GB2234898A - Oral pharmaceutical dosage form improving bioavailability - Google Patents

Oral pharmaceutical dosage form improving bioavailability Download PDF

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Publication number
GB2234898A
GB2234898A GB9017144A GB9017144A GB2234898A GB 2234898 A GB2234898 A GB 2234898A GB 9017144 A GB9017144 A GB 9017144A GB 9017144 A GB9017144 A GB 9017144A GB 2234898 A GB2234898 A GB 2234898A
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United Kingdom
Prior art keywords
pharmaceutical composition
composition according
prosobel
oxodipine
natural proteins
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Withdrawn
Application number
GB9017144A
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GB9017144D0 (en
Inventor
Denis Besancon
Alain Dufour
Fabrice Egros
Jean-Marc Aiache
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Laboratoires Delagrange SA
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Laboratoires Delagrange SA
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Publication of GB9017144D0 publication Critical patent/GB9017144D0/en
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Withdrawn legal-status Critical Current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
    • A61K31/435—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • 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
    • A61K9/2063—Proteins, e.g. gelatin
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Description

1 ORAL PHARMACEUTICAL DOSAGE FORM IMPROVING BIOAVAILABILITY The invention
is concerned with a pharmaceutical dosage form that enables the bioavailability of medicinal products, especially calcium inhibitors, to be controlled.
The use of dihydropyridine derivatives, which are calcium inhibitors having valuable cardiovascular properties, is limited by problems of dissolution in vivo, and consequently in an aqueous medium.
Research has therefore been carried out to obtain a pharmaceutical dosage form that matches the in vivo release of such active principles with the production of plasma levels sufficient for one daily dose, irrespective of the solubility of these active principles.
The invention is based on the discovery that a specific protein substrate enables such matching to be attained, and in particular that the combination of a solid solution (of oxodipine with polyvinylpyrrolidone, for example) and proteins results in a satisfactory therapeutic system that can ensure the controi of absorption and bioavailability.
It is known that an active principle can be combined with a water-soluble crystalline substrate, such as polyethylene glycol or polyvinylpyrrolidone, in the form of a dispersant, to obtain sustainedrelease forms as is described, for example, in French Patent Specification No. 2,565,822, which, however, states that the resulting dispersion, when converted into tablets or hard gelatin capsules with conventional excipients, undergoes a rapid release of the medicinal product during passage through the stomach unless protected by a fatty acid glyceryl ester, or by an enteric coating, for gastrointestinal absorption. This rapid release generally causes side effects such as headaches and skin blotches.
Experience has shown that the production of these dispersions under known physicochemical conditions generally leads to a product in the form of solid lumps that it is difficult to grind. Since grinding causes heating, the active principle becomes unstable and runs the risk of at least partially decomposing. In other cases, sticky ubstances, which it is difficult to recover and which are hence incapable of -i 2 industrial exploitation, are obtained ["Stability Problems Under Special Consideration of Solid Dispersion of Drugs", S.T.P. Pharma 1 (7) 660-665 (1985)].
The many solutions proposed in the literature have not hitherto succeeded in satisfying the absorption conditions capable of offering immediate cover after ingestion of the medicinal product and of continuing regularly over 24 hours.
This invention provides a pharmaceutical composition having controlled bioavailability, comprising at least one active principle acting as a calcium inhibitor, at least one common excipient and at least one natural protein. This oral dosage form can offer constant cover over 24 hours with a single daily dose, even when these compounds are only sparingly soluble or insoluble in water. Control of bioavailability implies, depending on the case, slowing down or speeding up diffusion, but above all making it regular.
Oxodipine (or methyl ethyl 1,4-dihydro-4-(2,3methylenedioxyphenyl)-3,5pyridinedicarboxylate), which is described in French Patent No. 2,562,069, has evinced a potent calcium inhibitory activity capable of application in the treatment of cardiovascular disorders such as hypertension. However, its iow solubility in water appeared to limit its possibilities of use in pharmaceutical compositions.
However, the use of common means of solubilization, such as nonaqueous solvents (ethanol, for example) or the addition of wetting agents, is not always compatible with an in vivo administration.
A study of the kinetics of dissolution in vitro, carried out'on the one hand in distilled water and on the other hand in intestinal juice, shows that improvement could be obtained by using an oxodipine/polyvinylpyrrolidone coprecipitate rather than pure oxodipine whose dissolution is slow and limited and thus results in a slow and limited absorption in vivo.
