Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
  • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
• • 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
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

• compositions in the form of beadlets suitable for filling into hard shell pharmaceutical capsules, are described.
• the beadlets are characterized in that the medicament therein is released in two separate and distinct doses. In part, this is accomplished by means of an enteric coatin containing zein and an abietic acid type rosin.
• beadlets are described in which the active medicament is released in a more or less continuous fashion over a predetermined period of time.
• compositions in general, to novel pharmaceutical compositions. More particularly, the invention relates to compositions, in the form of small discrete beadlets, which beadlets contain an active drug component and are capable of being embodied, in large numbers, into conventional, pharmaceutical hard shell capsules.
• an active drug is advantageously embodied in a formulation which permits or causes the drug to be liberated in some desired regulated pattern of release.
• the active medicament is released from such a dosage form in a more or less continuous manner over a predetermined period of time.
• the present invention provides pharmaceutical compositions in the form of beadlets, which beadlets are characterized in that the medicament therein is released in two separate and distinct doses, i.e., repeat action beadlets.
• the invention provides pharmaceutical compositions in the form of beadlets, which beadlets are characterized in that the medicament therein is released in a more or less continuous fashion over a predetermined period of time, i.e., sustained release beadlets.
• the invention provides capsules which contain a multiplicity of the medicament-containing repeat action beadlets.
• the invention provides capsules which contain a multiplicity of the medicament-containing sustained release beadlets.
• the invention provides capsules which contain (1) a multiplicity of repeat action beadlets having embodied therein an active drug component and (2) a multiplicity of sustained release beadlets having embodied therein an active drug component other than that embodied in the aforesaid repeat action beadlets.
• the present invention is applicable to (1) any drug which is advantageously administered in the form of a repeat action composition and (2) to any drug which is advantageously administered in the form of a sustained release composition.
• the drugs which are administered beneficially in repeat action dosage form are the well known 7-chloro 2 methylamino-S- phenyl-3H-1,4-benzodiazepinel-oxide, and its medicinally acceptable acid addition salts; 7-chloro 1-methyl-5- phenyl 3H-l,4-benzodiazepin 2(lH)one, and its medicinally acceptable acid addition salts; l methyl-3-benziloyloxy-quinuclidinium halides; etc.
• Such drugs can be employed in the practice of this invention. Included among the drugs which are administered beneficially in sustained release form are the known dextroamphetamine, and its medicinally acceptable acid addition salts; the aforementioned 1-methyl-3-benziloyloxy-quinuclidinium halide; etc. Such drugs, and others, can be employed as the active drug component of the sustained release beadlets of this invention.
• capsules which contain (1) chlordiazepoxide-containing repeat action beadlets (2) dex-troamphetamine-sulfate-containing sustained release beadlets
• the invention is operable, in like manner, to provide capsules having embodied therein beadlets which contain either of these drugs as the only active medicament.
• Chlordiazepoxide is useful, and it is used, in treating various neuroses and in elevating the mood of depressed patients.
• Dextroamphetamine, and its medicinally acceptable acid addition salts are useful, and they are used, as anorexigenic agents.
• chlordiazepoxide and dextroamphetamiue are beneficially administered, in combination, in the treatment of obese patients and, particularly in the treatment of emotionally disturbed obese patients.
• the present invention provides an oral dosage form, i.e. capsules, containing (1) beadlets which contain and furnish two separate and distinct doses of an active medicament, e.g. chlordiazepoxide, and/or (2) beadlets which contain and permit an active medicament, e.g. dextroamphetamine, to be released therefrom in a continuous fashion.
• an active medicament e.g. chlordiazepoxide
• an active medicament e.g. dextroamphetamine
• the chlordiazepoxide-containing beadlets because of the particular pattern in which the active drug is released therefrom, will be referred to herein simply as repeat action beadlets.
• the active medicament is released more or less continuously over an extended period of time, for example, up to about eight hours, such beadlets will be referred to herein simply as sustained release beadlets.
• chlordiazepoxide beadlets are readily prepared.
