IL25710A - Method of preparing solid stable preparations of sensitive active substances - Google Patents

Method of preparing solid stable preparations of sensitive active substances

Info

Publication number
IL25710A
IL25710A IL25710A IL2571066A IL25710A IL 25710 A IL25710 A IL 25710A IL 25710 A IL25710 A IL 25710A IL 2571066 A IL2571066 A IL 2571066A IL 25710 A IL25710 A IL 25710A
Authority
IL
Israel
Prior art keywords
active substance
active
active substances
cellulose
soluble
Prior art date
Application number
IL25710A
Other languages
Hebrew (he)
Original Assignee
Merck Ag E
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Ag E filed Critical Merck Ag E
Publication of IL25710A publication Critical patent/IL25710A/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/174—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P20/00—Coating of foodstuffs; Coatings therefor; Making laminated, multi-layered, stuffed or hollow foodstuffs
    • A23P20/10—Coating with edible coatings, e.g. with oils or fats
    • A23P20/105—Coating with compositions containing vegetable or microbial fermentation gums, e.g. cellulose or derivatives; Coating with edible polymers, e.g. polyvinyalcohol
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Polymers & Plastics (AREA)
  • Food Science & Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • Mycology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Animal Husbandry (AREA)
  • Nutrition Science (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

C O H E N Z E D E K & S P I S B A C H REGD. PATENT ATTORNEYS 24, LEVONTIN STR., P. O. B. 1169 I E L - AV I V P A T E N T S & D E S I G N S O R D I N A N C E 15332/66 SPECIFICATION METHOD OP PBEPABING SOLID STABLE PREP RATIONS OP SENSITIVE ACTIVE SUBST NCES p't i p '»yD p^iaino D'.PS'* c psio n* For the purposes of the present specification the term "active substances" is used to mean pharmaceuticals or additives to pharmaceuticals, foodstuffs and feeding stuff3, which are (i) sensitive, for example to chemical influences such as atmospheric oxygen and/or moisture, to temperature and/or light, and (ii) difficultly soluble in water.
Examples of such active substances are: vitamins, such as vitamins A, D^, 0, K and their derivatives which are difficultly soluble in water, e.g. their esters and addition compounds, steroids and other drugs containing groups which are sensitive, particular^ to atmospheric oxygen, e.g. 17c--ethinyl-steroids , such as 17c:-ethinyl-19-»nor-testosterone, ethinyl-oes radiol and its 3-methyl ethers, 17 -ethinyl-3-keto-5 (lO)-oestren-1?β-ο1 , and 17cc-ethinyl-testosterone; steroids with exocyclic methylene groups, such as 16-methylene-prednisolone and 6-methyl-6-dehydro-16~methylene-17 N-methyl-5-cyclo-hexenyl-5-methyl-barbituric acid, 1^βηζ ΐ-3-βΐ¾.7ΐ-6,7^ΐΕΐβ½θ3ς3Γ-ΐ3ο υίηοϋηβ, and l--,(2- Yridyl)-l-p-bromophenyl-3-dimetb laminopropane; antibiotics such as insoluble penicillins , chloramphenicol and erythromycin; flavouring substances, e.g. natural and synthetic citrus flavourings, such as oil of orange and oil of lemon; citral, citronellal, and citronellol.
It is known that these active substances often cannot be worked up into satisfactorily stable preparations or additives, as used, for example, to vitaminise feeding stuffs or foodstuffs. Even in dry preparations, such as tablets, dragees, capsules and granules, there is generally considerable deterioration of the active substance content under normal storage conditions even after relatively brief storage. This deterioration is caused by various factors, such as the influence of temperature, atmospheric oxygen, and moisture, to which the active substances are subjected during manufacture and/or during storage.
Deterioration of the active substance is particularly serious in those preparations which contain relatively small amounts of the active substance or which are administered in relatively low doses. One example is vitamin, D tablets containing approximately 1,000 international units and less, which are used for prophylaxis against rickets. Efforts made hitherto to find a method of making solid preparations which are sufficiently stable against deterioration of the active substance have not met with success. These efforts have been based upon the addition of anti-oxidants or by the use of protective manufacturing processes, such as dry granulation and/or attaching the active ingredient to inert bases by means of anhydrous organic solvents.
It has, for example, been proposed to distribute vitamins, 5 hormones or medical drugs in ^dibi - L, colloidal protein-containing substances . It has been found , however, that embedding of vitamin I>2 in milk protein, for example, does not result in completely satisfactory stabilisation of the active substance.
We have now found that 'solid, stable preparations of active substances in embedded form can be obtained ■ by dissolving both the active substance and the / cellulose derivative ga¾e^34da^«ie¾e«ae? separately or together in an inert solvent other than water, combining the solutions where necessary, removing the solvent and drying the residue obtained. This product can then be ground to the usual fine particle size necessary for tablet manufacture„ Removal of the solvent and drying of the residue can be / must be instantly soluble (or able to .form colloidal dispersions) in water, in order that the active substance may be rapidly and completely released in the stomach or the digestive juices. Physiologically acceptable cellulose derivatives are s-eebS¾a= abe ¾ag=»©*½=a=e=.
According to the present invention therefore, we provide a method of producing solid-stable preparations of active substances (as herein defined), which comprises finely dispersing / . jBe >e d~i&g> the active substance in a physiologically acceptable cellulose derivative which is (i) soluble or colloidally dispersible in water and (ii) soluble in at least one inert solvent other than water in which the active substance is also soluble.
Suitable cellulose derivatives for use in the method according to the invention are, for example, methyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose, which are soluble or colloidally dispersible in water. A commercially available water-soluble methyl cellulose having a viscosity of 200 centipoises in 2% aqueous solution, has proved particularly suitable. Commercially available products with the following properties have also proved successfulΪ a) Hydroxypropyl cellulose: Viscosity in 5% aqueous solution at 25°C 75-150 centipois Particle size 95% by 30 mesh 99% by 20 mesh pH of a 2% solution 5.0 - 8.0 Ash content generally :0.1%; maximum 0.5% Moisture content generally 3.0 ; maximum 5·0% b) Hydro:sypropylmethyl cellulose: Metho: rl content 20 - 30% Propylene glycol ether content 7 - 12% Viscosity in 2% aqueous solution at 20°C 0 centipoise Specific weight of 10% aqueous solution at 20°/4°C 1.0245 Surface tension of the aqueous solution at 25°C (below 500 centipoise regardless of the concentration) » - 50 dyn cm For practical reasons, the use of cellulose derivatives which are as readily soluble as possible is recommended. Solutions containing 5 to ICf/o by weight of cellulose derivative are preferably used; if difficultly soluble cellulose derivatives are used as embedding materials, a greater quantity of solvent has to be evaporated away. In carrying out the method, the active substance and the enbedding material are either dissolved together in an inert solvent or each is dissolved separately in an inert solvent and the solutions are then combined; care must be taken that no precipitation of the active substance or the embedding material occurs. The evaporation of the solvent is preferably carried out under reduced pressure and at low temperatures, preferably up to 0°C. The residue from evaporation is then dried, under reduced pressure if desired, disintegrated, preferably by grinding, and sieved when necessary.
