CA1235661A - Pharmaceutical composition containing a liquid lubricant - Google Patents
Pharmaceutical composition containing a liquid lubricantInfo
- Publication number
- CA1235661A CA1235661A CA000458340A CA458340A CA1235661A CA 1235661 A CA1235661 A CA 1235661A CA 000458340 A CA000458340 A CA 000458340A CA 458340 A CA458340 A CA 458340A CA 1235661 A CA1235661 A CA 1235661A
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- Prior art keywords
- pharmaceutical composition
- milligrams
- lubricant
- molecular weight
- oxazepam
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
-
- 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
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Abstract of the Disclosure Pharmaceutical compositions produced with liquid, hydrophilic lubricants possessing markedly improved dissolution rates.
Description
lZ3~;6~
The present invention relates -to a pharmaceutica composition contairling a liquid lubricant.
Solid, hydrophobic lubricants continue to be currently used in the pharmaceutical art of tableting and filling of hard gelatin capsules even though it is known that the use of hydro-phobic lubxicants such as magnesium stearate diminish dissolu-tiOIl rates, and consequently could possibly reduce absorption rates, of the dosage formulation. Diminished dissolution rates of several capsule formulations with increases of maynesium stearate concentration were disclosed by Samyn and Jung, J.
Pharm. Sci. 59, 169 (1970). Iranloye et al., J. Pharm. Sci. 67, 535, (1978), studied the effects of concentration of hydro-phobic lubricants (calcium stearte, glyceryl monostearate, magnesium s-tearate, stearic acid and talc) on the dissolution rate of salicylic acid, aspirin and equimolar mixtures thereof and reported decreased dissolution rates with increased concen-tration of each lubricant other than talc. The authors con-cluded that, if hydrophobic lubricants slow dissolution, highly water-soluble lubricants might enhance dissolution. ~lowever, polyethylene glycol 4000 failed to affect dissolution at concen-trations as high as 5 percent, leading -the authors to speculate that the lubricant must simultaneously be water-soluble and surface active to enhance dissolution. Levy et al., J. Pharm.
Sci. 52, 1139 (1963), had previously shown tha-t sodium lauryl sulfate increased dissolution rates of salicylic acid over that of magnesium stearate in compressed tablets.
The use of surfactants in pharmaceutical formulations to assist in disintegration and dissolu-tion of drug material is well ~cnown. Lachman et al., Theory and Practice of Industrlal Pharmacy, Second Edition, pp. 108-9, disclose the use of surface active agents or surfactahts in almost every dosage form includ-ing liquids, semi-solids and solids. The surface active agents c~ - 1 -~23S66~
play an important role in the absorption and efficacy of certain dru~s. Irhe nature of this role is quite obscure. Both enhance~
ment of ahsorption and retardation of druy absorption have been credited to the presence of surface active agents. It cannot always be determined whether the function of a surfactan-t is to alter solubility, dissolution rates, and/or absorbability of the drug based upon its action on the drug itself or on a semi-\
- la -- ~Z~566~' permeable membrane wlthln the host body. Slmllarly, whether the formatlon of mlcelle unlts and thelr polar/non-polar molecule orlenta-tlon Is crltlcal to the functlon of the surfactants Is not readlly ascertalnable.
Chlou et al., J. Pharm. Scl. 65, 170Z (1976), dlsclose enhanced dlssolutlon rates for poorly watér soluble drugs by crystalllzatlon from an aqueous surfactant solutlon. Polysorbate 80 (a trademar~) (Tween 80, a trademark) was employed In 2.5%
aqueous solutlon for the purpose of drug preclpltatlon.
Lerk et al., J. Pharm. Scl. 67, 935 (1978), dlsclose hydrophlllc coatlng of hydrophoblc drug partlcles to enhance wet-tlng and dlssolutlon. Hersh, U.S. 3,927,196, had shown earller that a hydrophoblc lubrlcant could be coated wlth a hydrophlllc materlal to enhance dlssolutlon of a therapeutlc composltlon con-talnlng the lubrlcant.
Goodhart et al., J. Pharm. Scl. 62, 30~ (1973), dls-close a method for testlng tablet and capsule dlssolutlon rates.The authors note that prevlous studles have demonstrated pro-longed dlslntegratlon/dlssolutlon tImes wlth an Increase In the level of magneslum stearate whlch Is the standard lubrlcant employed In hard gelatln capsule formulatlons. The magneslum stearate in effect waterproofs the contents of a hard gelatlon capsule. The authors noted on page 308, that the addltlon of a surfactant such as sodlum lauryl sulfate Improved dlslntegratlon of the capsules when tested In artlflclal gastrlc fluld wlthout enzymes.
Short et al., J. Pharm. Scl. 61, 1733 (1972), dlsclose the dlssolutlon of hydrocortlsone In a number of systems contaln-lng an N-alkylpolyoxyethylene surfactant.
U.S. Patent 3,862,311 granted January 21, 1975, to Lee-son, dlscloses the use of varlous types of surfactants In con-, ~
~35661' Junctlon wlth polyethylene 01ycol carrlers for asslstance In dls solutlon and absorptlon of composl~lons contalnlng progesterone.
The preferred surfactants are non-lonlcs.
Geneldl et al., J. Pharm. Scl. 67, 114 (1978), dlsclose the theoretlcal relatlonshlp between enhancement of dlssolutlon rate of a drug and Its Gl absorptlon rate;
~5 _ 2a -1~3~6~' Description of the Invention In accordance with this invention, there is provided a solid pharmaceutical - composition of matter comprising a therapeutic agent in intimate admixture with a pharmaceutically-acceptableJ liquid, hydrophilic lubricant. The solid pharmaceutical composition is suitable for use in hard capsule production or tableting.
The liquid, hydrophilic lubricant employed in the pharmaceutical composi-tions of this invention functions as a classical solid, hydrophobic lubricant in as much as it provides for proper flow characteristics of the dry composition when filling a hard gelatin capsule body [Reier et al., J. Pharm. Sci. 57, 660 (1968) ], prevents binding of the rotary auger in the powder filled hopper [C. Lindenwald, Pharm. Ind.
28, 614 (1965) ] employed in filling hard gelatin capsules and permits smooth telescoping closure of the filied capsule body part into the cap, while not reducing the friction between the capsule halves to the point where they will easily separate upon further manipulation.