However, this solid dispersion has the deficiencies already emphasized in the prior art, that is to say it releases almost all of the active principle intensely and very rapidly, which does not permit of good control of the bioavailability over the course of a day.
Figure 1 of the accompanying drawings shows the kinetics of intestinal dissolution in vivo in man of two known oxodipine 1 It tt X 3 preparations administered orally, namely "powder" of pure oxodipine and "solid solution" of oxodipine in polyvinylpyrrolidone, by comparison with a reference oral aqueous-alcoholic solution giving 100% absorption. Each dosage form contains 20 mg of active principle. It will be seen that the "powder" releases at most 20% of the 20 mg administered, while the "solid solution" releases 100% of it, and this is totally absorbed, almost immediately.
Among the proteins used in accordance with the invention, two were specifically distinguished since they make it possible to bring insoluble matter into solution, control release of the soluble matter, make available to the body a rapid (loading) dose and a controlled dose, and improve the dissolution, absorption and bioavailability in vivo in man.
These natural proteins are extracted from fresh skimmed milk and are marketed under the name PROSOBEL - L 85 and PROSOBEL - L 60.
Tablets and hard gelatin capsules were made, with oxodipine or other dihydropyridines as the active principle. They were then administered orally to healthy volunteers; the plasma levels of active principle were monitored at regular intervals.
Example 1 shows the preparation of a starting material for use in Examples 2 and 3, which illustrate compositions in accordance with the present invention.
Example 1
Preparation of an oxodipine/polyvinylpyrrolidone coprecipitate 5,800 ml of absolute ethanol was introduced into a 20-litre reactor, followed, portionwise with stirring, by 2,600 g of polyvinylpyrrolidone. The mixture was heated to approximately 300C to effect complete dissolution and 650 g of oxodipine was added. The mixture was heated gently to approximately 800C so as to obtain a complete solution, and left to stand.
A few crystals reappeared on the walls of the flask. 1 litre of ethanol was added and the mixture was again brought to 800C in order to dissolve the product. The mixture was left standing for 24 hours at room temperature (approximately 200C) and the solution was then evaporated. The product obtained was dried for several hours at 800C, ground, and sieved through a 400-micron sieve.
f 1 -7, 4 Assay by UV spectrometry gave the following results:
(360 nm) OXODIPINE: 19.9% PVP: 77.6% Residual ethanol 1200 ppm Example 2 Preparation of hard gelatin capsules containing 10 mg of oxodipine The components (A) are introduced into the chamber of a 11Turbulal' mixer and homogenized for 10 minutes. 10 The preparation is mixed with the lubricating components (B) and No. 1 hard gelatin capsules are filled with this mixture. Each capsule contains 0.2314 g, made up as follows:
Reference capsules F (A) Oxodipine coprecipitate (containing 20% or 10 mg of oxodipine HPMC 15000 (hydroxypropylmethylcellulose) PROSOBEL - L 60 Maize starch Lactose (B) Tale (2301 - ZA) Mg stearate (2493-SW) Reference capsule G 0. 050 g 0.050 9 0.113 9 0.014 g 0.032 g 0.227 9 0. 0022 g 0. 0022 g The same quantities and the same components are taken, but PROSOBEL - L 60 is replaced by PROSOBEL - L 85.
Example 3
A single double-layer tablet is produced, consisting of two "sub-tablets", viz. (C) rapid-release and (D) slow-release.
physically combined (bonded). It contains the active principle combined with common excipients and with PROSOBEL - L85 or - L60 (which give similar results).
1 4 91 The whole constitutes a therapeutic system which permits of the controlled release of loading and maintenance doses.
The preferred proportions of these sub-tablets are:
sub-tablet C (in percentage by weight) Oxodipine coprecipitate ELCEMA G250 PRIMOJEL (carboxymethylstarch) 23.4 70.1 6.5 100 sub-table D (in percentage by weight) Oxodipine coprecipitate 22 PROSOBEL (L85 or L60) 50 HPMC 8 Starch 6 Lactose 4 COMPRITOL 8 Talc 1 Mg stearate 1 By way of example, the sub-tablet C contains 5 mg of oxodipine and the sub-tablet D 10, 15 or 20 mg of oxodipine, which makes it possible to have unit dosages containing 15, 20 and 25 mg of oxodipine.