• powdered chlordiazepoxide preferably in the form of the free base, is dispersed, e.g., by dusting, onto a medicinally acceptable core material.
• core material non-pareil seeds are preferably employed. It should be understood that, while the non-pareil seeds will be referred to herein collectively as the core, each such non-pareil seed is a separate core.
• Adhesion of the chlordiazepoxide on the core is accomplished by overlaying, e.g. by spraying, the core with a specially prepared, edible acaccia syrup adhesive prior to dusting the chlordiazepoxide thereon.
• the first step of the preparative method is the spraying of the adhesive on the core and the second step involves the dusting of chlordiazepoxide onto the thus sprayed core.
• the syrup which is employed as the adhesive in the first step of the preparative method is a significant feature of this invention and this syrup, and its preparation, will be described hereinafter.
• the chlordiazepoxide which, in the second step of the process, is dusted directly on the adhesive-treated core is the repeat action dose, i.e., the second dose which is released to the patients system.
• the chlordiazepoxide-coated core is, in the third step of the preparative method, dried by appropriate means.
• enteric coated beadlet After drying, an appropriate number of edible enteric coatings are overlayed each chlordiazepoxide-coated core to provide a composition which will be referred to hereinafter as an enteric coated beadlet.
• the number of enteric coats which will be applied in this step of the process is vari able. Generally, the application of at least about ten separate enteric coats is desirable. It will be obvious, however, that a fewer or a greater number of such coats can be applied to afford desired modifications in the release characteristics.
• the enteric coating composition which is used in this step of the process is also an important feature of this invention. This coating composition, its preparation and the manner in which it is applied will be described hereinafter.
• an additional quantity of powdered chlordiazepoxide is dispersed, e.g., by dusting, on the beadlets.
• the acacia syrup referred to heretofore, is used once again as the adhesive.
• the beadlet is overlayed with the adhesive, preferably by spraying, following which the chlordiazepoxide powder is dusted thereon.
• the chlordiazepoxide, Which is applied to the enteric coated beadlets in this second dusting step, is the dose which will be released first into the system of the patient when the capsule containing the beadlets is swallowed.
• the repeat action chlordiazepoxide beadlets which are thus obtained, are dried by appropriate means.
• the repeat action beadlets provide two separate and distinct doses of chlordiazepoxide.
• the first dose is released shortly after the capsule containing the beadlets is administered orally to the patient.
• the second dose is released at some predetermined point of time subsequent to the release of the first dose.
• the duration of time intervening the release of the first and second doses is determined, for the most part, by the amount of enteric coating, i.e., the number of enteric coats, applied to the chlordiazepoxide-coated core. As indicated heretofore, it is preferable to apply at least about ten separate coats.
• the time which elapses between the release of the first dose and second dose is about four hours.
• the interval between the release of the first dose and the second dose will be decreased.
• the time intervening the release of the two doses will be increased.
• the sustained release beadlets which contain dextroamphetamine sulfate are also readily prepared.
• dextroamphetamine sulfate in the from of a powder, is dusted onto a medicinally acceptable core material, such as, non-pareil seeds.
• a medicinally acceptable core material such as, non-pareil seeds.
• the non-pareil seeds will be referred to collectively as the core, with the understanding that each seed is a separate core.
• Adhesion of the powdered dextroamphetamine sulfate to the core is accomplished by spraying the core with the aforementioned edible acacia syrup adhesive, prior to dusting the powdered dextroamphetamine sulfate thereon.
• Each dextroamphetamine sulfate-coated core is then coated with a permeable film using, as the film-forming composition, an edible composition comprising shellac, polyethylene glycol and an anhydrous lower aliphatic alcohol.
• the number of coats of the shellac-containing coating composition applied in this step of the process is variable. However, the application of at least about ten separate coats is preferred.
• a representative samplingof the beadlets are tested by conventional in vitro procedures to determine the release rates.
• a half-change method is preferably used in this determination.