In addition, the use of a liquid as the lubricant markedly reduces the production of dust which conventionally attends the filling of capsules and prepara-tion of pharmaceutical powder mixes. The reduction of atmospheric dust is of great value in the handling of tranquilizers, barbiturates, analgesics, antibiotics, antihyper-tensives, antiinflammatory agents, steroids (hormones), etc., which may cause contact dermatitis or induce systemic effects upon inhalation by workers. When using a liquid lubricant, the reduction in dust is such that it is no longer necessary to polish hard gelatin capsules after filling.
Furthermore, the liquid lubricant provides an ideal medium for inclusion, by solution, suspension or emulsion, of surfactants, low level actives or other adjuvants which are desireably made as homogeneous as possible in a solid pharma-ceutical formulation. And, the liquid lubricant present in a hard gelatin capsule tends to reduce aging (hardening of the gelatin capsule via further polymerization) which results in lower dissolution rates.
Similar advantages attend the use of the pharmaceutical compositions of this invention in production of tablets. The liquid lubricant provides good flow and compression characteristics of the powder mix, minimiæes dust formation and Z3S6~
transport, and adequately lubrlcates the dle and punch to prevent blndlng of the tablet and metal parts.
The llquld, hydrophlllc lubrIcants whlch may be employed In varlous pharmaceutlcal formulatlons Include polyalky-lene glycols of molecular welght between about 200 and about 900, such as, polyethylene glycol and polypropylene glycol; glycerln, propylene glycol, and llquld polyhydrlde alcohol fatty acld esters (e.g. Glycomul ~ or Glycosperse ~ ). Each of these lubrlcants pose unlque problems whlch mlght dlctate agalnst thelr use In a speclflc appllcatlon. For example, glycerln and propy-lene glycol are so hydroscoplc that they may cause physlcal and chemlcal problems wlth the pharmaceutlcal. The more vlscous Gly-cosperse ~ tends to coat the external llp portlon of a hard cap-sule body and provlde such a frictlonless blndlng that the cap-sules tend to separate on handlIng. Hence, the preferred llquld lubrlcants are the polyethylene glycols of molecular welght from about 200 to about 900. The most preferred llquld lubrlcant Is polyethylene glycol havlng a molecular welght range of from about 20 380 to about 420 (PEG 400). These lubrIcants exert some level of surface actlvlty In addltlon to lubrlcatlon and otherwlse appear to be Ideally sulted for use In productlon of pharmaceutlcal com-posltlons for hard gelatln capsule fllllng.
26 In addltlon, thls Inventlon provldes solld pharmaceutl-cal composltlons comprlslng a therapeutlc agent In IntImate admlxtur0 wlth a pharmaceutlcally acceptable, llquld, hydrophlllc lubrlcant and a surface actlve agent. The surfactant further Improves the dlssolutlon rate by reduclng the surface tenslon at the llquld-solld lnterface created between the pharmaceutlcal composltlon and fluld dlssolvlng the composltlon. Thus, the hydrophlllclty of the llquld lubrlcant alds In drawlng water Into the matrlx of the tablet or capsule whlle the surface actlve agent Improves the wettablllty of the solId materlal to afford, In concert, a markedly Improved dlssolutlon rate. Typlcal sur-factants whlch are Incorporated Into the pharmaceutlcal compo~1-~ 3566~' tlons Of thls Inventlon are catlonlc, anlonlc and non-lonlc sur-face actlve agents well-known In the art, such as, the fatty esters of polyoxyethylene sorbltan (Tween (a trademar~) serles 20 to 85, ICI, Unlted States), a polyoxyethylene condensate of a hydrophoblc base formed by polymerlzatlon of propylene oxlde and propylene glycol (Pluronlc (a trademark) or Poloxamer (a trade-mark) serles, BASF Wyandotte Chemlcal Co.), sorbltan monolaurate (Span 20 (a trademark), ICI Unlted States), octylphenoxy polyethoxy cthanol ~Trlton X, a trademark) Rohm and Haas), cetyl-pryldlnlum chlorlde, dloctyl sodlum sulfosucclnate, and the llke.
The quan-tlty of llquld, hydrophlllc lubrlcant and sur-factant employed In the manufacture of the pharmaceutlcal compo-sltlons of thls Inventlon may vary greatly dependlng upon the characterlstlcs of the therapeutlc agent and other tablet or cap-sule adJuvants employed. The optlmum quantlty of elther or both Is, however, readlly determlned by emplrlcal Investlgatlon. For example, a serles of Incremental 5 percent Increases of PEG 400 admlxed wlth the conventlonal formulatlon contalnlng oxazepam as presented In Example 1, Infra, demonstrated a maxlmum useful con-centratlon of lubrlcant at about 25 percent by welght, at whlch polnt the formulatlon was clumpy and would not run In automatlc or seml-automatlc flllers. AdJustment of the quantlty of llquld lubrlcant and surfactant to provlde 75 percent or be-tter dlssolu-tlon in forty-flve mlnutes Is also readlly achleved by emplrlcal Investlgatlon of In vltro dlssolutlon rates.
The therapeutlc agent contemPlated for use In the novel pharmaceutlcal composlt ! ons of thls Inventlon Is any known thera-peutlc agent adaptable for admlnlstratlon vla a hard gelatln cap-sule or a tablet. In general, the comblnatlon of a pharmaceutl-cally acceptable llquld lubrlcant and surfactant Is employed wlth greatest advantage for the purpose of dramatlcally Improvlng the dlssolutlon rate of poorly soluble therapeutlc agents Includlng tranqulllzers, barblturates, analgeslcs, antlblotlcs, antlhyper-tenslves, antl-lnflammatorles, hormonal sterolds, and the llke, 1~35~
whlch exhlblt slow In vltro avallablllty rates. D I sso I utlon enhancement of the composltlons of thls Inventlon contalnlng the poorly soluble actlve pharmaceutlcal Is further optImlzed after Incluslon of the lubr I cant~surfactant comblnatlon by achlevlng maxlmum dlstrlbutlon of the lubrlcant-surfactant comblnatlon vla mllllng or screenlng to reduce agglomerates of loosely adherlng partlcles. Multlple mllllng or screenlng may enhance the dlsso-lutlon rate, dependlng Upon the efflclency of the Inltlal agglom-erated partlcle dlsruptlon.
