulation is achieved.
The granules thus formed are milled if required and then dried to the desired moisture content. The granules are mixed with extra-granular excipients such as fillers, disintegrants andlu-bricants to give specified tablet weigh-t and size, disintegra-lion properties and desired flow properties for tabulating.
The resulting material is then ready for compression into tablet form. The compressed tablet core may then be fllm-coated by conventional methods.
It has been known for some time that 800 my. of cimetidine given twice daily in 400 my. doses is effective for the treatment of duodenal ulcer (see Kerr et at. "Cimetidine:
twice daily administration in duodenal ulcer results of a US and Ireland multicentre study": C~mQ~d~nQ on ho 80~;
1981: Long man Group Limited, at page 9 and Eckardt et at.
"Cimetidine: twice daily administrationiin duodenal ulcer--results of a European multicentre study"; C~mQ~d~nQ on ho 80~;
1981: Long man Group Limited, at page 14).
Among the cimetidine manufacturers in the Canadian pharmaceutical industry, it was Frank W. Homer Inc. that first marketed in Canada a 400 my. twice-a-day cimetidine regimen, allowing for significantly lower cost but equally effective cimetidine therapy with the considerable advantage flower overall dosage. This regimen was marketed after Homer carried out further clinical trials demonstrating that the rates of healing and duration of treatment necessary to obtain endoscopic healing of ulcers and complete disappearance of symptoms were ~2~9552 comparable for a regimen of 400 my. twice per day and 300 my.
four times per day (see Levis, D. et at., Comparative efficacy of two dosage regimens of cimetidine in the treatment of symptomatic duodenal ulcer: Results of a multi center 5 clinical trial, CU~L~(en~ The~ap~u~c Roy, 33:70 (1983)).
Homer also clinically established the efficacy ox an 800 mar once-a-day cimetidine regimen (see Lacerate, M et at.
Single daily dose of cimetidine for the treatment of symptomatic duodenal ulcer: Results of a comparative two-cen-tre clinical lo trial, CULT ~hQ~apQ~t~c RQ~Qa~ch, 35:777 (1984)). It will be appreciated that such a regimen would increase Patient compliance, since the patient would need to take 800 my. of cimetldine once-a-day only rather than 400 my. twice-a-day or 300 my. four times a day as with other regimens. Patient compliance could be even further enhanced if it were possible to have a single tablet containing 800 my. of cimetidine, if it were not for the offsetting increase in patient reluctance due to the size of a tablet which has 67 to 76 . % w/w of cimetidine and 24 to 33 % w/w of pharmaceutically acceptable excipient.
It will thus be seen that it would be a significant advantage in obtaining patient compliance if a single 800 my.
strength tablet could be provided with a reduction in size so that there would be no apprehension about being able to swallow same.
In a medicinal tablet composition however, the : nature and quantity of pharmaceutically acceptable excipiènts are most important from many points of view, including Forum-ecological, toxic and allergenic, manufacturing, and aesthetic.
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the choice of excipients and limitations on the amounts thereof involves a careful weighing of several factors, some of which are competing. The active ingredient itself must be well granulated and processed with intragranular excipients to form granules of such a consistent size and density that con-sistent biopharmaceutical and handling properties are achieved.
During tabulating, the flow properties of the granulated mat-trial must be such as to ensure a smooth and consistent flow of material into the tablet die. Good compressibility with sufficient hardness and low friability is required where tablets are to be film-coated as in the case of cimetidine tablets because of the relatively rough treatment of the tablet cores in film-coating apparatus. The surface properties of the tablet cores must be such as to give proper adherence of the tablet coating solution. The compressibility is also important to minimize tablet lamination and capping. These very problems were encountered by Leonard et at,. (The Pharmaceutical Develop-mint and Bioavailability of Cimetidine Capsule and Tablet Formulations, Dow ~evQ~pmQn~ and Hindu a Pharmacy, I
217-226 (1979) with a 77% cimetidine formulation but were avoided upon reducing the percentage of cimetidine to 72%
and altering the granulating base.
Furthermore, the bioavailability of the tablet must be such as to satisfy clinical and regulatory requirements.
It is known that different tablet compositions may exhibit varying levels of bioavailability due to varying factors affecting the formulation and processing of the dosage form;
for example, manufacturing procedures and excipients. It has been suggested that, in the case of cimetidine, bioavailability is partly dependent on the rate of dissolution or disintegration (see Leonard et at., The Pharmaceutical Development and Bevel-~2;~3552 Ability of Cimetidine Capsule and Tablet Formulations, Dug VQvcQ~pmQ~ and Lou a Pharmacy, I, 217-226 (1979)).
Leonard et at. also pointed out the significant effect that the addition of even a single excipien-tto a cimetldine form-elation may have on the undesirable phenomenon of rapidly increasing dissolution time over normal compression ratios.
It will thus be appreciated that many significant problems are encountered in providing a tablet composition with a higher percentage of cimetidine than that encountered in known cimetidine tablet compositions.
Surprisingly, it has now been found that a cimetidine tablet composition may be obtained with a higher percentage of cimetidine than has heretofore been achieved, for example about 94 % w/w, while maintaining adequate hardness, disintegration, friability and other required parameters. Such a higher percentage will minimize or eliminate patient reluctance - due to size in ingesting a cimetidine tablet containing 800 my. of cimetidine which would otherwise, if known percent-ages were utilized, present considerable compliance problems.
The higher percentage has been achieved upon the discovery that cimetidine has unsuspected granulating properties which could be utilized to obtain a surprising and unexpected reduction in the w/w percentage of pharmaceutically acceptable ...... ... __ 3~Z~55~
excipients heretofore thought necessary to enable processing and maintain the tablet properties required, and an even more surprising and unexpected reduction in the v/v percentage of such excipients.
Size considerations apart, the lower percentage of excipients also results in lower production costs for tablets containing any quantity of cimetidine and results in less excipient being introduced into the system of the patient.
According to the present invention, a cimetidine tab-let composition, processed with facility and having the requisite properties, but of significantly reduced size, contains from about 84 to about 98.25% w/w of cimetidine, a binder in an amount of about 1% w/w or greater, a disintegrant in an amount of about 0.25% w/w or greater and a lubricant in an amount from about 0.5 to 1.5% w/w.
; In a preferred embodiment, the present invention provides a tablet composition containing about 94% w/w of cimetidine, from 2 to 4.5% w/w of a binder, from l to 3.5%
w/w of a disintegrant and from 0.5 to 1.5% w/w of a lubricant, which cimetidlne, in further preferred embodiments, is present in quantities of about 200 to 800 my.
- According to another aspect of the present invention, there is provided a process for preparing a tablet composition which comprises mixing about 84 to about 98.25% w/w of cimetidine with about 1% w/w or greater of a binder, about 0.25% w/w or greater of a disintegrant and from about 0.5 to 1.5% w/w of a lubricant.
As used herein, "cimetidine" means that compound having the chemical formula N-cyano-N'-methyl-N"-(2((4~methyl-5-imidazolyl)methylthio)ethyl) guanidine as identified in Thy MCKEE dQX, Thea eon., Merck & Co. Inc., Roy, New :~2Z9SS2 Jersey, U.S.A. (1983) at page 323 and includes any forum-ceutically acceptable acid addition salt thereof.