• a typical release pattern is about release of the medicament after thirty minutes, about 19% release after two hours, about 63% release after four hours and about 71% release after six hours. If the release rate is faster than desired, additional coats of the shellac-polyethylene glycol solution are applied as needed.
• the beadlets are sprayed again with the acacia adhesive, following which, by dusting, they are overlaycd with an additional quantity of dextroamphetamine sulfate. The overlayed portion of the medicament is liberated shortly after the capsule containing the pellets is administered to the patient.
• the acacia syrup which is used as the adhesive in the practice of this invention comprises powdered gum acacia, sucrose and distilled water.
• the quantities of powdered gum acacia and sucrose which are used in preparing the adhesive composition are variable. In the preferred practice of the invention, however, there will be used a syrup containing from about 5% to by weight of powdered gum acacia, 35% to about 45% by weight of sucrose and from about 40% to about 60% by weight of distilled water.
• a preferred adhesive composition comprises from about 9.5% to 10.0% by weight of gum acacia, from about 38% to about 38.5% by weight of sucrose and from about 51.5% to about 52.5% by weight of distilled water.
• the adhesive is prepared simply by adding the gum acacia and sucrose to water and stirring same therein. This can be accomplished at room temperature, or at a temperature which is elevated somewhat above room temperature.
• the enteric coating which is used in preparing the repeat action chlordiazepoxide beadlets of this invention is a composition produced by mixing the following named ingredients, in the quantities hereinafter indicated:
• anhydrous lower aliphatic alcohol component there can be used, for example, methyl alcohol, ethyl alcohol or any such alcohol in which the lacquer is soluble.
• a preferred enteric coating contains about 825.0 parts by weight of an abietic acid-type rosin sold commercially as Nelio Rosin; 432.0 parts by weight of zein; 36.0 parts by weight of white neutral soap as the wetting agent; 171.0 parts by weight of white oleic acid as the 75 plasticizer; and about 1500.0 parts by weight of ethyl alcohol.
• the wetting agent for example, Pluronic F-68, dioctyl sodium sulfosuccinate, sodium lauryl sulfate, a poly-oxyethylene sorbitan fatty acid ester, such as, polyoxyethylene sorbitan monooleate, etc.
• oleic acid castor oil, diethyl phthalate, triacetin, etc.
• the desired lacquer composition is prepared readily by adding the rosin, zein, wetting agent and plasticizer to the anhydrous alcohol and stirring same therein. This can be accomplished at room temperature or at a temperature which is elevated somewhat above room temperature. Prior to its use as the enteric coating, however, the lacquer composition, described heretofore, is diluted further with from 80% to about 110% of its weight of an anhydrous lower aliphatic alcohol.
• the permeable film-forming composition which is used in. producing the sustained release dextroamphetamine beadlets of this invention comprises shellac, a polyethylene glycol wetting agent, for example, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 20,000, and a lower molecular weight aliphatic alcohol, such as, methyl alcohol, ethyl alcohol, etc.
• the composition is prepared simply by mixing the various ingredients at a temperature which is elevated somewhat above room temperature. The quantities of the three ingredients comprising these products can be varied within relatively wide ranges. However, in the preferred embodimeat of the invention there is used a composition containing from about 45% to about 55% by weight of shellac "(40% to 50% solids), from about 4.5% to about 5.5%
• polyethylene glycol 6000 by weight of polyethylene glycol 6000 and from about 40% to about 50% by weight of ethyl alcohol.
• the number of coats of the enteric coating composition which are applied to the chlordiazepoxide-coated beadlets is variable.
• four distinct and separate coats are first applied, with the pellets being dried and then dusted with talc and sucrose between each coat. Thereafter, six additional coats of the enteric coating are applied, with the pellets being dried and dusted with talc between each coat.
• the number of shellac-polyethylene glycol coats which are applied in the production of the sustained release dextroamphetamine beadlets is similarly variable.
• about ten separate and distinct coats are applied with the beadlets being dusted with talc and dried between each coat.