Oxazepam Is employed as the therapeutlc agent In the followlng examples of therapeutlc composltlons for fllllng hard gelatln capsules because It Is a good example of a compound wlth a slow dlssolutlon rate. It Is to be understood that the Inven-tlon Is not llmlted to use wlth oxazepam or drugs whlch are rela-tlvely Insol Ub I e. The use of a llquld, hydrophlllc lubrlcant-surfactant, wlth or wlthout the addltlon of an addltlonal surface actlve agent, serves to Increase the dlssolutlon rate of tableted and hard encapsulated pharmaceutlcal composltlons whlch are cus-tomarlly and presently formulated wlth solId hydrophoblc lubrl-cants such as magneslum stearate, talc, or stearlc acld, even when the drug Itself Is readlly soluble In vltro and In vlvo.
In each of the followlng formulatlons employed to Illustrate the typlcal Improvement In dlssolutlon rates achleved wlth thls Inventlon, the solld Ingredlents conslstlng of the actlve materlal (oxazepam) and tablet exclplents (lactose and croscarmellose) are fIrst mlxed In a sultable mlxer. The llquld Ingredlents conslstlng of the lubrlcant (PEG 400) and surfactant (supplled under the trademark Polysorbate 80) are comblned and mlxed wlth a sultable mlxer. Thls comblnatlon Is added slowly to the mlxed powders and mlxed to achleve adequate dlsperslon. Thls wetted materlal Is passed through a No. 30 screen and then remlxed to further homogeneous dlspersal. In formulatlons where magneslum stearate Is present, thls solId hydrophoblc lubrlcant Is added through a fIne screen to the mlxed powders whlch are 23S66~`
then thoroughly mlxed. All components of these formulatlons are In mllllgrams.
.
- 6a -~;' \
, " ~3S66~' a) :~1 U o' O ~ ~o c~ _ cn ~ ~ CO
~ a~
P
.qlo w ~ ~ ~ E
Q s ~3 Wa ~
~ CO
O ~C
~ ., ~;
o ~1 ~ o ~ I I I co ~n .
V C
_.
n eU' ~ ~ wU~ I ~
~;~35~6~' As may be readily seen, the dissolution rate is markedly improved in Formula II by merely reducing the quantity of solid ~lydrophobic lubricant (magnesium - stearate) and adding an internally cross-linked carboxymel:hylcellulose sodium salt disintegrant (croscarmellose sodium). The resuits obtained from Formula III demon-strate that the addition of a disintegrant alone with exclusion of a lubricant is not the answer to the problem. ~issolution of Formula IV demonstrates a marked improve-ment resulting from the addition of a liquid, hydrophilic, low molecular weight polyethylene glycol (PEG 400) which acts as a lubricant and weak surfactant. Upon addition of a minor amount of another surfactant (Polysorbate 80) the thirty minute in vitro dissolution rate is improved to between 85 to 95 percent of the composition dosage. This exceeds the desired in vitro dissolution rate of not less than 75 percent in forty-five minutes currently propounded by the U.S.P. XX - N.F. XV, 1980, as desireable.
Other surface active agents work similarly well with the liquid, hydro-philic lubricant to afford rapid dissolution of the pharmaceutical compositions as may be seen in the following examples:
Example No. VI VII VIII IX
PEG & Sorbitan PEG andPEG and PEG and Monolaurate TritonCet~lpyrid. DSS *
~O Oxazepam, mg 30 30 30 30 Lactose USP 147.1 147.1 147.1 182 Croscarmellose Sodium, USP 6.6 6.6 6.6 6.6 PEG 400, NF 1.1 1.1 1.1 1.1 Triton X-100 - 0.185 Cetylpyridinium Chloride - - 0.185 Sorbitan monolaurate 1). l 85 Dioctyl Sodium ~0 Sulfosuccinate * - - - 0.26 Magnesium Stearate, USP
~6 dissolved in 30 91 96 86 93 1~35f~
All of the in vitr_ dissolution studies wl.ich produced the data reported above were run by the method descri.bed .i.n the U.S. Pharmacopeia XX, The Ma-terial Formulary ~V page 959 (1980) using 0.1 N hydxochloric acid as dissolution medium. In actual practice, hard gelatin capsules fi.lled wlth -the pharmaceutical formulation of Example V, supra, provided bioavailability ln vivo which was not statistically distinct with respect -to rate and extent of absorption from compressed tablets now employed in the trade, a very desireable but difficult result to achieve ~ with any given drug. Thus, a -typical pharmaceu-tical formula-tion employing oxazepam as the active ingredient contains from about 10 to about 30 milligrams oxazepam; 0.5 to about 25 weigh-t percent of composition of liquid polyalkylene glycol of molecu-lar weight from about 200 to about 900; about 0.1 to about 25 weight percent of composition of surfactant, plus a filler.
The preferred formulations for oxazepam to be employed in filling hard gelatin capsules contain from abou-t 10 to about 30 milligrams oxazepam, about 3 to about 11 weight percent ratio to active of polyethylene glycol lubricant of molecular weight ~ from about 380 to 420, about 0.5 to about 2.5 weight percent ratio to active of nonionic surfactant, made up with filler and/or adjuvant(s) to provide a unit dose of from about 165 to 205 milligrams.
Three specific examples of formulations for unit dosage administration via hard gelatin capsules, expressed in milligrams, are:
oxazepam, USP 10 15 30 Lactose, USP 167 162 147 Croscarmellose Sodium, NF 6.6 6.6 6.6 PEG 400, NF 1.1 1.1 1.1 Polysorbate 80, NF ~ 0.22 0.22 0.22 g . .
The present invention relates -to a pharmaceutica composition contairling a liquid lubricant.
Solid, hydrophobic lubricants continue to be currently used in the pharmaceutical art of tableting and filling of hard gelatin capsules even though it is known that the use of hydro-phobic lubxicants such as magnesium stearate diminish dissolu-tiOIl rates, and consequently could possibly reduce absorption rates, of the dosage formulation. Diminished dissolution rates of several capsule formulations with increases of maynesium stearate concentration were disclosed by Samyn and Jung, J.