As used herein, "pharmaceutically acceptable acid addition salt" means an acid addition salt possessing the properties of the free compound and being not biologically or otherwise undesirable and includes the hydrochloric, hydra-bromic, sulfuric and malefic addition salts and the like.
As used herein, "pharmaceutically acceptable excip-tent" means an excipient which is not biologically, forum-ecologically, or otherwise undesirable. It will be appreciated by those skilled in the art that references herein to excipients such as binders, lubricants and disintegrants are necessarily restricted to those excipients which are pharmaceutically acceptable.
Binders which may be used in the present invention are those binders commonly used in the art and include starch, gelatin, cellulose derivatives; for example methylcelluloses, ethylcelluloses and propylcelluloses, and preferably polyvinyl-pyrrolidone; for example Plasdone* K-39-22.
Disintegrants which may be used in the present invent lion are those disintegrants commonly used in the art and include starch, sodium starch glycolate; for example, Primojel*, and preferably carboxymethyl starch; for example, Explotab*.
Lubricants which may be used in the present invent lion are those lubricants commonly used in the art and in-elude Starkey acid and its salts e.g. magnesium, calcium or sodium Stewart.
*trade mark ~ZZ955Z
A further understanding of the invention and its further advantages can be had from the following non-limiting examples.
Example I
35.5 g. of Plasdone* K-29-32 (polyvinylpyrrolidone) was mixed with 176 ml. of purified water until dissolution WAS complete. 500 g. of cimetidine was mixed with 23.7 g. of Explotab* (carboxymethyl starch) for 5 minutes and then grant slated wit the prepared Plasdone*/water solution. The grant slated material was then tray-dried overnight in a convection oven set at 45C until a moisture content of 0.4% to 1.2%
(Congo scale) was obtained. The granules thus dried were passed through a No. 12 screen and then mixed for a further 3 minutes.
Approximately 8 g. of screened and mixed granules were with-drawn and mixed with 8.9 g. of magnesium Stewart, passed through a No. 12 screen and returned to the previously screened and mixed granules. This mixture was mixed for 10 minutes with 23.7 g. of Explotab* (carboxymethyl starch). The resulting mixture was compressed on a Majesty* F-3 single press compress soon machine to provide tablets having a hardness range of 9.0 to 11.0 kg. (Stokes scale) and a moisture content of 0.4% at compression. Average tablet weight was 946 my., containing 800 my. of cimetidine.
EXAMPLE II
10.4 g. of Plasdone* K-29-32 (polyvinylpyrrolidone) was mixed with 51.6 ml. of purified water until dissolution was complete. 500 g. of cimetidine was mixed with 2.6 g. of Explotab* (carboxymethyl starch) for 5 minutes and then grant--fated with the prepared Plasdone*/water solution. The *trade mark I
translated material was then tray-~lried overnight in a convect lion oven set at 45C until a moisture content of 0.4% to 1.2%
(Congo scale) was obtained. The granules thus dried were passed through a No. 12 screen and then mixed for a further 3 minutes. Approximately 8 g. of screened and mixed granules were withdrawn and mixed with 2.6 g. of magnesium Stewart, passed through a No. 12 screen and returned to the previously screened and mixed granules. This mixture was mixed for 10 minutes with 2.6 g. of Explotab* (carboxymethyl starch). The resulting mixture was compressed on a Majesty* F-3 single press compression machine to provide tablets having a hardness range of 9.0 to 11.0 kg. (Stokes scale) and a moisture content of 0.4% at compression. Average tablet weight was 829 my., con-twining 800 my. of cimetidine.
EXAMPLE III
18.6 g. of Plasdone* K-29-32 (polyvinylpyrrolidone) was mixed with 92.2 ml. of purified water until dissolution was complete. 500 g. of cimetidine was mixed with 5.3 I. of Explotab* (carboxymethyl starch) for 5 minutes and then grant-fated with the prepared Plasdone*/water solution. The grant-fated material was then tray-dried overnight in a convection oven set at 45C until a moisture content of 0.4% to 1.2%
(Congo scale) was obtained. The granules thus dried were passed through a No. 12 screen and then mixed for a further 3 minutes. Approximately 8 g. of screened and mixed granules were withdrawn and mixed with 2.7 g. of magnesium Stewart, passed through a No. 12 screen and returned to the previously screened and mixed granules. This mixture was mixed for 10 minutes with 5.3 g. of Explotab* (carboxymethyl starch). The * trade mark ssz~:
exulting mixture was compressed on a Majesty* F-3 single press compression machine to provide concave, beveled, ellipsoid tablets of dimensions 11/32" x 23/32" having a hardness range of 9.0 to 11.0 kg. (Stokes scale) and a moist lure content off% at compression. Average tablet wits 851 my., containing 800 my. of cimetidine.
EXAMPLE IV
20.0 g. of Plasdone* K-29-32 (polyvinylpyrrolidone) was mixed with 100 ml. of purified water until dissolution was complete. 500 g. of cimetidine was mixed with 5.3 g. of Explotab* (carboxymethyl starch) for 5 minutes and then grant-fated with the prepared Plasdone*/water solution. The grant-fated material was then tray-dried overnight in a convection oven set at 45C until a moisture content of 0.4% to 1.2%
(Congo scale) was obtained. The granules thus dried were passed through a No. 12 screen and then mixed for a further 3 minutes. Approximately 8 g. of screened and mixed granules were withdrawn and mixed with 2.7 g. of magnesium Stewart, passed through a No. 12 screen and returned to the previously screened and mixed granules. This mixture was mixed for lo minutes with 5.3 g. of Explotab* (carboxymethyl starch). The resulting mixture was compressed on a rqaneSty* F-3 single press compression machine to provide concave, beveled, ellipsoid tablets of dimensions 11/32" x 23/32" having a hardness range of 9.0 to 11.0 kg. (Stokes scale) and a moisture content of 0.4% at compression. Average tablet weight was 853 my., con-twining 800 my. of cimetidine.
EXAMPLE V
Granules ready for tabulating were prepared as in * trade mark issue example IV. Concave, beveled, round tablets of 5/16" diameter were compressed on a Majesty* F-3 single press compression ma-chine having a hardness range of 5.0 to 7.0 kg. (Stokes scale) and a moisture content of 0~4% at compression. Average tablet weight was 213 my., containing 200 my. of cimetidine.
EXAMPLE VI
Granules ready for tabulating were prepared as in Example IV. Concave, beveled, round tablets of 3/8" die-meter were compressed on a Majesty* F-3 single press compress soon machine having a hardness range of 5.0 to 7.0 kg. (Stokes scale) and a moisture content of 0.4% at compression. Average tablet weight was 319 my., containing 300 my. of cime-tidine.
EXAMPLE VII
Granules ready for tabulating were prepared as in Example IV. Concave, beveled, round tablets of 7/16" die-meter were compressed on a Majesty* F-3 single press compress soon machine having a hardness value of 5.0 to 8.0 kg. (Stokes scale) and a moisture content of 0.4% at compression. Average tablet weight was 426 my., containing 400 my. of cimetidine.
