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AU663000B2 - Adsorbate of an auxiliary mixture and a non-solid active compound for the preparation of pharmaceutical compositions - Google Patents

Adsorbate of an auxiliary mixture and a non-solid active compound for the preparation of pharmaceutical compositions Download PDF

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Publication number
AU663000B2
AU663000B2 AU46262/93A AU4626293A AU663000B2 AU 663000 B2 AU663000 B2 AU 663000B2 AU 46262/93 A AU46262/93 A AU 46262/93A AU 4626293 A AU4626293 A AU 4626293A AU 663000 B2 AU663000 B2 AU 663000B2
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Australia
Prior art keywords
adsorbate
active compound
preparation
pyridine
mixture
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
AU46262/93A
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AU4626293A (en
Inventor
Theophil Hornykiewytsch
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Hoechst AG
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Hoechst AG
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Filing date
Publication date
Application filed by Hoechst AG filed Critical Hoechst AG
Publication of AU4626293A publication Critical patent/AU4626293A/en
Application granted granted Critical
Publication of AU663000B2 publication Critical patent/AU663000B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K9/145—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 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • A61K9/2009—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Pyridine Compounds (AREA)

Description

Rogullor 32(a2)
AUSTRALIA
Patents Act 1990 663ooo
ORIGINAL
COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: n 4 I nvention Title: ADSORBATE OF AN AUXILIARY MIXTURE AND A NON-SOLID ACTIVE COMPOUND FOR THE PREPARTION 0' PHARMACEUTICAL
COMPOSITICNS
The following statement Is a full description of this invention, Including the best method of performing it known to :-US HOECHST AKTIENGESELLSCHAFT HOE 92/F 293 Dr. D/St
DESCRIPTION
Adsorbate of an auxiliary mixture and a non-solid active compound for the preparation of pharmaceutical compositions N,N'-(3-Methoxypropyl)-pyridine-2,4-dicarboxamide (also known as HOE 277), like the other diamides described in EP 0,409,119, is a highly viscous, tacky substance at room temperature, which is strongly hygroscopic.
Pyridine-2,4-dicarboxamides inhibit proline hydroxylase and lysine hydroxylase and are suitable as fibrosuppressants and immunosuppressants (EP 0,409,119).
The object was to process HOE 277 to give tablets for administration to humans using pharmaceutically customary auxiliaries. The format of the tablets should be chosen such that it is also st.ll accepted by patients on the international scale, for example even in Japan. The maximum dimensions prescribed were 15 x 7 mm. The dose should be about 50-100 mg per tablet.
Said substance properties of HOE 277 are very unfavorable for the preparation of tablets and lead, when using a normal recipe and preparation process as is given in pharmaceutical technology handbooks, to a number of difficulties. Inter alia, HOE 277 adhered very strongly to the wall of the apparatus used, for example the mixer.
HOE 277 formed a solid crust on the wall, which was difficult to break down mechanically, with the auxiliaries used. Agglomerate formation in the active compound-auxiliary mixtures or granules led to inhomogeneities of the tablets prepared therefrom. The tablet cores pressed from the granules had only a low hardness and were therefore not very suitable for filmcoating. Film-coating is necessary to mask the bitter taste of the active compound and to protect it from the direct action of light.
-2 The absorption of active compounds on highly disperse SiO 2 has already been repeatedly described (for example EP-B-0,158,120, EP-A-487,335, US Patent 2,879,161, J. Pharm. Sci. 61, 1430 (1972) and J. Pharm. Sci. 73, 401 (1984)). As a rule, this is carried out to increase the solubility of poorly soluble active compounds by increasing the surface area. Two processes for this are described. Either highly disperse SiO 2 is added with stirring to a solution of the active compound until the solution has been completely absorbed by the solid. The Ssolvent can then be removed by drying. Alternatively, the active compound is mixed with the SiO 2 in a suitable mixer and in this way absorbed as homogeneously as possible on the SiO 2 The two processes cannot be used owing to the particular properties of HOE 277. The stirring of SiO, into a solution of HOE 277 in water led to the formation of a pasty mass, which adhered tenaciously to the apparatus and could no longer be stirred.
o* o o 20 The addition of HOE 277 in undiluted form or in aqueous solution to initially introduced SiO 2 leads immediately to the formation of agglomerates or of crusts on the mixing implement and container wall.
*s We have now found that these difficulties can be overcome if a mixture of 10-30% of highly disperse SiO2, 50-70%, for example, of lactose and 0-30%, for example, of cornstarch is initially introduced and the active compound solution is slowly added.
The invention therefore relates to an adsorbate comprising a pyridine-2,4-dicarboxylic acid N,N'-diamide as the active compound, 10-30% of highly disperse silica, to 70% of an inert auxiliary and 0 to 30% of starch.
-3 The adsorbate is suitable for the preparation of pharmaceutical compositions.