Pharm. Sci. 59, 169 (1970). Iranloye et al., J. Pharm. Sci. 67, 535, (1978), studied the effects of concentration of hydro-phobic lubricants (calcium stearte, glyceryl monostearate, magnesium s-tearate, stearic acid and talc) on the dissolution rate of salicylic acid, aspirin and equimolar mixtures thereof and reported decreased dissolution rates with increased concen-tration of each lubricant other than talc. The authors con-cluded that, if hydrophobic lubricants slow dissolution, highly water-soluble lubricants might enhance dissolution. ~lowever, polyethylene glycol 4000 failed to affect dissolution at concen-trations as high as 5 percent, leading -the authors to speculate that the lubricant must simultaneously be water-soluble and surface active to enhance dissolution. Levy et al., J. Pharm.
Sci. 52, 1139 (1963), had previously shown tha-t sodium lauryl sulfate increased dissolution rates of salicylic acid over that of magnesium stearate in compressed tablets.
The use of surfactants in pharmaceutical formulations to assist in disintegration and dissolu-tion of drug material is well ~cnown. Lachman et al., Theory and Practice of Industrlal Pharmacy, Second Edition, pp. 108-9, disclose the use of surface active agents or surfactahts in almost every dosage form includ-ing liquids, semi-solids and solids. The surface active agents c~ - 1 -~23S66~
play an important role in the absorption and efficacy of certain dru~s. Irhe nature of this role is quite obscure. Both enhance~
ment of ahsorption and retardation of druy absorption have been credited to the presence of surface active agents. It cannot always be determined whether the function of a surfactan-t is to alter solubility, dissolution rates, and/or absorbability of the drug based upon its action on the drug itself or on a semi-\
- la -- ~Z~566~' permeable membrane wlthln the host body. Slmllarly, whether the formatlon of mlcelle unlts and thelr polar/non-polar molecule orlenta-tlon Is crltlcal to the functlon of the surfactants Is not readlly ascertalnable.
Chlou et al., J. Pharm. Scl. 65, 170Z (1976), dlsclose enhanced dlssolutlon rates for poorly watér soluble drugs by crystalllzatlon from an aqueous surfactant solutlon. Polysorbate 80 (a trademar~) (Tween 80, a trademark) was employed In 2.5%
aqueous solutlon for the purpose of drug preclpltatlon.
Lerk et al., J. Pharm. Scl. 67, 935 (1978), dlsclose hydrophlllc coatlng of hydrophoblc drug partlcles to enhance wet-tlng and dlssolutlon. Hersh, U.S. 3,927,196, had shown earller that a hydrophoblc lubrlcant could be coated wlth a hydrophlllc materlal to enhance dlssolutlon of a therapeutlc composltlon con-talnlng the lubrlcant.
Goodhart et al., J. Pharm. Scl. 62, 30~ (1973), dls-close a method for testlng tablet and capsule dlssolutlon rates.The authors note that prevlous studles have demonstrated pro-longed dlslntegratlon/dlssolutlon tImes wlth an Increase In the level of magneslum stearate whlch Is the standard lubrlcant employed In hard gelatln capsule formulatlons. The magneslum stearate in effect waterproofs the contents of a hard gelatlon capsule. The authors noted on page 308, that the addltlon of a surfactant such as sodlum lauryl sulfate Improved dlslntegratlon of the capsules when tested In artlflclal gastrlc fluld wlthout enzymes.
Short et al., J. Pharm. Scl. 61, 1733 (1972), dlsclose the dlssolutlon of hydrocortlsone In a number of systems contaln-lng an N-alkylpolyoxyethylene surfactant.
U.S. Patent 3,862,311 granted January 21, 1975, to Lee-son, dlscloses the use of varlous types of surfactants In con-, ~
~35661' Junctlon wlth polyethylene 01ycol carrlers for asslstance In dls solutlon and absorptlon of composl~lons contalnlng progesterone.
The preferred surfactants are non-lonlcs.
Geneldl et al., J. Pharm. Scl. 67, 114 (1978), dlsclose the theoretlcal relatlonshlp between enhancement of dlssolutlon rate of a drug and Its Gl absorptlon rate;
~5 _ 2a -1~3~6~' Description of the Invention In accordance with this invention, there is provided a solid pharmaceutical - composition of matter comprising a therapeutic agent in intimate admixture with a pharmaceutically-acceptableJ liquid, hydrophilic lubricant. The solid pharmaceutical composition is suitable for use in hard capsule production or tableting.
The liquid, hydrophilic lubricant employed in the pharmaceutical composi-tions of this invention functions as a classical solid, hydrophobic lubricant in as much as it provides for proper flow characteristics of the dry composition when filling a hard gelatin capsule body [Reier et al., J. Pharm. Sci. 57, 660 (1968) ], prevents binding of the rotary auger in the powder filled hopper [C. Lindenwald, Pharm. Ind.
28, 614 (1965) ] employed in filling hard gelatin capsules and permits smooth telescoping closure of the filied capsule body part into the cap, while not reducing the friction between the capsule halves to the point where they will easily separate upon further manipulation.
In addition, the use of a liquid as the lubricant markedly reduces the production of dust which conventionally attends the filling of capsules and prepara-tion of pharmaceutical powder mixes. The reduction of atmospheric dust is of great value in the handling of tranquilizers, barbiturates, analgesics, antibiotics, antihyper-tensives, antiinflammatory agents, steroids (hormones), etc., which may cause contact dermatitis or induce systemic effects upon inhalation by workers. When using a liquid lubricant, the reduction in dust is such that it is no longer necessary to polish hard gelatin capsules after filling.
Furthermore, the liquid lubricant provides an ideal medium for inclusion, by solution, suspension or emulsion, of surfactants, low level actives or other adjuvants which are desireably made as homogeneous as possible in a solid pharma-ceutical formulation. And, the liquid lubricant present in a hard gelatin capsule tends to reduce aging (hardening of the gelatin capsule via further polymerization) which results in lower dissolution rates.
Similar advantages attend the use of the pharmaceutical compositions of this invention in production of tablets. The liquid lubricant provides good flow and compression characteristics of the powder mix, minimiæes dust formation and Z3S6~
transport, and adequately lubrlcates the dle and punch to prevent blndlng of the tablet and metal parts.