SAMPLE VIII
Granules ready for tabulating were prepared as in Example IV. Concave, beveled, round tablets of 15/32" die-meter were compressed on a Majesty* F-3 single press compress soon machine having a hardness value of 6.0 to 8.0 kg. (Stokes 25` scale) and a moisture content of 0.4% at compression. Average tablet weight was 639 my., containing 600 my. of cimetidine.
EXAMPLE IX
17.5 g. of Plasdone* K-29-32 (polyvinylpyrrolidone~
was mixed with 80 ml. of purified water until dissolution was * trade mark :~L22~SS2 complete. 470.05 g. of cimetidine was mixed with 5.0 g. of Explotab* (carboxymethyl starch) for 2 minutes and transferred to a mortar. The cimetidine/Explotab* mixture was granulated with the prepared Plasdone*/water solution, an additional 59 ml. of purified water being added. The granulated material was then tray-dried for 1 3/4 hours in a convection oven to a moisture content of 1.2% (Congo scale). The granules thus dried were passed through a No. 15 screen and transferred to a plastic bag. 2.45 g. of magnesium Stewart was mixed with an equal weight of screened granules withdrawn from the pies-tic bag. This mixture was passed through a No. 15 screen and returned to the plastic bag containing the remaining granules.
This mixture was mixed with 5.0 g. of Explotab* (carboxymethyl starch) for 2 minutes and compressed on a Majesty* E-3 single press compression machine using a 5/8" concave, round, plain punch to provide tablets of thickness 5.56 mm. having a hardness range of 9-10 kg. (Stokes scale) and a moisture content of 0.9% at compress soon. Average tablet weight was 851 my., containing 800 my. of cimetidine. The tablets had a friability value of 0.31% and a disintegration time of 5 minutes in HO at 37C.
_ AMPLE X
The procedure of Example IX was followed substituting the following quantities of materials:
Cimetidine 200 g.
Explotab* (intragranular) 2.1 g Plasdone* 4.19 g.
Purified water 36.5 ml.
Extra water added 33 ml.
Explotab* (extra granular) 2.1 g.
Magnesium Stewart 1.05 g.
* trade mark - 13 -~.~7Z~3/SS;~
Llabletting was carried out on a Majesty* F-3 single press compression machine using a 5/8" concave, round, plain punch to provide tablets having hardness values of 6 1/2 kg. and 8 kg. (Stokes scale) and a moisture content of 1.1% at come press ion. Average tablet weight was 838 my., containing 800 my. of cimetidine. The tablets having a hardness value of 6 1/2 kg. had a friability value of 0.36% and a disinter-ration time of 2 minutes in HO at 37C, and those having a hardness value of 8 kg. had a friability value of 0.36%
and a disintegration time of 5 minutes in HO at 37C.
EXAMPLE XI
The procedure of Example IX was followed substitute in the following quantities of materials:
; Cimetidine 200 g.
; 15 Explotab* (intragranular) 2.14 g.
Plasdone* 8.56 g.
Purified Water 36.5 ml.
Extra water added 23 ml.
Explotab* (extra granular) 2.14 g.
Magnesium Stewart 1.07 g.
Tabulating was carried out on a Majesty* F-3 single press compression machine using a 5/8" concave, round, plain punch to provide tablets having hardness values of 7 to 8 kg. and 10 kg. (Stokes scale) and a moisture content owe 0.5% at come press ion. Average tablet weight was 856 my., containing 800 my. of cimetidine. The tablets having a hardness value of 7 to 8 kg. had a friability value of 0.35% and a disintegration time of 5 minutes in HO at SUE and those having a hardness value of 10 kg. had a friability value of 0.26% and a disk integration time of 9 minutes in HO at 37C.
* trade mark ;~LZZ9S52 EXAMPLE XII
The procedure of Example IX was followed substitute in the following quantities of materials:
Cimetidine 200 g.
Explotab* (intragranular) 4.42 g.
Plasdone* 11.05 g.
Purified Water 36.5 ml.
Extra water added 18.5 ml.
- Explotab* (extra granular) 4.42 g.
magnesium Stewart 1.105 g.
Tabulating was carried out on a Majesty* F-3 single press compression machine using a 5/8" concave, round, plain punch to provide tablets having a hardness value of 8 to 9 kg.
(Stokes scale) and a moisture con-tent of 0.8% at compression.
Average tablet weight was 884 my., containing 800 my. of cimetidi,ne. The tablets had a friability value of 0.39% and a disintegration time of 12 minutes in HO at 37C.
E SAMPLE XI I I
10.8 kg. of Plasdone* K-29-32 (polyvinylpyrrolidone) was mixed with 53.0 1. of purified water until dissolution was complete. 290.0 kg. of cimetidine was mixed with 3080 g. of Explotab* (carboxymethyl starch) for 5 minutes and then granulated with the prepared Plasdone*/water solution. The granulated material was then tray-dried overnight in a convection 25' oven set at 45C until a moisture content of 0.4% to 1.2%
(Congo Schulz obtained. The granules thus dried were passed through a No. 12 screen and then mixed for a further 3 minutes. Approximately 5 kg. of screened and mixed granules were withdrawn and mixed with 1817 q. of magnesium Stewart, passed through a No. 12 screen and returned to the previously * trade mark - 15 -955~
screened and mixed granules. This mixture was rnlxéd for 10 minutes with 3080 g. of Explotab* (carboxymethyl starch.
The resulting mixture was compressed on a Stokes D-3 machine to provide concave, beveled, ellipsoid tablets of dimensions 11/32" x 23/32" having a hardness range of 9.0 to 11.0 kg.
(Stokes scale). Average tablet weight was 852 my., containing 800 my. of cimetidine.
EXAMPLE XIV
18.52 g. of -Plasdone* X 29-32 (polyvinylpyrrolidone) was mixed with 40 ml. of purified water until dissolution was complete.- 500 g. of cimetidine was mixed with 2.63 g. of Explotab* (carboxymethyl starch) for 2 minutes and transferred to a mortar. The cimetidine/Explotab* mixture was granulated with the prepared Plasdone*/water solution, an additional 80 ml. of purified water being added. The granulated material was then tray dried in a convection oven to a moisture content of 0.6% (Congo scale). The granules thus dried were passed through a No. 15 screen and transferred to a plastic bag. 2.7 g.
of magnesium Stewart was mixed with an equal weight of screened granules withdrawn from the plastic bag. This mixture was passed through a No. 15 screen and returned to the plastic bag containing the remaining granules. This mixture was mixed for 2 minutes and compressed on a Majesty* F-3 single press compression machine using an ellipsoid, biconcave, beveled punch to give tablets of dimensions 11/32" x 23/32" having a hardness of 8.5 kg. (Stokes scale). Average tablet weight was 838 my., containing 800 my. of cimetidine. The tablets had a disintegration time of 2 minutes in HO at 37C and 2 minutes CUSP method).