Suitable inert solvents are, for example: dichloromethane , chloroform, carbon tetrachloride, methanol, ethanol, n-propanol , isopropanol, acetone, ethyl acetate, benzene, dioxane, trichlo^thylene , monofluorotrichloromethane , difluorodichloromethane , trifluoromonochloromethane, monofluorodichloromethane, difl oromonochloromethane , 1 ,2 ,2-trifluorotrichloroethane , 1,1,2,2-tetrafluorodichloroethane , and octafluorocyclobutane or mixtures thereof. It is also possible to dissolve the derivative active substance and the aa-e iai in differen inert solvents which are miscible with one another and then combine the solutions. The combination of dichloromethane and methanol has proved particularly successful, v In many cases it is advantageous to incorporate further additives. Such additives can either be added to the initial solution or to the m ture; before or during the grinding process. Such additives are, for example: anti-oxidants , such as a-tocopherol, ascorbyl b yl hydroxp palmitate, butyl hydrox oluene or In U.S. Patent No. 2, 555,463 there is described finely dispersing a method of embeadiag sodium pantothenate in water-soluble cellulose derivatives. Sodium pantothenate, however, is a water-soluble hygroscopic substance, and dispersing a particular advantage of the es edd-i-ftg is stated to be •the reduction of the hygroscopic properties of sodium pantothenate. It cannot be inferred from this U.S. Patent, however, that the product which is obtained finely dispersing by eia¾ed .as a non-hygroscopic active substance which is difficultly soluble in water in a cellulose derivative would be distinguished by good stability. Furthermore the cellulose derivatives mentioned in the U.S. Patent are not soluble in inert solvents other than water. If the manner of operation indicated in the U.S. Patent is applied to the active substances of the present invention, a two-phase system has to be employed; it is then not possible to obtain a molecularly dispersed distribution ί dispersion matrix of the active substance in the eabediiHg iae?e¾»4el and the properties of the embedded products obtained do not conform to the desired requirements of the present invention.
The em edded products obtained according to the invention can be further worked up in the usual way into any of the pharmaceutical formulations which are suitable for application in any of the body cavities (oral, rectal or vaginal). Suitable formulations are, for example i tablets , pills , dragees , beads , capsules , granules, suppositories, ovules and styli. They may, if necessary, be sterilised and/or mixed with auxiliary substances, for example with preserving, stabilising, lubricating, wetting or disintegrating agents or with buffer substances. Also, if desired, substances may be added which retard the solubility of the embedded product in water, e.g. ethyl cellulose, shellac, and cellulose acetate phthalate; in thin way depot or slow-release effects can be obtained.
The -embedded products prepared by the method according to the invention, because they are physiologically harmless, can also be added, to foodstuffs or feeding stuffs. They may, for example, be used to vitaminise foodstuffs or feeding stuffs.
In order that the invention may be more fully understood, the following examples are given by way of illustration only;- * SamgleJL . : - . 134- g Hydroxypropyl methyl cellulose were dissolved in 31. chloroform and the solution was then mixed with 21. ethanol, 2 g Calciferol (vitamin E>2) were also dissolved in 200 ml dichloromethane and g butyl hydroxyanisol were added. The two solutions were combined and 60 g calcium silicate were added thereto. Thorough mixing was carried out and the resultant gel was poured on to enamel trays to form a layer thereon having a thickness of from 0,5 to 2 cm. The product gel layer was freed of solvents in a vacuum cabinet, which the heat was transmitted directly to the trays, _ at about 0°C and a pressure of 20 to 50 mm. Hg. After. most of the solvent had been evaporated, the mass was disintegrated to a preparation having a particle size of 1 to 5 Em and again dried under the conditions indicated. After "all the solvent had been removed, further disintegration was carried out in a mill to a particle size of 0.5 to 1 mm.
A still finer disintegration cran then be carried out in a high-speed mill to a particle size of approximately 0 to 500μ. The temperature in the various grinding processes should not exceed -4-5°C. - The powder obtained can be worked up in the usual way, e.g. into tablets.
Example 2 To a mixture of 53.5 g hydroxypropyl methyl 7 cellulose, 1.2 litres chloroform and 0.8 litres methanol there was added a solution of S cholecalciferol (vitamin D^) and 1.5 g butyl hydroxytoluene in 500 ml chloroform. While stirring well, 0 g highly dispersed silicic acid were added in portions and the resulting mixture was then further treated to form a fine, dr powder, as described in Example 1.
Example 3 2 g Vitamin D^-cholesterol (molecular compound 1 : 1) , 1.8 g butyl hydroxyanisol and 2 g a-tocopherol were dissolved in 1 litre dichloromethane. 700 ml Methanol and then, with continuous stirring, 44.2 g methyl cellulose were added. Stirring was continued until a homogenous gel had formed* 50 g Highly dispersed silicic acid were then added in portions with further stirring, care being taken that a lump-free, homogenous, gel-like mixture was formed. The mixture was then further processed as in Example 1 , Example 4 A product containing: It,*¾-diacetyl-thio-l¾» methyl-testosterone 10 g highly dispersed silicic acid 20 g and methyl cellulose 70 g was prepared in a similar manner to Example 3 « 2 litres dichloromethane and 1 litre methanol were used as solvents.
Example 5 1 g Ethinyl oestradiol was dissolved in 1.2 litres dichloromethane. 5 g Methyl cellulose were added to the solution with stirring, then 1 litre acetone and · finally 49 g calcium silicate were added in portions, stirring being continued until a homogenous gel had formed, Further processing was carried out as in Example 1.
Example 6 In a similar manner to Example 4, a product containing 33. 3 g chloramphenicol and 66.7 g methyl cellulose was prepared, 1.6 litres trichloroethylene and 1 litre iso ro anol bein used as solvents.