• the coating processes involve the placing of an appropriate number of medicament-coated cores in the standard coating pan, followed by the addition thereto of a sufficient quantity of the coating composition to completely wet the cores. The pan is rotated until all of the coating composition has been taken up by the cores. In the case of the coating for the dextroamphetamine seeds, it is preferred to keep the coating composition warm to prevent the precipitation of the polyethylene glycol 6000 therefrom.
• the first coating operation is completed, the beadlets are dried. Thereafter, the remaining coats are applied in a similar manner.
• the repeat action chlordiazepoxide beadlets and the sustained release dextroamphetamine beadlets are in the practice of this invention, filled into suitable hard shell capsules. Untreated non-pareil seeds are used as inert fillers to obtain a proper capsule fill.
• the number of chlordiazepoxide-containing beadlets and the number of dextroamphetamine sulfate-containing beadlets to be incorporated into a single capsule is variable. In any instance, the number of beadlets filled into any one capsule will be determined by the levels of active medicament which it is desired to have in the final product. The number of beadlets needed to achieve such level of medication will be dependent upon the amount of medicament present in the individual pellets.
• the primary objective is to provide capsules containing a safe, but yet effective, dose of the drugs.
• a suflicient number of each type beadlet will be added to the capsule to provide a unit dosage containing from about 10 mg. to about 25 mg. of chlordiazepoxide base and 10 mg. to 25 mg. of dextroamphetamine sulfate.
• the non-pareil seeds were dusted with 2244.0 parts of dextroamphetamine sulfate.
• the beadlets were then dried overnight at a temperature of 43 C.
• a coating solution was prepared by mixing 1320 parts of shellac, 132 parts of polyethylene glycol 6000 and sufiicient ethyl alcohol to make 6000 parts by volume. This solution was applied to the coated nonpareil seeds, described in the preceding paragraph, in ten separate coats, there being used in each coating operation, 600 cc. of the coating solution. Between coats, the beadlets were dusted with 700 parts by weight of talc. Between each coat, the beadlets were dried with warm air for a period of about 20 to 30 minutes. After ten coats of the shellac solution had been applied thereto, the beadlets were aged for a period of about four days at a temperature of from about 60 C. to 65 C.
• the beadlets were tested, in vitro, by a half change method to determine the release rate of dextroamphetamine sulfate. Thereafter, the beadlets were over- .layed with the immediate release portion of dextroamphetamine sulfate. This was accomplished by spraying the beadlets with 800 cc. of acacia syrup and, subsequently, dusting the sprayed pellets with 595 parts of dextroamphetamine sulfate.
• the chlordiazepoxide had been dusted onto the seeds, the seeds were dried overnight at a temperature of 43 C. Thereafter, the beadlets, thus obtained, were coated with an enteric coating.
• the coating which was used contained the following named ingredients in the quantities hereinafter indicated:
• the beadlets were dusted with a mixture of 180 parts of sucrose and 820 parts of talc. Thereafter, six additional separate coats of the lacquer solution, each coat utilizing 600 cc. of the coating solution, were applied to the beadlets. Between each of these coats, the beadlets were dusted with about 1500 parts of tale. The beadlets were then dried overnight at a temperature of about 43 C.
• the enteric coated chlordiazepoxide beadlets were sprayed with 650 cc. of the acacia-sucrose syrup described heretofore and the sprayed beadlets were then dusted with 1580 parts of chlordiazepoxide.
• chlordiazepoxide base 15 mg. of dextroamphetamine sulfate. It was established that the chlordiazepoxide was released from the beadlets in two separate and distinct 7.5 mg. doses, the first dose being released immediately, the second being released approximately four hours after the first. In the case of the dextroamphetamine sulfatecontaining beadlets, the dextroamphetamine was released according to the following pattern: 30 minutes, 37%; 2 hours, 44%; 4 hours, 68%; and 7 hours, 83%.
• chlordiazepoxide in repeat action form and dextroamphetamine sulfate in sustained release form.