The llquld, hydrophlllc lubrIcants whlch may be employed In varlous pharmaceutlcal formulatlons Include polyalky-lene glycols of molecular welght between about 200 and about 900, such as, polyethylene glycol and polypropylene glycol; glycerln, propylene glycol, and llquld polyhydrlde alcohol fatty acld esters (e.g. Glycomul ~ or Glycosperse ~ ). Each of these lubrlcants pose unlque problems whlch mlght dlctate agalnst thelr use In a speclflc appllcatlon. For example, glycerln and propy-lene glycol are so hydroscoplc that they may cause physlcal and chemlcal problems wlth the pharmaceutlcal. The more vlscous Gly-cosperse ~ tends to coat the external llp portlon of a hard cap-sule body and provlde such a frictlonless blndlng that the cap-sules tend to separate on handlIng. Hence, the preferred llquld lubrlcants are the polyethylene glycols of molecular welght from about 200 to about 900. The most preferred llquld lubrlcant Is polyethylene glycol havlng a molecular welght range of from about 20 380 to about 420 (PEG 400). These lubrIcants exert some level of surface actlvlty In addltlon to lubrlcatlon and otherwlse appear to be Ideally sulted for use In productlon of pharmaceutlcal com-posltlons for hard gelatln capsule fllllng.
26 In addltlon, thls Inventlon provldes solld pharmaceutl-cal composltlons comprlslng a therapeutlc agent In IntImate admlxtur0 wlth a pharmaceutlcally acceptable, llquld, hydrophlllc lubrlcant and a surface actlve agent. The surfactant further Improves the dlssolutlon rate by reduclng the surface tenslon at the llquld-solld lnterface created between the pharmaceutlcal composltlon and fluld dlssolvlng the composltlon. Thus, the hydrophlllclty of the llquld lubrlcant alds In drawlng water Into the matrlx of the tablet or capsule whlle the surface actlve agent Improves the wettablllty of the solId materlal to afford, In concert, a markedly Improved dlssolutlon rate. Typlcal sur-factants whlch are Incorporated Into the pharmaceutlcal compo~1-~ 3566~' tlons Of thls Inventlon are catlonlc, anlonlc and non-lonlc sur-face actlve agents well-known In the art, such as, the fatty esters of polyoxyethylene sorbltan (Tween (a trademar~) serles 20 to 85, ICI, Unlted States), a polyoxyethylene condensate of a hydrophoblc base formed by polymerlzatlon of propylene oxlde and propylene glycol (Pluronlc (a trademark) or Poloxamer (a trade-mark) serles, BASF Wyandotte Chemlcal Co.), sorbltan monolaurate (Span 20 (a trademark), ICI Unlted States), octylphenoxy polyethoxy cthanol ~Trlton X, a trademark) Rohm and Haas), cetyl-pryldlnlum chlorlde, dloctyl sodlum sulfosucclnate, and the llke.
The quan-tlty of llquld, hydrophlllc lubrlcant and sur-factant employed In the manufacture of the pharmaceutlcal compo-sltlons of thls Inventlon may vary greatly dependlng upon the characterlstlcs of the therapeutlc agent and other tablet or cap-sule adJuvants employed. The optlmum quantlty of elther or both Is, however, readlly determlned by emplrlcal Investlgatlon. For example, a serles of Incremental 5 percent Increases of PEG 400 admlxed wlth the conventlonal formulatlon contalnlng oxazepam as presented In Example 1, Infra, demonstrated a maxlmum useful con-centratlon of lubrlcant at about 25 percent by welght, at whlch polnt the formulatlon was clumpy and would not run In automatlc or seml-automatlc flllers. AdJustment of the quantlty of llquld lubrlcant and surfactant to provlde 75 percent or be-tter dlssolu-tlon in forty-flve mlnutes Is also readlly achleved by emplrlcal Investlgatlon of In vltro dlssolutlon rates.
The therapeutlc agent contemPlated for use In the novel pharmaceutlcal composlt ! ons of thls Inventlon Is any known thera-peutlc agent adaptable for admlnlstratlon vla a hard gelatln cap-sule or a tablet. In general, the comblnatlon of a pharmaceutl-cally acceptable llquld lubrlcant and surfactant Is employed wlth greatest advantage for the purpose of dramatlcally Improvlng the dlssolutlon rate of poorly soluble therapeutlc agents Includlng tranqulllzers, barblturates, analgeslcs, antlblotlcs, antlhyper-tenslves, antl-lnflammatorles, hormonal sterolds, and the llke, 1~35~
whlch exhlblt slow In vltro avallablllty rates. D I sso I utlon enhancement of the composltlons of thls Inventlon contalnlng the poorly soluble actlve pharmaceutlcal Is further optImlzed after Incluslon of the lubr I cant~surfactant comblnatlon by achlevlng maxlmum dlstrlbutlon of the lubrlcant-surfactant comblnatlon vla mllllng or screenlng to reduce agglomerates of loosely adherlng partlcles. Multlple mllllng or screenlng may enhance the dlsso-lutlon rate, dependlng Upon the efflclency of the Inltlal agglom-erated partlcle dlsruptlon.
Oxazepam Is employed as the therapeutlc agent In the followlng examples of therapeutlc composltlons for fllllng hard gelatln capsules because It Is a good example of a compound wlth a slow dlssolutlon rate. It Is to be understood that the Inven-tlon Is not llmlted to use wlth oxazepam or drugs whlch are rela-tlvely Insol Ub I e. The use of a llquld, hydrophlllc lubrlcant-surfactant, wlth or wlthout the addltlon of an addltlonal surface actlve agent, serves to Increase the dlssolutlon rate of tableted and hard encapsulated pharmaceutlcal composltlons whlch are cus-tomarlly and presently formulated wlth solId hydrophoblc lubrl-cants such as magneslum stearate, talc, or stearlc acld, even when the drug Itself Is readlly soluble In vltro and In vlvo.
In each of the followlng formulatlons employed to Illustrate the typlcal Improvement In dlssolutlon rates achleved wlth thls Inventlon, the solld Ingredlents conslstlng of the actlve materlal (oxazepam) and tablet exclplents (lactose and croscarmellose) are fIrst mlxed In a sultable mlxer. The llquld Ingredlents conslstlng of the lubrlcant (PEG 400) and surfactant (supplled under the trademark Polysorbate 80) are comblned and mlxed wlth a sultable mlxer. Thls comblnatlon Is added slowly to the mlxed powders and mlxed to achleve adequate dlsperslon. Thls wetted materlal Is passed through a No. 30 screen and then remlxed to further homogeneous dlspersal. In formulatlons where magneslum stearate Is present, thls solId hydrophoblc lubrlcant Is added through a fIne screen to the mlxed powders whlch are 23S66~`
then thoroughly mlxed. All components of these formulatlons are In mllllgrams.