Claims (1)

1. HOW particularly described and tained the nature said invention in what manner the same is to be we declare that What we claim A method of producing solid stable preparations of active substances herein finely dispersing which comprises the active substance in a physiologically acceptable cellulose derivative which is soluble or colloidally dispersible in water and soluble in at one inert solvent other than in which the active substance is also A method according to Claim in which the active substance and the cellulose derivative are dissolved separately or together in an inert solvent other than the solutions are combined where the solvent is removed and the residue obtained is A method according to Claim in which removal of the solvent and drying of the residue is effected by spray A method according to an of Claims 1 to in which the active substance is a vitamin a derivative a and antibiotic or a flavouring A method according to Claim in which the active substance is vitamin or E or an ester or addition compound of any of said A method according to any of Claims 1 to in which the cellulose derivative cellulose or hydroxypropylmethyl A method according to any of Claims 1 to in which an ia present with the active A method according to Claim which the is method according to any of Claims 1 to in which highly dispersed silici present with the active Λ method of producing solid stable preparations of active substances herein substantially as herein described in any of the Solid stable preparations of active substances herein when produced by the method claimed in any of the preceding THIS day of arn insufficientOCRQuality
IL25710A 1965-05-18 1966-05-04 Method of preparing solid stable preparations of sensitive active substances IL25710A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DEM0065285 1965-05-18