* trade mark ~Z~5~5S~
APPLE XV
18.52 g. of Plasdone* I~-29-32 (polyvinylpyrrolidone) was mixed with 40 ml. of purified water until dissolution was complete. 500 g. of cimetidine was placed in a mortar and granulated with the prepared Plasdone*/water solution, an additional 80 ml., approximately of water being added.
The granulated material was then tray-dried in a convection oven to a moisture content of 0.6% (Congo scale). The grant vies thus dried were passed through a No. 15 screen and transferred to a plastic bag. 2.7 g. of magnesium Stewart was mixed with an equal weight of screened granules with-drawn from the plastic bag. This mixture was Dossed through a No. 15 screen and returned to the plastic bag containing the remaining granules. This mixture was mixed for 2 mint vies with 2.63 g. of Explotab* (carboxymethyl starch) and compressed on a Majesty* F-3 single press compression machine using an ellipsoid, biconcave, beveled punch to give tablets of dimensions 11/32" x 23/3Z" having a hardness value of 10 kg.
(Stokes scale). Average tablet weight was 838 my., containing 800 my. of cimetidine. The tablets had a disintegration time of 5 minutes in HO at 37C and 4 minutes CUSP method).
EXAMPLE XVI
The procedure of Example XV was followed but substitu-tying 1.30 g. of ASSIDUOUSLY* (microcrystalline cellulose derivative) for the 2.63 g. of Explotab* used in Example XV. Tablets were compressed on a Majesty* F-3 single press compression machine using an ellipsoid, biconcave, beveled punch to give tablets of dimensions 11/32" x 23/32" having a hardness value of 10 kg.
(Stokes scale). Average tablet weight was 836 my., containing 800 my.
* trade mark - 17 -so of cimetidine. The tablets had a disintegration time of 5 minutes in HO at 37C and 2 minutes CUSP method).
Although the foregoing examples have been directed to the preparation of high percentage cimetidine tablets for human consumption, the present invention would extend, for example, to cimetidine tablets for veterinary use as well.
Nor is the practice of the present invention restricted, for example, to particular excipients or brands thereof or to a specify lo process for the preparation of the tablets of the present invention. Therefore, although various preferred embodiments have been described herein in detail, it will be appreciated by those skilled in the art that variations may be made without departing from the spirit of the invention or the scope of the appended claims.
.
The present invention relates to pharmaceutical compositions for oral administration an din particular, to tablets which contain as their active ingredient cimetidine.
The compound known by common name as cimetidine, described as an amorphous off-white powder, has the chemical formula N-cyano-N'-methyl-N"-(2-((4-methyl-5-imidazolyl)-methylthio)ethyl)guanidine and the structural formula:
NON
H3C cH2scH2cH2NHcNHcH3 HO N
Cimetidine has been found to inhibit competitively the action of histamine at the histamine Ho receptor and is useful for mammalian treatment where the inhibition of gastric acid secretion is desired such as duodenal and non-malignant gastric ulcer and other conditions associated with gastric acid secretion. The efficacy of cimetidine in the treatment of duodenal ulcer has been confirmed by numerically well-docu-minted studies.
Initially, a large variety of dally doses ranging from 800 my. to 2000 my. have been shown to be effective (see Brogdenj R.N. et at., Doug 15: 93 (1978)). Although in all-Nikolai studies, cimetidine has been used in dosages us to 2400 my. per diem in divided doses, the usual dosage of cimetidine recommended for the treatment in human subjects of acute duo-dental ulcer is 1200 my. per diem in four divided doses of 300 my. each given with meals and at bedtime. Following cimetidine-induced ulcer healing, a daily maintenance regimen of 400 my.
at bedtime for 6 to 12 months is recommended.
~2Z9~Z
To these ends, cime-tidine is available from a number of manufacturers in a variety of dosage forms and strengths including tablets which contain 200, 300, 400 and 600 my. of cimetidine as active ingredient. These tablets generally contain about 67 to 76 % w/w of cimetidine and about 24 to 33 % w/w of pharmaceutically acceptable excip-tents such as granulating agents and aids, disintegrants, lit-tens and lubricants. Cimetidine tablets are generally film-coated using conventional coating solutions and film-coating methods for the purpose of masking the bitter taste of cimetidine and attaining better elegance. A dye or dyes is usually added to the tablet composition or, in the case of a film-coated tablet, to the film-coating solution to provide for color in the finished cimetidine tablet.
It is standard practice to manufacture cimetidine tablets using a wet granulation process, as the physical net-use of the material together with the high content of active ingredient in the composition render tabulating by direct compression undesirable. In a standard wet granulation pro-cuss, the cimetidine is mixed with intra-granular excipients such as fillers and disintegrants. The filler in this case may act as an aid to granulation, controlling wet mass consistency and doughtiness. The disintegrants act as granule disintegrants. This mix is blended with one or more binders in aqueous or non-aqueous solution until grant elation is achieved; that is, wet massing to form partial agglomeration. The binders may be added out of solution to the dry mix of cimetidine and intragranular So xcipients. Granulation is then achieved by wetting the dry mass with a granulating solvent until granulation is achieved.
The granules thus formed are milled if required and then dried to the desired moisture content. The granules are mixed with extra-granular excipients such as fillers, disintegrants andlu-bricants to give specified tablet weigh-t and size, disintegra-lion properties and desired flow properties for tabulating.
The resulting material is then ready for compression into tablet form. The compressed tablet core may then be fllm-coated by conventional methods.
It has been known for some time that 800 my. of cimetidine given twice daily in 400 my. doses is effective for the treatment of duodenal ulcer (see Kerr et at. "Cimetidine:
twice daily administration in duodenal ulcer results of a US and Ireland multicentre study": C~mQ~d~nQ on ho 80~;
1981: Long man Group Limited, at page 9 and Eckardt et at.
"Cimetidine: twice daily administrationiin duodenal ulcer--results of a European multicentre study"; C~mQ~d~nQ on ho 80~;
1981: Long man Group Limited, at page 14).
Among the cimetidine manufacturers in the Canadian pharmaceutical industry, it was Frank W. Homer Inc. that first marketed in Canada a 400 my. twice-a-day cimetidine regimen, allowing for significantly lower cost but equally effective cimetidine therapy with the considerable advantage flower overall dosage. This regimen was marketed after Homer carried out further clinical trials demonstrating that the rates of healing and duration of treatment necessary to obtain endoscopic healing of ulcers and complete disappearance of symptoms were ~2~9552 comparable for a regimen of 400 my. twice per day and 300 my.
four times per day (see Levis, D. et at., Comparative efficacy of two dosage regimens of cimetidine in the treatment of symptomatic duodenal ulcer: Results of a multi center 5 clinical trial, CU~L~(en~ The~ap~u~c Roy, 33:70 (1983)).
Homer also clinically established the efficacy ox an 800 mar once-a-day cimetidine regimen (see Lacerate, M et at.