.
- 6a -~;' \
, " ~3S66~' a) :~1 U o' O ~ ~o c~ _ cn ~ ~ CO
~ a~
P
.qlo w ~ ~ ~ E
Q s ~3 Wa ~
~ CO
O ~C
~ ., ~;
o ~1 ~ o ~ I I I co ~n .
V C
_.
n eU' ~ ~ wU~ I ~
~;~35~6~' As may be readily seen, the dissolution rate is markedly improved in Formula II by merely reducing the quantity of solid ~lydrophobic lubricant (magnesium - stearate) and adding an internally cross-linked carboxymel:hylcellulose sodium salt disintegrant (croscarmellose sodium). The resuits obtained from Formula III demon-strate that the addition of a disintegrant alone with exclusion of a lubricant is not the answer to the problem. ~issolution of Formula IV demonstrates a marked improve-ment resulting from the addition of a liquid, hydrophilic, low molecular weight polyethylene glycol (PEG 400) which acts as a lubricant and weak surfactant. Upon addition of a minor amount of another surfactant (Polysorbate 80) the thirty minute in vitro dissolution rate is improved to between 85 to 95 percent of the composition dosage. This exceeds the desired in vitro dissolution rate of not less than 75 percent in forty-five minutes currently propounded by the U.S.P. XX - N.F. XV, 1980, as desireable.
Other surface active agents work similarly well with the liquid, hydro-philic lubricant to afford rapid dissolution of the pharmaceutical compositions as may be seen in the following examples:
Example No. VI VII VIII IX
PEG & Sorbitan PEG andPEG and PEG and Monolaurate TritonCet~lpyrid. DSS *
~O Oxazepam, mg 30 30 30 30 Lactose USP 147.1 147.1 147.1 182 Croscarmellose Sodium, USP 6.6 6.6 6.6 6.6 PEG 400, NF 1.1 1.1 1.1 1.1 Triton X-100 - 0.185 Cetylpyridinium Chloride - - 0.185 Sorbitan monolaurate 1). l 85 Dioctyl Sodium ~0 Sulfosuccinate * - - - 0.26 Magnesium Stearate, USP
~6 dissolved in 30 91 96 86 93 1~35f~
All of the in vitr_ dissolution studies wl.ich produced the data reported above were run by the method descri.bed .i.n the U.S. Pharmacopeia XX, The Ma-terial Formulary ~V page 959 (1980) using 0.1 N hydxochloric acid as dissolution medium. In actual practice, hard gelatin capsules fi.lled wlth -the pharmaceutical formulation of Example V, supra, provided bioavailability ln vivo which was not statistically distinct with respect -to rate and extent of absorption from compressed tablets now employed in the trade, a very desireable but difficult result to achieve ~ with any given drug. Thus, a -typical pharmaceu-tical formula-tion employing oxazepam as the active ingredient contains from about 10 to about 30 milligrams oxazepam; 0.5 to about 25 weigh-t percent of composition of liquid polyalkylene glycol of molecu-lar weight from about 200 to about 900; about 0.1 to about 25 weight percent of composition of surfactant, plus a filler.
The preferred formulations for oxazepam to be employed in filling hard gelatin capsules contain from abou-t 10 to about 30 milligrams oxazepam, about 3 to about 11 weight percent ratio to active of polyethylene glycol lubricant of molecular weight ~ from about 380 to 420, about 0.5 to about 2.5 weight percent ratio to active of nonionic surfactant, made up with filler and/or adjuvant(s) to provide a unit dose of from about 165 to 205 milligrams.
Three specific examples of formulations for unit dosage administration via hard gelatin capsules, expressed in milligrams, are:
oxazepam, USP 10 15 30 Lactose, USP 167 162 147 Croscarmellose Sodium, NF 6.6 6.6 6.6 PEG 400, NF 1.1 1.1 1.1 Polysorbate 80, NF ~ 0.22 0.22 0.22 g . .
Claims (42)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A solid pharmaceutical composition comprising a solid therapeutic agent in intimate admixture with a non-solubi-lizing amount of a pharmaceutically-acceptable, liquid, hydrophilic lubricant.
2. A pharmaceutical composition of claim 1, in which said lubricant is a liquid polyalkylene glycol of molecular weight from about 200 to about 900.
3. A pharmaceutical composition of claim 2, in which said polyalkylene glycol is a polyethylene glycol which possesses a molecular weight of about 380 to about 420.
4. A pharmaceutical composition of claim 1, in which said admixture contains a pharmaceutically acceptable surface active agent.
5. A pharmaceutical composition of claim 4, in which said surface active agent is a fatty ester of polyoxytheyiene sorbitan, a polyoxyethylene condensate of a hydrophobic base formed by polymerization of propylene oxide and propylene glycol, sorbitan monolaurate, octylphenoxypolyethoxy ethanol, cetylpyrl-dinium chloride or dioctyl sodium sulfosuccinate.
6. A pharmaceutical composition of claim 1, in which said therapeutic agent in conventional formulation has an in vltro dissolution rate below 75 percent at forty-five minutes.
7. A pharmaceutical composition of claim 1, in which said therapeutic agent is oxazepam.
8. A pharmaceutical composition of claim 1 for filling hard gelatin capsules which comprises from abut 10 to about 30 milligrams oxazepam, about 0.5 to about 25 weight percent of com-position of liquid polyalkylene glycol of molecular weight from about 200 to about 900, about 0.1 to about 25 weight percent of composition of surfactant, plus a filler.
9. A pharmaceutical composition of Claim 1 for filling hard gelatin capsules which comprises from about 10 to about 30 milligrams oxazepam, about 3 to about 11 weight percent ratio to active of polyethylene glycol lubricant of molecular weight from about 380 to 420, about 0.5 to about 2.5 weight percent ratio to active of nonionic surfactant, and a filler.