The new pharmaceutical dosage forms according to the invention form the subject of in vitro and in vivo studies, the results of such studies being set out in Figures 1 to 7 of the accompanying drawings, which are described below.
Figure 1 expresses, for the same dose, the percentage of active principle absorbed into the human body (intestinal juice) for pure oxodipine (powder) and oxodipine in a solid solution of oxodipine/polyvinylpyrrolidone coprecipitate (containing 20 of oxodipine). it is seen that, in the case of th-e solid solution, there is immediate and massive release of oxodipine (which causes the side effects already described) while, in the case of pure oxodipine, a 20 6 absorption is not exceeded, which is insufficient.
The hard gelatin capsules F and G (according to Example 2) were administered to six healthy volunteers, and the plasma oxodipine levels as well as the percentages of absorbed oxodipine were monitored through a twenty -four -hour period. The results were compared with those obtained with the known dosage forms (hydroalcoholic solution, coprecipitate and powder of pure oxodipine).
Figure 2 presents the results at 3 hours, and demonstrates maximum concentrations reduced by one half relative to the coprecipitate.
Figure 3 shows that the percentages absorbed from the hard gelatin capsules containing PROSOBEL are intermediate between an excessively rapid (coprecipitate) or excessively slow (powder) absorption, which is evidence of an improved control of absorption with PROSOBEL.
Furthermore, it is seen that the variety of PROSOBEL selected (L60 or L85) does not influence the result in vivo in man.
Tablets according to Example 3, containing 15, 20 and 25 mg of oxodipine, were administered to six healthy volunteers. Figure 4 and Table I show the changes in the plasma concentrations, monitored throughout a twenty-four-hour period. The results are compared with those obtained after oral administration of the powder and of the coprecipitate it t -1 z Table I is 15-mg tablet 20-mg tablet 25-mg tablet Time (h) Concentration Concentration Concentration in ng/ml in ng/ml in ng/ml 0.00 0.0 0.0 0.0 0.17 2.0 1.8 2.9 0.33 10.0 11.9 12.0 0.50 19.5 17.2 16.1 0.66 19.9 18.1 17.0 0.83 17.8 17.1 18.6 1.00 17.0 16.2 15.7 1.25 18.2 14.2 14.4 1.50 16.4 12.8 14.3 2.00 16.0 13.3 12.0 3.00 12.2 13.8 14.4 4.00 8.0 12.5 14.7 6.00 3.7 8.4 9.3 8.00 2.0 4.2 5.5 10.00 1.7 3.4 4.3 12.00 1.6 2.8 3.2 14.00 0.9 2.1 2.8 24.00 - 1.0 1.3 28.00 0.6 0.6 Plasma concentrations observed after single administration of the 15-,, 20- and 25-mg tablets to 6 healthy subjects (mean).
The example of the 20-mg tablet is extended and compared to the same dose in the known dosage forms (Table II).
1 j.
Table II mg powder 20 mg 20-mg tablet coprecipitate Time (h) Concentration Concentration Concentration in nglml in nglml in ng/ml 0.00 0.0 0.0 0.0 0.17 1.2 1.4 1.8 0.33 1.4 28.9 11.9 0.50 2.7 76.3 17.2 0.66 4.2 95.5 18.1 0.83 5.0 93.4 17.1 1.00 6.0 75.8 16.2 1.25 6.8 55.7 14.2 1.50 6.5 43.4 12.8 2.00 6.2 28.2 13.3 3.00 5.1 15.7 13.8 4.00 4.0 10.5 12.5 6.00 2.4 5.0 8.4 8.00 1.6 3.0 4.2 10.00 1.4 2.2 3.4 12.00 1.2 1.9 2.8 14.00 1.0 1.4 2.1 24.00 1.2 1.0 1.0 28.00 - 0.6 Plasma concentrations observed after single oral administration of the three dosage forms of oxodipine in 6 healthy subjects (mean).
This comparison underlines the fact that the controlled levels achieved are truly intermediate between those arising 'from the two known dosage forms (Figure 5), and are perfectly regulated during the 24-hour period. It will be noted, in particular, that, in less than one hour, the coprecipitate induces a blood concentration of 95 nglml of serum. and that the corresponding curve is 1 1 1 T k- is plotted in Figure 5 only from 1 h 50 min (43 ng/ml) for reasons of clarity of the drawing.