Publications (1)

Publication Number Publication Date
IL25710A true IL25710A (en) 1970-02-19

Family

ID=7311393

Family Applications (1)

Application Number Title Priority Date Filing Date
IL25710A IL25710A (en) 1965-05-18 1966-05-04 Method of preparing solid stable preparations of sensitive active substances

Country Status (10)

Country Link
BE (1) BE681216A (en)
BR (1) BR6679597D0 (en)
CH (1) CH483201A (en)
DE (1) DE1492034A1 (en)
DK (1) DK113235B (en)
ES (1) ES326829A1 (en)
FR (1) FR1522233A (en)
GB (1) GB1081667A (en)
IL (1) IL25710A (en)
NL (1) NL6605645A (en)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE791458A (en) * 1972-07-31 1973-05-16 Merck & Co Inc MICROENCAPSULE PRODUCT
ZA739543B (en) * 1973-02-16 1975-03-26 Hoffmann La Roche Free-flowing, directly tablettable, pharmaceutically active substances
DE2309202A1 (en) * 1973-02-21 1974-08-29 Schering Ag MEDICINAL FORMS WITH MICRO-ENCAPSULATED MEDICINAL ACTIVE
NL7711916A (en) * 1977-10-29 1979-05-02 Akzo Nv PROCESS FOR PREPARING HIGHLY CONCENTRATED PHARMACEUTICAL PREPARATIONS OF STEROIDS.
NZ189022A (en) * 1977-12-08 1981-11-19 Beecham Group Ltd Pharmaceutically acceptable particles of clavulanates dispersed in a polymeric binder
DE2845326C2 (en) * 1978-10-18 1985-05-23 Beiersdorf Ag, 2000 Hamburg Use of a specific microdisperse, amorphous, porous silica for the production of digoxin-containing tablets with a strongly accelerated release of active ingredient
JPS5668609A (en) 1979-11-07 1981-06-09 Nippon Kayaku Co Ltd Phthalazinol preparation
JPS59155309A (en) * 1983-02-22 1984-09-04 Teijin Ltd Active type vitamin d3 composition and its preparation
GB8608080D0 (en) * 1986-04-02 1986-05-08 Fujisawa Pharmaceutical Co Solid dispersion composition
DE3877331T2 (en) * 1987-11-11 1993-05-27 Pharmascience Lab EXIFON AND A WATER-SOLUBLE POLYMER CONTAINING PHARMACEUTICAL PREPARATION.
JP2525478B2 (en) * 1989-03-01 1996-08-21 帝人株式会社 Active Vitamin D with improved stability (3) Lower solid preparation
FR2741533B1 (en) * 1995-11-28 1998-02-06 Grinda Jean Robert PROCESS FOR THE STABILIZATION OF POLYUNSATURATED FATTY ACIDS AND THE USE OF THESE STABILIZED PRODUCTS IN COSMETOLOGY
US7368138B2 (en) 2002-03-21 2008-05-06 Archer-Daniels-Midland Company Extraction of phytosterols from corn fiber using green solvents
US20040033903A1 (en) * 2002-05-02 2004-02-19 Volker Kuellmer Coated, agglomerated phytochemicals
WO2007068287A1 (en) * 2005-12-15 2007-06-21 Laboratoria Qualiphar Sustained release vitamin preparation
EP1997480A1 (en) * 2007-06-01 2008-12-03 The Jordanian Pharmaceutical Manufacturing Co. Mineral-fiber solid dispersion, method for preparing the same and use thereof as pharmaceutical tableting aid
US8563066B2 (en) 2007-12-17 2013-10-22 New World Pharmaceuticals, Llc Sustained release of nutrients in vivo
CA2713765A1 (en) * 2008-02-06 2009-08-13 Innov'ia Pulverulent composition and a process for preparing the same

Also Published As

Publication number Publication date
GB1081667A (en) 1967-08-31
NL6605645A (en) 1966-11-21
ES326829A1 (en) 1967-07-01
BE681216A (en) 1966-11-18
FR1522233A (en) 1968-04-26
CH483201A (en) 1969-12-31
DK113235B (en) 1969-03-03
DE1492034A1 (en) 1969-02-20
BR6679597D0 (en) 1973-10-23

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