10. A pharmaceutical composition of Claim 9 which comprises about 10 milligrams oxazepam, about 167 milligrams lactose, about 6.6 milligrams croscarmel-lose sodium, about 1.1 milligram polyethylene glycol of molecular weight from about 380 to about 420 and about 0.22 milligrams of a fatty ester of polyoxyethylene sorbitan surfactant.
11. A pharmaceutical composition of Claim 9 which comprises about 15 milligrams oxazepam, about 162 milligrams lactose, about 6.6 milligrams croscarmel-lose sodium, about 1.1 milligram polyethylene glycol of molecular weight from about 380 to about 420 and about 0.22 milligrams of a fatty ester of polyoxyethylene sorbitan surfactant.
12. A pharmaceutical composition of Claim 9 which comprises about 30 milligrams oxazepam, about 147 milligrams lactose, about 6.6 milligrams croscarmel-lose sodium, about 1.1 milligram polyethylene glycol of molecular weight from about 380 to about 420 and about 0.22 milligrams of a fatty ester of polyoxyethylene sorbitan surfactant.
13. A method for improving dissolution of hard gelatin capsules or tablets containing therapeutic formulations and a lubricant which comprises employing a liquid, hydrophilic polyalkylene glycol of molecular weight from about 200 to about 900 as said lubricant.
14. The method of claim 13 in which said polyalky-lene glycol is a polyethylene glycol which possesses a molecu-lar weight from about 380 to about 420.
15. A solid pharmaceutical composition free of solid hydrophobic lubricant comprising a dry, powdery, dust-produc-ing therapeutic agent in intimate admixture with a non-solubi-lizing amount of a pharmaceutically acceptable, liquid, hydrophilic, dust-reducing, lubricant, said lubricant being a polyethylene glycol of molecular weight from about 200 to about 900, present in said admixture in from about 0.5 to about 25 weight percent of composition.
16. A composition of claim 15 in which said lubri-cant is a polytheylene glycol which possesses a molecular weight of about 380 to about 420.
17. A composition of claim 15 in which said admix-ture contains a pharmaceutically acceptable surface active agent.
18. A composition of claim 15 in which said surface active agent is a fatty ester of polyoxyethylene sorbitan, a polyoxyethylene condensate of a hydrophobic base formed by polymerization of propylene oxide and propylene glycol, sorbi-tan monolaurate, octylphenoxypolyethoxy ethanol, cetylpyri-dinium chloride or dioctyl sodium sulfonsuccinate.
19. A composition of claim 15 in which said thera-peutic agent is oxazepam.
20. A hard gelatin, telescoping two-piece cap and body capsule filled with a solid pharmaceutical composition free of solid hydrophobic lubricant comprising a dry, powdery, dust-producing therapeutic agent in intimate admixture with a non-solubilizing amount of a pharmaceutically acceptable, liquid, hydrophilic, dust-reducing, lubricant, said lubricant being a polyethylene glycol of molecular weight from about 200 to about 900, present in said admixture in from about 0.5 to about 25 weight percent of composition.
21. A filled hard gelatin capsule of claim 20 in which said lubricant is a polyethylene glycol which possesses a molecular weight of about 380 to about 420.
22. A filled hard gelatin capsule of claim 20 in which said admixture contains a pharmaceutically acceptable surface active agent.
23. A filled hard gelatin capsule of claim 20 in which said surface active agent is a fatty ester of poly-oxyethylene sorbitan, a polyoxyethylene condensate of a hydrophobic base formed by polymerization of propylene oxide and propylene glycol, sorbitan monolaurate, octylphenoxy-polyethoxy ethanol, cetylpyridinium chloride or dioctyl sodium sulfonsuccinate.
24. A filled hard gelatin capsule of claim 20 in which said therapeutic agent is oxazepam.
25. A filled hard gelatin capsule of claim 20 in which said solid pharmaceutical composition comprises from about 10 to about 30 milligrams oxazepam, about 0.5 to about 25 weight percent of composition of liquid polyethylene glycol of molecular weight from about 200 to about 900, about 0.1 to about 25 weight percent of composition of surfactant, plus a filler.
26. A filled hard gelatin capsule of claim 20 in which said solid pharmaceutical composition comprises from about 10 to about 30 milligrams oxazepam, about 3 to about 11 weight percent ratio to active of polyethylene glycol lubri-cant of molecular weight from about 380 to 420, about 0.5 to about 2.5 weight percent ratio to active of non-ionic surfac-tant, and a filler.
27. A filled hard gelatin capsule of claim 26 in which said solid pharmaceutical composition comprises about 10 milligrams oxazepam, about 167 milligrams lactose, about 6.6 milligrams croscarmellose sodium, about 1.1 milligram polyethylene glycol of molecular weight from about 380 to about 420 and about 0.22 milligrams of a fatty ester of poly-oxyethylene sorbitan surfactant.
28. A filled hard gelatin capsule of claim 26 in which said solid pharmaceutical composition comprises about 15 milligrams oxazepam, about 162 milligrams lactose, about 6.6 milligrams croscarmellose sodium, about 1.1 milligram polyethylene glycol of molecular weight from about 380 to about 420 and about 0.22 milligrams of a fatty ester of poly-oxyethylene sorbitan surfactant.
29. A filled hard gelatin capsule of claim 26 in which said solid pharmaceutical composition comprises about 30 milligrams oxazepam, about 147 milligrams lactose, about 6.6 milligrams croscarmellose sodium, about 1.1 milligram polyethylene glycol of molecular weight from about 380 to about 420 and about 0.22 milligrams of a fatty ester of poly-oxyethylene sorbitan surfactant.
30. A solid pharmaceutical composition contained in a hard gelatin capsule comprising a therapeutic agent in inti-mate admixture with a pharmaceutically acceptable, liquid, hy-drophilic polyalkylene glycol lubricant, the lubricant being present in a non-solubilising amount.
31. A solid pharmaceutical composition for filling a hard gelatin capsule which comprises a therapeutic agent other than sodium dicloxacillin in intimate admixture with a pharmaceutically acceptable liquid, hydrophilic polyalkylene glycol lubricant, the lubricant being present in a non-solubilising amount.
32. A pharmaceutical composition as claimed in Claim 30 in which the lubricant is a polyalkylene glycol of molecular weight from about 200 to about 900.