Single daily dose of cimetidine for the treatment of symptomatic duodenal ulcer: Results of a comparative two-cen-tre clinical lo trial, CULT ~hQ~apQ~t~c RQ~Qa~ch, 35:777 (1984)). It will be appreciated that such a regimen would increase Patient compliance, since the patient would need to take 800 my. of cimetldine once-a-day only rather than 400 my. twice-a-day or 300 my. four times a day as with other regimens. Patient compliance could be even further enhanced if it were possible to have a single tablet containing 800 my. of cimetidine, if it were not for the offsetting increase in patient reluctance due to the size of a tablet which has 67 to 76 . % w/w of cimetidine and 24 to 33 % w/w of pharmaceutically acceptable excipient.
It will thus be seen that it would be a significant advantage in obtaining patient compliance if a single 800 my.
strength tablet could be provided with a reduction in size so that there would be no apprehension about being able to swallow same.
In a medicinal tablet composition however, the : nature and quantity of pharmaceutically acceptable excipiènts are most important from many points of view, including Forum-ecological, toxic and allergenic, manufacturing, and aesthetic.
~2~5S~
the choice of excipients and limitations on the amounts thereof involves a careful weighing of several factors, some of which are competing. The active ingredient itself must be well granulated and processed with intragranular excipients to form granules of such a consistent size and density that con-sistent biopharmaceutical and handling properties are achieved.
During tabulating, the flow properties of the granulated mat-trial must be such as to ensure a smooth and consistent flow of material into the tablet die. Good compressibility with sufficient hardness and low friability is required where tablets are to be film-coated as in the case of cimetidine tablets because of the relatively rough treatment of the tablet cores in film-coating apparatus. The surface properties of the tablet cores must be such as to give proper adherence of the tablet coating solution. The compressibility is also important to minimize tablet lamination and capping. These very problems were encountered by Leonard et at,. (The Pharmaceutical Develop-mint and Bioavailability of Cimetidine Capsule and Tablet Formulations, Dow ~evQ~pmQn~ and Hindu a Pharmacy, I
217-226 (1979) with a 77% cimetidine formulation but were avoided upon reducing the percentage of cimetidine to 72%
and altering the granulating base.
Furthermore, the bioavailability of the tablet must be such as to satisfy clinical and regulatory requirements.
It is known that different tablet compositions may exhibit varying levels of bioavailability due to varying factors affecting the formulation and processing of the dosage form;
for example, manufacturing procedures and excipients. It has been suggested that, in the case of cimetidine, bioavailability is partly dependent on the rate of dissolution or disintegration (see Leonard et at., The Pharmaceutical Development and Bevel-~2;~3552 Ability of Cimetidine Capsule and Tablet Formulations, Dug VQvcQ~pmQ~ and Lou a Pharmacy, I, 217-226 (1979)).
Leonard et at. also pointed out the significant effect that the addition of even a single excipien-tto a cimetldine form-elation may have on the undesirable phenomenon of rapidly increasing dissolution time over normal compression ratios.
It will thus be appreciated that many significant problems are encountered in providing a tablet composition with a higher percentage of cimetidine than that encountered in known cimetidine tablet compositions.
Surprisingly, it has now been found that a cimetidine tablet composition may be obtained with a higher percentage of cimetidine than has heretofore been achieved, for example about 94 % w/w, while maintaining adequate hardness, disintegration, friability and other required parameters. Such a higher percentage will minimize or eliminate patient reluctance - due to size in ingesting a cimetidine tablet containing 800 my. of cimetidine which would otherwise, if known percent-ages were utilized, present considerable compliance problems.
The higher percentage has been achieved upon the discovery that cimetidine has unsuspected granulating properties which could be utilized to obtain a surprising and unexpected reduction in the w/w percentage of pharmaceutically acceptable ...... ... __ 3~Z~55~
excipients heretofore thought necessary to enable processing and maintain the tablet properties required, and an even more surprising and unexpected reduction in the v/v percentage of such excipients.
Size considerations apart, the lower percentage of excipients also results in lower production costs for tablets containing any quantity of cimetidine and results in less excipient being introduced into the system of the patient.
According to the present invention, a cimetidine tab-let composition, processed with facility and having the requisite properties, but of significantly reduced size, contains from about 84 to about 98.25% w/w of cimetidine, a binder in an amount of about 1% w/w or greater, a disintegrant in an amount of about 0.25% w/w or greater and a lubricant in an amount from about 0.5 to 1.5% w/w.
; In a preferred embodiment, the present invention provides a tablet composition containing about 94% w/w of cimetidine, from 2 to 4.5% w/w of a binder, from l to 3.5%
w/w of a disintegrant and from 0.5 to 1.5% w/w of a lubricant, which cimetidlne, in further preferred embodiments, is present in quantities of about 200 to 800 my.
- According to another aspect of the present invention, there is provided a process for preparing a tablet composition which comprises mixing about 84 to about 98.25% w/w of cimetidine with about 1% w/w or greater of a binder, about 0.25% w/w or greater of a disintegrant and from about 0.5 to 1.5% w/w of a lubricant.
As used herein, "cimetidine" means that compound having the chemical formula N-cyano-N'-methyl-N"-(2((4~methyl-5-imidazolyl)methylthio)ethyl) guanidine as identified in Thy MCKEE dQX, Thea eon., Merck & Co. Inc., Roy, New :~2Z9SS2 Jersey, U.S.A. (1983) at page 323 and includes any forum-ceutically acceptable acid addition salt thereof.
As used herein, "pharmaceutically acceptable acid addition salt" means an acid addition salt possessing the properties of the free compound and being not biologically or otherwise undesirable and includes the hydrochloric, hydra-bromic, sulfuric and malefic addition salts and the like.
As used herein, "pharmaceutically acceptable excip-tent" means an excipient which is not biologically, forum-ecologically, or otherwise undesirable. It will be appreciated by those skilled in the art that references herein to excipients such as binders, lubricants and disintegrants are necessarily restricted to those excipients which are pharmaceutically acceptable.
Binders which may be used in the present invention are those binders commonly used in the art and include starch, gelatin, cellulose derivatives; for example methylcelluloses, ethylcelluloses and propylcelluloses, and preferably polyvinyl-pyrrolidone; for example Plasdone* K-39-22.
Disintegrants which may be used in the present invent lion are those disintegrants commonly used in the art and include starch, sodium starch glycolate; for example, Primojel*, and preferably carboxymethyl starch; for example, Explotab*.
Lubricants which may be used in the present invent lion are those lubricants commonly used in the art and in-elude Starkey acid and its salts e.g. magnesium, calcium or sodium Stewart.
*trade mark ~ZZ955Z
A further understanding of the invention and its further advantages can be had from the following non-limiting examples.
Example I
35.5 g. of Plasdone* K-29-32 (polyvinylpyrrolidone) was mixed with 176 ml. of purified water until dissolution WAS complete. 500 g. of cimetidine was mixed with 23.7 g. of Explotab* (carboxymethyl starch) for 5 minutes and then grant slated wit the prepared Plasdone*/water solution. The grant slated material was then tray-dried overnight in a convection oven set at 45C until a moisture content of 0.4% to 1.2%
(Congo scale) was obtained. The granules thus dried were passed through a No. 12 screen and then mixed for a further 3 minutes.