The invention further relates to a process for the preparation of an adsorbate, which comprises initially introducing a mixture of 10-30% of highly disperse silica, 50-70% of inert auxiliary and 0-30% of starch and adding an aqueous solution of a pyridine-2,4-dicarboxylic acid N,N'-diamide to this mixture and optionally converting the homogeneous adsorbate obtained into a suitable administration form.
The percentage data are percentages by weight.
The active compound is preferably HOE 277.
The highly disperse SiO 2 particularly has a surface area between 150-400 m 2 /g and a mean size of the primary particles of 6 to 16 nanometers. Pharmaceutically suitable inert auxiliaries are, for example, cellulose and modified cellulose derivatives, sugars, sugar alcohols, Ca phosphates and Ca carbonate, in particular lactose.
Suitable starches are, for example, cornstarch, modified cornstarch, rice starch, potato starch and wheat starch.
The SiO 2 content should be kept as low as possible because of the volume and the other technologically critical properties of the SiO 2 a ratio of 1:1 with the active compound HOE 277 proved to be adequate. The homogeneous adsorbate preferably contains 1-30% of active compound.
A homogeneous adsorbate can be prepared by stepwise addition of a concentrated active compound solution (8 mg of HOE 277 2 mg of H20). This can be poured into hard gelatin capsules or processed further to give tablets or film tablets.
-4- In the preparation of the adsorbate according to the invention, the customarily unpleasant properties of the active compounds are positively used, i.e. the tacky, viscous active compound has the function of a binder in concentrated, aqueous solution.
It has proven advantageous for the properties of the granules and the tablets during conversion into an administration form optionally to admix in dry form an S. actual binder, for example polyvinylpyrrolidone, modified "0 or pregelatinized starch, cellulose derivatives, for C@ example methyl-, hydroxypropyl- or carboxymethylcellulose, polyethylene glycols, to the homogeneous adsorbate and then to prepare the final granules by addition of the amount of water which is still lacking.
A drying operation can be saved by means of the process described. This is advantageous for reasons of time and energy saving.
C
In order to prepare tablet cores having adequate hardness and rapid disintegration, it is necessary to dry the 20 moist granules at high temperature to about 10-20% rel.
humidity before pressing. In the outer phase, the tablet hardness can be distinctly increased during dusting by the addition of about 5% of microcrystalline cellulose.
A further addition (more than 10%) leads to no further improvement.
On account of the bitter taste of the active compound, the tablets prepared from the adsorbate, optionally after granulation, customarily receive a coating film. The coating film consists, for example, of a commercially available film-forming agent, a plasticizer, a pigment and a covering substance.
After the film-coating, an unusual increase in the hardness of about 50% is again observed, which remains without negative effect on the disintegration time.
5 The hardness of tablet cores comprising HOE 277 prepared according to the invention was determined using an Erweka hardness-measuring apparatus. The hardness of the film tablets was also determined according to Examples 1 and 2. The mean values of 10 determinations are shown below.
Dose 40 mg 80 mg Hardness 39 N 52 N Hardness of film tablets 61 N 71 N
S.
9.
Purified water is used as the granulating auxiliary, and 10 also as a solvent or suspending medium for the active compound and the constituents of the film covering and is not a constituent of the finished composition.
3. and 4. are mixed. A concentrated, aqueous solution of 1. is added stepwise to this mixture. The adsorbate is mixed dry with 7. and 8. and, after addition of water, granulated moist and pressed to give tablet cores.
These are then coated with a film covering.
00 0 s* e
OO
oo S. S 5* 0S 0**S 5. 0 0* *5 0 S eQ..
S
OS .9 0
S
S. St 50 S. S
SO
4. 0 0004 0
CS..
4 5 6- Example 1: 40 mg HOE 277 film tablets Composition of a dose unit Substance Amount in the individual dose [mg] 1. HOE 277 40.000 2. Highly disperse silica 40.000 3. Lactose 80.000 4. Cornstarch 30.000 Polyvinylpyrrolidone 10.000 6. Sodium starch glycolate 8.000 7. Microcrystalline cellulose 10.000 8. Magnesium stearate 2.000 Film covering 5.000 225.000 7 Example 2: 80 mg HOE 277 film tablets Composition of a dose unit as ea.:
SO
S
6 0 0 r Substance Amount in the individual dose [mg] 1. HOE 277 80.000 2. Highly disperse silica 80.000 3. Lactose 160.000 4. Cornstarch 60.000 Polyvinylpyrrolidone 20.000 6. Sodium starch glycolate 16.000 7. Microcrystalline cellulose 20.000 8. Magnesium stearate 4.000 Film covering 10.000 450.00 Se 5 4 *500 00 0 0604
S
Purified water is used as the granulating auxiliary, and also as a solvent or suspending medium for the active compound and the constituents of the film covering and is not a constituent of the finished composition.
Preparation is carried out as described in Example 1.
8 Example 3: 40 mg HOE 277 film tablets Composition of a dose unit 10 i 00 d C .5
S
Substance Amount in the individual dose [mg] 1. HOE 277 40.000 2. Highly disperse silica 40.000 3. Lactose 220.000 4. Cornstarch 70.000 Polyvinylpyrrolidone 20.000 6. Sodium starch glycolate 16.000 7. Microcrystalline cellulose 20.000 8. Magnesium stearate 4.000 Film covering 10.000 440.00 Purified water is used as the granulating auxiliary, and also as a solvent or suspending medium for the active compound and the constituents of the film covering and is not a constituent of the finished composition.
Preparation is carried out analagously to Example 1.
The film tablets according to Examples 1 to 3 are stable.