33. A pharmaceutical composition as claimed in Claim 31 in which the lubricant is a polyalkylene glycol of molecular weight from about 200 to about 900.
34. A pharmaceutical composition as claimed in Claim 32 or 33 in which said polyalkylene glycol is a polyethylene glycol which possesses a molecular weight of about 380 to about 420.
35. A pharmaceutical composition as claimed in Claim 30 in which said admixture contains a pharmaceutically acceptable surface active agent.
36. A pharmaceutical composition as claimed in Claim 31 in which said admixture contains a pharmaceutically acceptable surface active agent.
37. A pharmaceutical composition as claimed in Claim 35 or 36 in which the surface active agent is a fatty ester of polyoxyethylene sorbitan, a polyoxyethylene conden-sate of a hydrophobic base formed by polymerization of propy-lene oxide and propylene glycol, sorbitan monolaurate, octylphenoxypolyethoxy ethanol, cetylpyridinium chloride or dioctyl sodium sulfosuccinate.
38. A pharmaceutical composition as claimed in Claim 30, 31 or 32 in which said therapeutic agent in conven-tional formulation has an in vitro dissolution rate below 75 percent at forty-five minutes in 0.1 N hydrochloric acid.
39. A pharmaceutical composition as claimed in Claim 30, 31 or 32 in which the therapeutic agent is oxazepam.
40. A pharmaceutical composition as claimed in Claim 30 also comprising a disintegrant.
41. A pharmaceutical composition as claimed in Claim 31 also comprising a disintegrant.
42. A pharmaceutical composition as claimed in Claim 40 or 41 in which the disintegrant is croscarmellose sodium.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US51180183A | 1983-07-07 | 1983-07-07 | |
| US511,801 | 1983-07-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1235661A true CA1235661A (en) | 1988-04-26 |
Family
ID=24036506
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000458340A Expired CA1235661A (en) | 1983-07-07 | 1984-07-06 | Pharmaceutical composition containing a liquid lubricant |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS6036424A (en) |
| KR (1) | KR890000182B1 (en) |
| AU (1) | AU569902B2 (en) |
| CA (1) | CA1235661A (en) |
| DE (1) | DE3424975A1 (en) |
| FR (1) | FR2548539B1 (en) |
| GB (1) | GB2142824B (en) |
| ZA (1) | ZA845180B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5030632A (en) * | 1986-09-23 | 1991-07-09 | Sandoz Pharm. Corp. | Low dose temazepam |
| US5629310A (en) * | 1986-09-23 | 1997-05-13 | Sterling; William R. | Low dose temazepam |
| US5211954A (en) * | 1986-09-23 | 1993-05-18 | Sandoz Ltd. | Low dose temazepam |
| CN1053570C (en) * | 1987-10-07 | 2000-06-21 | 默尔多药物公司 | Pharmaceutical composition for piperidinoalkanol-decongestant combination |
| AR240018A1 (en) * | 1987-10-07 | 1990-01-31 | Merrell Pharma Inc | PROCEDURE FOR PREPARING A COMPOSITION THAT INCLUDES DERIVATIVES OF PIPERIDINOALCANOL. |
| JPH01283222A (en) * | 1988-05-10 | 1989-11-14 | Tokai Kapuseru Kk | Soft capsule agent of sodium picosulfate |
| US5447966A (en) * | 1988-07-19 | 1995-09-05 | United States Surgical Corporation | Treating bioabsorbable surgical articles by coating with glycerine, polalkyleneoxide block copolymer and gelatin |
| GB2281697A (en) * | 1993-09-14 | 1995-03-15 | Euro Celtique Sa | Laxative compositions in capsules |
| GB9325445D0 (en) | 1993-12-13 | 1994-02-16 | Cortecs Ltd | Pharmaceutical formulations |
| FR2868079B1 (en) * | 2004-03-29 | 2007-06-08 | Seppic Sa | POWDER SURFACTANTS USEFUL IN COMPRESSES OR GELULES PREPARATION METHOD AND COMPOSITIONS CONTAINING SAME |
| US20080254119A1 (en) | 2007-04-16 | 2008-10-16 | Wyeth | Imbedded liquid lubricants for tableting |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB752362A (en) * | 1953-11-09 | 1956-07-11 | Scherer Corp R P | Plasticized gelatin capsules |
| IT1158722B (en) * | 1977-07-08 | 1987-02-25 | Simes | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF SLEEP TURBES |
| EP0001247A1 (en) * | 1977-09-14 | 1979-04-04 | Kanebo, Ltd. | Pharmaceutical preparation containing nifedipine and a method for producing the same. |
| GB2064321B (en) * | 1980-11-20 | 1984-02-15 | Beecham Group Ltd | Injectable solutions of sodium dicloxacillin |
| US4366145A (en) * | 1981-06-24 | 1982-12-28 | Sandoz, Inc. | Soft gelatin capsule with a liquid ergot alkaloid center fill solution and method of preparation |
-
1984
- 1984-07-05 ZA ZA845180A patent/ZA845180B/en unknown
- 1984-07-05 GB GB08417154A patent/GB2142824B/en not_active Expired
- 1984-07-06 DE DE19843424975 patent/DE3424975A1/en not_active Withdrawn
- 1984-07-06 FR FR8410803A patent/FR2548539B1/en not_active Expired
- 1984-07-06 AU AU30356/84A patent/AU569902B2/en not_active Ceased
- 1984-07-06 CA CA000458340A patent/CA1235661A/en not_active Expired
- 1984-07-06 JP JP59141295A patent/JPS6036424A/en active Pending
- 1984-07-06 KR KR1019840003931A patent/KR890000182B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ZA845180B (en) | 1986-02-26 |
| FR2548539B1 (en) | 1988-06-24 |
| GB2142824B (en) | 1987-02-11 |
| JPS6036424A (en) | 1985-02-25 |
| FR2548539A1 (en) | 1985-01-11 |
| AU3035684A (en) | 1985-01-10 |
| AU569902B2 (en) | 1988-02-25 |
| GB2142824A (en) | 1985-01-30 |
| KR850000974A (en) | 1985-03-14 |
| DE3424975A1 (en) | 1985-01-17 |
| GB8417154D0 (en) | 1984-08-08 |
| KR890000182B1 (en) | 1989-03-09 |
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