Approximately 8 g. of screened and mixed granules were with-drawn and mixed with 8.9 g. of magnesium Stewart, passed through a No. 12 screen and returned to the previously screened and mixed granules. This mixture was mixed for 10 minutes with 23.7 g. of Explotab* (carboxymethyl starch). The resulting mixture was compressed on a Majesty* F-3 single press compress soon machine to provide tablets having a hardness range of 9.0 to 11.0 kg. (Stokes scale) and a moisture content of 0.4% at compression. Average tablet weight was 946 my., containing 800 my. of cimetidine.
EXAMPLE II
10.4 g. of Plasdone* K-29-32 (polyvinylpyrrolidone) was mixed with 51.6 ml. of purified water until dissolution was complete. 500 g. of cimetidine was mixed with 2.6 g. of Explotab* (carboxymethyl starch) for 5 minutes and then grant--fated with the prepared Plasdone*/water solution. The *trade mark I
translated material was then tray-~lried overnight in a convect lion oven set at 45C until a moisture content of 0.4% to 1.2%
(Congo scale) was obtained. The granules thus dried were passed through a No. 12 screen and then mixed for a further 3 minutes. Approximately 8 g. of screened and mixed granules were withdrawn and mixed with 2.6 g. of magnesium Stewart, passed through a No. 12 screen and returned to the previously screened and mixed granules. This mixture was mixed for 10 minutes with 2.6 g. of Explotab* (carboxymethyl starch). The resulting mixture was compressed on a Majesty* F-3 single press compression machine to provide tablets having a hardness range of 9.0 to 11.0 kg. (Stokes scale) and a moisture content of 0.4% at compression. Average tablet weight was 829 my., con-twining 800 my. of cimetidine.
EXAMPLE III
18.6 g. of Plasdone* K-29-32 (polyvinylpyrrolidone) was mixed with 92.2 ml. of purified water until dissolution was complete. 500 g. of cimetidine was mixed with 5.3 I. of Explotab* (carboxymethyl starch) for 5 minutes and then grant-fated with the prepared Plasdone*/water solution. The grant-fated material was then tray-dried overnight in a convection oven set at 45C until a moisture content of 0.4% to 1.2%
(Congo scale) was obtained. The granules thus dried were passed through a No. 12 screen and then mixed for a further 3 minutes. Approximately 8 g. of screened and mixed granules were withdrawn and mixed with 2.7 g. of magnesium Stewart, passed through a No. 12 screen and returned to the previously screened and mixed granules. This mixture was mixed for 10 minutes with 5.3 g. of Explotab* (carboxymethyl starch). The * trade mark ssz~:
exulting mixture was compressed on a Majesty* F-3 single press compression machine to provide concave, beveled, ellipsoid tablets of dimensions 11/32" x 23/32" having a hardness range of 9.0 to 11.0 kg. (Stokes scale) and a moist lure content off% at compression. Average tablet wits 851 my., containing 800 my. of cimetidine.
EXAMPLE IV
20.0 g. of Plasdone* K-29-32 (polyvinylpyrrolidone) was mixed with 100 ml. of purified water until dissolution was complete. 500 g. of cimetidine was mixed with 5.3 g. of Explotab* (carboxymethyl starch) for 5 minutes and then grant-fated with the prepared Plasdone*/water solution. The grant-fated material was then tray-dried overnight in a convection oven set at 45C until a moisture content of 0.4% to 1.2%
(Congo scale) was obtained. The granules thus dried were passed through a No. 12 screen and then mixed for a further 3 minutes. Approximately 8 g. of screened and mixed granules were withdrawn and mixed with 2.7 g. of magnesium Stewart, passed through a No. 12 screen and returned to the previously screened and mixed granules. This mixture was mixed for lo minutes with 5.3 g. of Explotab* (carboxymethyl starch). The resulting mixture was compressed on a rqaneSty* F-3 single press compression machine to provide concave, beveled, ellipsoid tablets of dimensions 11/32" x 23/32" having a hardness range of 9.0 to 11.0 kg. (Stokes scale) and a moisture content of 0.4% at compression. Average tablet weight was 853 my., con-twining 800 my. of cimetidine.
EXAMPLE V
Granules ready for tabulating were prepared as in * trade mark issue example IV. Concave, beveled, round tablets of 5/16" diameter were compressed on a Majesty* F-3 single press compression ma-chine having a hardness range of 5.0 to 7.0 kg. (Stokes scale) and a moisture content of 0~4% at compression. Average tablet weight was 213 my., containing 200 my. of cimetidine.
EXAMPLE VI
Granules ready for tabulating were prepared as in Example IV. Concave, beveled, round tablets of 3/8" die-meter were compressed on a Majesty* F-3 single press compress soon machine having a hardness range of 5.0 to 7.0 kg. (Stokes scale) and a moisture content of 0.4% at compression. Average tablet weight was 319 my., containing 300 my. of cime-tidine.
EXAMPLE VII
Granules ready for tabulating were prepared as in Example IV. Concave, beveled, round tablets of 7/16" die-meter were compressed on a Majesty* F-3 single press compress soon machine having a hardness value of 5.0 to 8.0 kg. (Stokes scale) and a moisture content of 0.4% at compression. Average tablet weight was 426 my., containing 400 my. of cimetidine.
SAMPLE VIII
Granules ready for tabulating were prepared as in Example IV. Concave, beveled, round tablets of 15/32" die-meter were compressed on a Majesty* F-3 single press compress soon machine having a hardness value of 6.0 to 8.0 kg. (Stokes 25` scale) and a moisture content of 0.4% at compression. Average tablet weight was 639 my., containing 600 my. of cimetidine.
EXAMPLE IX
17.5 g. of Plasdone* K-29-32 (polyvinylpyrrolidone~
was mixed with 80 ml. of purified water until dissolution was * trade mark :~L22~SS2 complete. 470.05 g. of cimetidine was mixed with 5.0 g. of Explotab* (carboxymethyl starch) for 2 minutes and transferred to a mortar. The cimetidine/Explotab* mixture was granulated with the prepared Plasdone*/water solution, an additional 59 ml. of purified water being added. The granulated material was then tray-dried for 1 3/4 hours in a convection oven to a moisture content of 1.2% (Congo scale). The granules thus dried were passed through a No. 15 screen and transferred to a plastic bag. 2.45 g. of magnesium Stewart was mixed with an equal weight of screened granules withdrawn from the pies-tic bag. This mixture was passed through a No. 15 screen and returned to the plastic bag containing the remaining granules.
This mixture was mixed with 5.0 g. of Explotab* (carboxymethyl starch) for 2 minutes and compressed on a Majesty* E-3 single press compression machine using a 5/8" concave, round, plain punch to provide tablets of thickness 5.56 mm. having a hardness range of 9-10 kg. (Stokes scale) and a moisture content of 0.9% at compress soon. Average tablet weight was 851 my., containing 800 my. of cimetidine. The tablets had a friability value of 0.31% and a disintegration time of 5 minutes in HO at 37C.
_ AMPLE X
The procedure of Example IX was followed substituting the following quantities of materials:
Cimetidine 200 g.
Explotab* (intragranular) 2.1 g Plasdone* 4.19 g.
Purified water 36.5 ml.