Claims (4)

1. An adsorbate comprising 1 to 30% of a pyridine-2,4-dicarboxylic acid N, N'-diamide as the active compound, 10-30% of highly disperse silica, 50 to of an inert auxiliary and 0 to 30% of starch and, if appropriate, other additives.
2. An adsorbate comprising 1 to 30% of N,N'-(3-methoxypropyl)-pyridine- 2,4-dicarboxamide as the active compound, 10-30% of highly disperse silica, to 70% of lactose and 0 to 30% of cornstarch.
3. A process for the preparation of an adsorbate, comprising 1 to 30% of a pyridine-2,4-dicarboxylic acid N,N'-diamide, which comprises initially introducing a mixture of 10-30% of highly disperse silica, 50-70% of inert auxiliary and 0 to 30% of starch and adding an aqueous solution of a pyridine- :o 2,4-dicarboxylic acid N,N'-diamide to this mixture and optionally converting the homogeneous adsorbate obtained into a suitable administration form.
4. The process as claimed in claim 3, wherein the actual binder is admixed to the homogeneous adsorbate, then the mixture is granulated moist and the granules are dried. DATED this 29th day of June, 1995 HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTOrtIA 3122 AUSTRALIA 1 Abstract HOE 92/F 293 Adsorbate of an auxiliary mixture ;.nd a non-solid active compound for the preparation of pharmaceutical compositions An adsorbate comprising a pyridine-2,4-dicarboxylic acid N,N'-diamide as the active compound, 10-30% of highly disperse silica, 50 to 70% of an inert auxiliary and 0 to if starch and, if appropriate, other additives, and a process for thp preparation of this adsorbate are described. 0 6 0* 0
AU46262/93A 1992-09-11 1993-09-10 Adsorbate of an auxiliary mixture and a non-solid active compound for the preparation of pharmaceutical compositions Ceased AU663000B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4230371 1992-09-11
DE4230371 1992-09-11