• Chlordiazepoxide-containing beadlets produced as described in Section (a) of this example were charged into No. 1 size capsules, 550 of such beadlets being employed for each capsule. A sufficient number of neutral non-pareil seeds were added to each capsule to obtain proper capsule fill. Each capsule provided a unit dosage of 15 mg. of chlordiazepoxide, 7.5 mg. of which was released almost immediately upon administration to the patient the remaining 7.5 mg. being released approximately four hours thereafter.
• a repeat action pharmaceutical composition in the form of discrete beadlets, each beadlet comprising (1) a medicinally acceptable core material, (2) an adhesive gum acacia composition overlaying said core material, (3) an active medicament dispersed upon said adhesivetreated core material and retained thereon by said adhesive composition, (4) an enteric coating of an abietic acid type rosin and zein overlaying the medicamentcoated core, (5) an adhesive gum acacia composition overlaying said enteric coating and (6) an active medicament dispersed upon the enteric coated core and retained thereon by said adhesive composition, the adhesive compositions (2) and (5) being the same in each instance, and having been applied in the form of a syrup comprising from about 5% to about by weight of gum acacia, from about 35% to about 45% by weight of sucrose and from about 40% to about 60% by weight of distilled water, and the enteric coating (4) being applied in the form of a solution comprising from about to about by weight of an abietic acid-type rosin, from about 10% to about 20% by weight of
• composition of claim 1 wherein the active medicament (3) and (6) is a member selected from the group consisting of 7-chloro-2-methylamino-5-phenyl-3H- 1,4-benzodiazepine-4-oxide and a medicinally acceptable acid addition salt thereof.
• composition of claim 1 wherein the active medicament (3) and (6) is a member selected from the group consisting of 7-chloro-1-methyl-5-phenyl-3I-I-1,4-benzodiazepin-2( lH)-one and a medicinally acceptable acid addition salt thereof.
• composition of claim 1 wherein the active medicament (3) and (6) is a l-methyl-S-benzyloxy quinuclidinium halide.
• Capsules for oral administration, containing (a) a multiplicity of the beadlets of claim 1 and (b) inert filler materials.
• a repeat action pharmaceutical composition in the form of discrete beadlets, each beadlet comprising (1) a non-pareil seed overlayed with (2) an adhesive gum acacia composition, (3) an active medicament dispersed upon the adhesive-overlayed non-pareil seed, (4) an enteric coating of an abietic acid type rosin and zein overlaying the medicament-coated non-pareil seeds, (5) an adhesive gum acacia composition overlaying said enteric coating and (6) an active medicament dispersed upon the enteric coated core and retained thereon by said adhesive composition, the adhesive compositions (2) and (5) being the same in each instance, and having been applied in the form of a syrup comprising from about 5% to about 15 by weight of gum acacia, from about 35% to about by weight of sucrose and from about 40% to about by weight of distilled water, and the enteric coating (4) being applied in the form of a solution comprising from about 25% to about 35% by weight of an abietic acid type rosin, from about 10% to about 20%
• composition of claim 6 wherein the active medicament (3) and (6) is a member selected from the group consisting of 7-chloro-2-methylamino-5-phenyl-3H- 1,4-benzodiazepine-4-oxide and a medicinally acceptable acid addition salt thereof.
• composition of claim 6 wherein the active medicament (3) and (6) is a member selected from the group consisting of 7-chloro-1-methyl-5-pheny1-3H-1,4- benzodiazepin-2(lH)-0ne and a medicinally acceptable acid addition salt thereof.
• composition of claim 6 wherein the active medicament (3) and (6) is a l-methyl-3-benzyloyloxy quinuclidinium halide.
• Capsules for oral administration, comprising (a) a multiplicity of the beadlets of claim 6 and (b) inert filler materials.