Extra water added 33 ml.
Explotab* (extra granular) 2.1 g.
Magnesium Stewart 1.05 g.
* trade mark - 13 -~.~7Z~3/SS;~
Llabletting was carried out on a Majesty* F-3 single press compression machine using a 5/8" concave, round, plain punch to provide tablets having hardness values of 6 1/2 kg. and 8 kg. (Stokes scale) and a moisture content of 1.1% at come press ion. Average tablet weight was 838 my., containing 800 my. of cimetidine. The tablets having a hardness value of 6 1/2 kg. had a friability value of 0.36% and a disinter-ration time of 2 minutes in HO at 37C, and those having a hardness value of 8 kg. had a friability value of 0.36%
and a disintegration time of 5 minutes in HO at 37C.
EXAMPLE XI
The procedure of Example IX was followed substitute in the following quantities of materials:
; Cimetidine 200 g.
; 15 Explotab* (intragranular) 2.14 g.
Plasdone* 8.56 g.
Purified Water 36.5 ml.
Extra water added 23 ml.
Explotab* (extra granular) 2.14 g.
Magnesium Stewart 1.07 g.
Tabulating was carried out on a Majesty* F-3 single press compression machine using a 5/8" concave, round, plain punch to provide tablets having hardness values of 7 to 8 kg. and 10 kg. (Stokes scale) and a moisture content owe 0.5% at come press ion. Average tablet weight was 856 my., containing 800 my. of cimetidine. The tablets having a hardness value of 7 to 8 kg. had a friability value of 0.35% and a disintegration time of 5 minutes in HO at SUE and those having a hardness value of 10 kg. had a friability value of 0.26% and a disk integration time of 9 minutes in HO at 37C.
* trade mark ;~LZZ9S52 EXAMPLE XII
The procedure of Example IX was followed substitute in the following quantities of materials:
Cimetidine 200 g.
Explotab* (intragranular) 4.42 g.
Plasdone* 11.05 g.
Purified Water 36.5 ml.
Extra water added 18.5 ml.
- Explotab* (extra granular) 4.42 g.
magnesium Stewart 1.105 g.
Tabulating was carried out on a Majesty* F-3 single press compression machine using a 5/8" concave, round, plain punch to provide tablets having a hardness value of 8 to 9 kg.
(Stokes scale) and a moisture con-tent of 0.8% at compression.
Average tablet weight was 884 my., containing 800 my. of cimetidi,ne. The tablets had a friability value of 0.39% and a disintegration time of 12 minutes in HO at 37C.
E SAMPLE XI I I
10.8 kg. of Plasdone* K-29-32 (polyvinylpyrrolidone) was mixed with 53.0 1. of purified water until dissolution was complete. 290.0 kg. of cimetidine was mixed with 3080 g. of Explotab* (carboxymethyl starch) for 5 minutes and then granulated with the prepared Plasdone*/water solution. The granulated material was then tray-dried overnight in a convection 25' oven set at 45C until a moisture content of 0.4% to 1.2%
(Congo Schulz obtained. The granules thus dried were passed through a No. 12 screen and then mixed for a further 3 minutes. Approximately 5 kg. of screened and mixed granules were withdrawn and mixed with 1817 q. of magnesium Stewart, passed through a No. 12 screen and returned to the previously * trade mark - 15 -955~
screened and mixed granules. This mixture was rnlxéd for 10 minutes with 3080 g. of Explotab* (carboxymethyl starch.
The resulting mixture was compressed on a Stokes D-3 machine to provide concave, beveled, ellipsoid tablets of dimensions 11/32" x 23/32" having a hardness range of 9.0 to 11.0 kg.
(Stokes scale). Average tablet weight was 852 my., containing 800 my. of cimetidine.
EXAMPLE XIV
18.52 g. of -Plasdone* X 29-32 (polyvinylpyrrolidone) was mixed with 40 ml. of purified water until dissolution was complete.- 500 g. of cimetidine was mixed with 2.63 g. of Explotab* (carboxymethyl starch) for 2 minutes and transferred to a mortar. The cimetidine/Explotab* mixture was granulated with the prepared Plasdone*/water solution, an additional 80 ml. of purified water being added. The granulated material was then tray dried in a convection oven to a moisture content of 0.6% (Congo scale). The granules thus dried were passed through a No. 15 screen and transferred to a plastic bag. 2.7 g.
of magnesium Stewart was mixed with an equal weight of screened granules withdrawn from the plastic bag. This mixture was passed through a No. 15 screen and returned to the plastic bag containing the remaining granules. This mixture was mixed for 2 minutes and compressed on a Majesty* F-3 single press compression machine using an ellipsoid, biconcave, beveled punch to give tablets of dimensions 11/32" x 23/32" having a hardness of 8.5 kg. (Stokes scale). Average tablet weight was 838 my., containing 800 my. of cimetidine. The tablets had a disintegration time of 2 minutes in HO at 37C and 2 minutes CUSP method).
* trade mark ~Z~5~5S~
APPLE XV
18.52 g. of Plasdone* I~-29-32 (polyvinylpyrrolidone) was mixed with 40 ml. of purified water until dissolution was complete. 500 g. of cimetidine was placed in a mortar and granulated with the prepared Plasdone*/water solution, an additional 80 ml., approximately of water being added.
The granulated material was then tray-dried in a convection oven to a moisture content of 0.6% (Congo scale). The grant vies thus dried were passed through a No. 15 screen and transferred to a plastic bag. 2.7 g. of magnesium Stewart was mixed with an equal weight of screened granules with-drawn from the plastic bag. This mixture was Dossed through a No. 15 screen and returned to the plastic bag containing the remaining granules. This mixture was mixed for 2 mint vies with 2.63 g. of Explotab* (carboxymethyl starch) and compressed on a Majesty* F-3 single press compression machine using an ellipsoid, biconcave, beveled punch to give tablets of dimensions 11/32" x 23/3Z" having a hardness value of 10 kg.
(Stokes scale). Average tablet weight was 838 my., containing 800 my. of cimetidine. The tablets had a disintegration time of 5 minutes in HO at 37C and 4 minutes CUSP method).
EXAMPLE XVI
The procedure of Example XV was followed but substitu-tying 1.30 g. of ASSIDUOUSLY* (microcrystalline cellulose derivative) for the 2.63 g. of Explotab* used in Example XV. Tablets were compressed on a Majesty* F-3 single press compression machine using an ellipsoid, biconcave, beveled punch to give tablets of dimensions 11/32" x 23/32" having a hardness value of 10 kg.
(Stokes scale). Average tablet weight was 836 my., containing 800 my.
* trade mark - 17 -so of cimetidine. The tablets had a disintegration time of 5 minutes in HO at 37C and 2 minutes CUSP method).
Although the foregoing examples have been directed to the preparation of high percentage cimetidine tablets for human consumption, the present invention would extend, for example, to cimetidine tablets for veterinary use as well.
Nor is the practice of the present invention restricted, for example, to particular excipients or brands thereof or to a specify lo process for the preparation of the tablets of the present invention. Therefore, although various preferred embodiments have been described herein in detail, it will be appreciated by those skilled in the art that variations may be made without departing from the spirit of the invention or the scope of the appended claims.