Publications (2)

Publication Number Publication Date
AU4626293A AU4626293A (en) 1994-03-17
AU663000B2 true AU663000B2 (en) 1995-09-21

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AU46262/93A Ceased AU663000B2 (en) 1992-09-11 1993-09-10 Adsorbate of an auxiliary mixture and a non-solid active compound for the preparation of pharmaceutical compositions

Country Status (13)

Country Link
EP (1) EP0587137A1 (en)
JP (1) JPH06192093A (en)
KR (1) KR940006583A (en)
AU (1) AU663000B2 (en)
CA (1) CA2105913A1 (en)
FI (1) FI933954A7 (en)
HU (1) HUT67577A (en)
IL (1) IL106953A0 (en)
MX (1) MX9305578A (en)
NO (1) NO933237L (en)
NZ (1) NZ248627A (en)
TW (1) TW222585B (en)
ZA (1) ZA936695B (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1166801A1 (en) * 1993-06-04 2002-01-02 Warner-Lambert Company Preparations containing silicon dioxide to improve the taste thereof
US5626878A (en) * 1995-01-10 1997-05-06 Warner Lambert Company Reduction of electrostatic forces between magnesium trisilicate adsorbates
CZ20012201A3 (en) * 1998-12-18 2001-09-12 Abbott Laboratories Controlled release formulation of divalproex sodium
WO2006000229A2 (en) * 2004-06-28 2006-01-05 Lifecycle Pharma A/S Porous tablets as carriers for liquid formulations

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2879161A (en) * 1956-05-14 1959-03-24 American Cyanamid Co Stable dry powder compositions containing choline chloride and methods of preparing same
EP0158120A1 (en) * 1984-03-13 1985-10-16 BASF Aktiengesellschaft Process for preparing free-flowing cholin-chloride-silicic-acid powders
EP0487335A1 (en) * 1990-11-20 1992-05-27 Montague Cecil Solomon Pharmaceutical dosage forms of dihydropyridines

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3924093A1 (en) * 1989-07-20 1991-02-07 Hoechst Ag N, N'-BIS (ALKOXY-ALKYL) -PYRIDINE-2,4-DICARBONESAUREDIAMIDES, METHOD FOR THE PRODUCTION AND USE THEREOF
DE4020570A1 (en) * 1990-06-28 1992-01-02 Hoechst Ag 2,4- AND 2,5-SUBSTITUTED PYRIDINE-N-OXIDES, METHOD FOR THE PRODUCTION AND USE THEREOF

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2879161A (en) * 1956-05-14 1959-03-24 American Cyanamid Co Stable dry powder compositions containing choline chloride and methods of preparing same
EP0158120A1 (en) * 1984-03-13 1985-10-16 BASF Aktiengesellschaft Process for preparing free-flowing cholin-chloride-silicic-acid powders
EP0487335A1 (en) * 1990-11-20 1992-05-27 Montague Cecil Solomon Pharmaceutical dosage forms of dihydropyridines

Also Published As

Publication number Publication date
NZ248627A (en) 1995-01-27
FI933954A0 (en) 1993-09-09
FI933954L (en) 1994-03-12
MX9305578A (en) 1994-03-31
NO933237L (en) 1994-03-14
TW222585B (en) 1994-04-21
HU9302555D0 (en) 1993-11-29
IL106953A0 (en) 1993-12-28
AU4626293A (en) 1994-03-17
NO933237D0 (en) 1993-09-10
KR940006583A (en) 1994-04-25
EP0587137A1 (en) 1994-03-16
JPH06192093A (en) 1994-07-12
CA2105913A1 (en) 1994-03-12
FI933954A7 (en) 1994-03-12
ZA936695B (en) 1994-04-05
HUT67577A (en) 1995-04-28

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