• a sustained release pharmaceutical composition in the form of discrete beadlets, each beadlet comprising (1) a medicinally acceptable core material, (2) an adhesive gum acacia composition overlaying said core material, (3) an active medicament dispersed upon said adhesive treated core material and retained thereon by said adhesive composition, (4) a permeable film of shellac and polyethylene glycol 4,000 to 20,000 overlaying the medicament-coated core, an adhesive gum acacia composition overlaying said permeable film and (6) an active medicament dispersed upon the film-coated core material and retained thereon by said adhesive composition, the adhesive component (2) and (5) being the same in each instance and having been applied in the form of a syrup comprising from about 5% to about 15% by weight of gum acacia, from about 35% to about 45% by weight of sucrose and from about 40% to about 60% by weight of distilled water, the permeable film (4) having been applied in the form of a solution comprising from about 45% to about 55% by weight of 40% to 50% solids shellac, from about 4.5%
• composition of claim 11 in which the active medicament is a member selected from the group consisting of dextroamphetamine and a medicinally acceptable acid addition salt thereof.
• composition of claim 11 in which the active medicament is a 1-mcthyl-3-benzyloyloxy-quinuclidinium halide.
• Capsules, for oral administration containing (a) a multiplicity of the beadlets of claim 11 and (b) inert filler materials.
• a pharmaceutical composition in oral dosage form, said composition comprising capsules containing (a) a multiplicity of repeat action medicament-containing beadlets, each of such beadlets comprising (1) a medicinally acceptable core material, (2) an adhesive gum acacia composition overlaying said core material, (3) an active medicament dispersed upon said adhesive-treated 5 core material and retained thereon by said adhesive composition, (4) an enteric coating of an abietic acid type rosin and zein overlaying the medicament-coated core, (5) an adhesive gum acacia composition overlaying said enteric coating and (6) an active medicament dispersed upon the enteric coated core and retained thereon by said adhesive composition, (b) a multiplicity of sustained release medicament-containing beadlets, each of such beadlets comprising (7) a medicinally acceptable core material, (8) an adhesive gum acacia composition overlaying said core material, (9) an active medicament dispersed upon said adhesive treated core material and retained thereon by said adhesive composition, (10) a permeable film of shellac and polyethylene glycol
• said enteric coating (4) having been applied in the form of a solution comprising from about 25% to about 35% by weight of an abietic acid type rosin, from about 10% to about 20% by weight of zein, from about 0.05% to about 0.5% by weight of a wetting agent, from about 40% to about 60% by weight of an anhydrous lower aliphatic alcohol and from about 1.0% to about 10.0% by weight of a plasticizer said solution having been diluted further with from about 80% to 110% by weight of an anhydrous lower aliphatic alcohol; and said permeable film (10) having been applied in the form of a solution comprising from about to about 55% by weight of 40% to solids shellac, from about 4.5% to about 5.5% by weight of a polyethylene glycol 4,000 to 20,000 and from about 40% to about 50% by weight of a lower molecular weight aliphatic alcohol.
• composition of claim 15 wherein the active medicament (3) and (6) is a member selected from the group consisting of 7-chloro-2-methylamino-5phenyl-3H- 1,4-benzodiazepine-4-oxide and a medicinally acceptable acid addition salt thereof and wherein the active medicament (9) and (12) is a member selected from the group consisting of dextroamphetamine and a medicinally acceptable salt thereof.
• composition of claim 17 wherein the active medicament (3) and (6) is a member selected from the group consisting of 7-chloro-2-n1ethylamino-5-phenyl-3H- 1,4-benzodiazepine-4-oxide and a medicinally acceptable acid addition salt thereof and wherein the active medicament (9) and (12) is a member selected from the group consisting of dextroarnphetamine and a medicinally acceptable acid addition salt thereof.

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Cited By (19)

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Citations (1)

• 1965
  • 1965-08-09 US US478437A patent/US3365365A/en not_active Expired - Lifetime
• 1966
  • 1966-08-08 BE BE685228D patent/BE685228A/xx unknown
  • 1966-08-08 BR BR181937/66A patent/BR6681937D0/pt unknown
  • 1966-08-08 ES ES0330013A patent/ES330013A1/es not_active Expired
  • 1966-08-09 NL NL6611190A patent/NL6611190A/xx unknown

Patent Citations (1)

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