.
Claims (34)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A tablet composition comprising from about 84 to about 98.25% w/w of cimetidine, about 1% w/w or greater of a binder, about 0.25% w/w or greater of a disintegrant and from about 0.5 to 1.5% w/w of a lubricant.
2. A tablet composition according to claim 1 compris-ing from 84.5 to 96.5 % w/w of cimetidine.
3. A tablet composition according to claim 2 wherein said binder is present in an amount from 2 to 6 % w/w and said disintegrant is present in an amount from 1 to 8 % w/w.
4. A tablet composition according to claim 2 compris-ing from 90 to 96.5 % w/w of cimetidine.
5. A tablet composition according to claim 4 compris-ing about 94 % w/w of cimetidine.
6. A tablet composition according to claim 5 wherein said binder is present in an amount from 2 to 4.5 % w/w and said disintegrant is present in an amount from 1 to 3.5 % w/w.
7. A tablet composition according to claim 6 wherein said binder is present in about 3.5 % w/w, said disintegrant is present in about 2 % w/w and said lubricant is present in about 0.5 % w/w.
8. A tablet composition according to claim 6 wherein said binder is present in about 3.5 % w/w, said disintegrant is present in about 2 % w/w and said lubricant is present in about 0.6 % w/w.
9. A tablet composition according to claim 1 comprising about 200 mg. of cimetidine.
10. A tablet composition according to claim 6 comprising about 200 mg. of cimetidine.
11. A tablet composition according to claim 1 comprising about 300 mg. of cimetidine.
12. A tablet composition according to claim 6 comprising about 300 mg. of cimetidine.
13. A tablet composition according to claim 1 comprising about 400 mg. of cimetidine.
14. A tablet composition according to claim 6 comprising about 400 mg. of cimetidine.
15. A tablet composition according to claim 1 comprising about 500 mg. of cimetidine.
16. A tablet composition according to claim 6 comprising about 500 mg. of cimetidine
17. A tablet composition according to claim 1 comprising about 600 mg. of cimetidine.
18. A tablet composition according to claim 6 comprising about 600 mg. of cimetidine.
19. A tablet composition according to claim 1 comprising about 700 mg. of cimetidine.
20. A tablet composition according to claim 6 comprising about 700 mg. of cimetidine.
21. A tablet composition according to claim 1 comprising about 800 mg. of cimetidine.
22. A tablet composition according to claim 6 comprising about 800 mg. of cimetidine.
23. A tablet composition according to claim 1, 2 or 3 wherein said binder is polyvinylpyrrolidone, said disintegrant is carboxymethyl starch and said lubricant is magnesium stearate.
24. A tablet composition according to claim 4, 5 or 6 wherein said binder is polyvinylpyrrolidone, said disintegrant is carboxymethyl starch and said lubricant is magnesium stearate.
25. A tablet composition according to claim 7, 8 or 9 wherein said binder is polyvinylpyrrolidone, said disintegrant is carboxymethyl starch and said lubricant is magnesium stearate.
26. A tablet composition according to claim 10, 11 or 12 wherein said binder is polyvinylpyrrolidone, said disintegrant is carboxymethyl starch and said lubricant is magnesium stearate.
27. A tablet composition according to claim 13, 14 or 15 wherein said binder is polyvinylpyrrolidone, said disintegrant is carboxymethyl starch and said lubricant is magnesium stearate.
28. A tablet composition according to claim 16, 17 or 18 wherein said binder is polyvinylpyrrolidone, said disintegrant is carboxymethyl starch and said lubricant is magnesium stearate.
29. A tablet composition according to claim 19, 20 or 21 wherein said binder is polyvinylpyrrolidone, said disintegrant is carboxymethyl starch and said lubricant is magnesium stearate.
30. A tablet composition according to claim 22 wherein said binder is polyvinylpyrrolidone, said disintegrant ia carboxymethyl starch and said lubricant is magnesium stearate.
31. A process for preparing a tablet composition which comprises mixing from about 84 to about 98.25% w/w of cimetidine with about 1% w/w or greater of a binder, about 0.25% w/w or greater of a disintegrant and from about 0.5 to 1.5% w/w of a lubricant.
32. A process according to claim 31 which comprises mixing about 94 % w/w of cimetidine with about 3.5 % w/w of said binder, about 2 % w/w of said disintegrant and about 0.5 % w/w of said lubricant.
33. A process according to claim 31 which comprises mixing about 94 % w/w of cimetidine with about 3.5 % w/w of said binder, about 2 % w/w of said disintegrant and about 0.6 % w/w of said lubricant.
34. A process according to claim 31, 32 or 33 where-in said binder is polyvinylpyrrolidone, said disintegrant is carboxymethyl starch and said lubricant is magnesium stearate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000458468A CA1229552A (en) | 1984-07-09 | 1984-07-09 | Cimetidine compositions |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000458468A CA1229552A (en) | 1984-07-09 | 1984-07-09 | Cimetidine compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1229552A true CA1229552A (en) | 1987-11-24 |
Family
ID=4128265
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000458468A Expired CA1229552A (en) | 1984-07-09 | 1984-07-09 | Cimetidine compositions |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1229552A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0347767A1 (en) * | 1988-06-23 | 1989-12-27 | LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d. | Dispersible cimetidine tablets |
| EP0349103A1 (en) * | 1988-05-04 | 1990-01-03 | Smith Kline & French Laboratories Limited | Chewable tablet |
| US5275823A (en) * | 1989-04-27 | 1994-01-04 | Smith Kline & French Laboratories Ltd. | Pharmaceutical compositions |
| FR2723586A1 (en) * | 1994-08-11 | 1996-02-16 | Seth Pawan | NEW COMPOSITIONS CONTAINING CIMETIDINE AND DERIVATIVE ASSOCIATIONS THEREOF |
| US8173161B2 (en) | 2002-12-04 | 2012-05-08 | Mcneil-Ppc, Inc. | Method of administering a pharmaceutical active ingredient |
-
1984
- 1984-07-09 CA CA000458468A patent/CA1229552A/en not_active Expired
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0349103A1 (en) * | 1988-05-04 | 1990-01-03 | Smith Kline & French Laboratories Limited | Chewable tablet |
| EP0347767A1 (en) * | 1988-06-23 | 1989-12-27 | LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d. | Dispersible cimetidine tablets |
| US5275823A (en) * | 1989-04-27 | 1994-01-04 | Smith Kline & French Laboratories Ltd. | Pharmaceutical compositions |
| FR2723586A1 (en) * | 1994-08-11 | 1996-02-16 | Seth Pawan | NEW COMPOSITIONS CONTAINING CIMETIDINE AND DERIVATIVE ASSOCIATIONS THEREOF |
| WO1996004892A1 (en) * | 1994-08-11 | 1996-02-22 | Pharma Pass | Novel cimetidine-containing compositions and combinations derived therefrom |
| US8173161B2 (en) | 2002-12-04 | 2012-05-08 | Mcneil-Ppc, Inc. | Method of administering a pharmaceutical active ingredient |
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