Analysis of the results confirms (Figure 6) the good control of the dissolution/absorption of the active principle from the tablet dosage form.
Table III OF DOSE ENTERING THE BODY AFTER ABSORPTION AND PASSAGE THROUGH THE'LIVER T111E (h) 20 ms ZWER WPRECIPITATE 15-M TABLET 1 20-mg TABLET 25-m& TABLET 0.00 - - - - - 0.17 2.5 32 2.4 2.1 5.9 0.33 1.6 60 12.6 12.1 15 0.50 4.5 75 26.2 20.3 23.5 0.66 6.6 87 32.7 24.5 26 0.83 7.0 93 35.5 26 28.1 1.00 9.3 96 38.9 31.9 28.3 1.25 11 96 46.4 31.0 30.5 1.50 11.4 97 50.2 33 32.8 2.00 14.0 97 59.0 41.1 39.2 3.00 16.6 100 68.7 51.0 48.1 4.00 18 100 72.7 61.7 53.7 6.00 19.8 100 74.5 71.1 61.0 8.00 21.2 100 75.6 74.8 63.8 10.00 22.6 100 77.2 78.5 66.6 12.00 23.8 100 79.2 81.1 68.2 RELATIVE 31% 100 86% 92% 88% BIOAVAIL ABILITY COMPARED WITH THE SOLUTION is The results seen in Table III show that the bioavailability of each dosage form is total for the coprecipitate (100%), low for the powder of pure oxodipine (31%) and excellent for the tablets (86 to 92%) after 12 hours.
These results were conf irmed by those obtained by the Applicant with other dihydropyridines, and in particular NIFEDIPINE.
Figure 7 shows the parallel behaviour between oxodipine and nifedipine. The kinetics of dissolution, very rapid for both of these dihydropyridines (in the crude state for nifedipine, which is very soluble in water, and in the state of a coprecipitate for oxodipine), are controlled by the addition of PROSOBEL, in the same formulae as in Examples 2 and 3.
It may be concluded from this that PROSOBEL, very unexpectedly from the standpoint of those skilled in the art, slows down the dissolution in an aqueous medium and enables new and original pharmaceutical dosage forms of dihydropyridines having controlled bioavailability to be obtained.
Naturally, it is not the object of the examples given to limit the invention, the latter being perfectly applicable and efficacious when the mixture containing PROSOBEL is presented in the form of granules, capsules or any solid or semi-solid oral dosage form such as a muco- adhesive gel or a paste, or even a suspension. Depending on the dosage form in question or depending on the solubility in water of the active principle introduced, experience showed that the addition of 10 to 70% of PROSOBEL enabled the bioavailability of the medicinal product to be matched to the desired plasma levels.

Claims (17)

1. A process for controlling the bioavailability of an oral medicinal product, which comprises incorporating 10 to 70% by weight of 5 natural proteins into the inactive excipients.
2. A process according to Claim 1, in which the natural proteins are extracted from milk.
3. A process according to Claim 1 or 2, in which the natural proteins are PROSOBEL.
4. A pharmaceutical composition having controlled bioavailability, comprising at least one active principle acting as a calcium inhibitor, at least one common excipient and at least one natural protein.
5. A pharmaceutical composition according to Claim 4, in which the calcium inhibitor is a dihydropyridine.
6. A pharmaceutical composition according to Claim 5, in which the active principle is oxodipine.
7. A pharmaceutical composition according to Claim 5, in which the active principle is nifedipine.
8. A pharmaceutical composition according to any one of Claims 4 to 7, in which the natural proteins are extracted from milk.
9. A pharmaceutical composition according to Claim 8, in which the 30 natural proteins are PROSOBEL.
10. A pharmaceutical composition according to Claim 6, that contains oxodipine and PROSOBEL L60.
11. A pharmaceutical composition according to Claim 6, that contains oxodipine and PROSOBEL L85.
f Z
12 12. A pharmaceutical composition according to Claim 7, that contains nifedipine and PROSOBEL L60.
t
13. A pharmaceutical composition according to Claim 7, that contains nifedipine and PROSOBEL L85.
A
14. A pharmaceutical composition according to any one of Claims 4 to 13 contained in a hard gelatin capsule containing a daily unit dose.
15. A pharmaceutical composition according to any one of Claims 4 to 13 in the form of a tablet containing a daily unit dose.
16. A pharmaceutical composition according to Claim 15, in which the tablet is bilayer, one of the layers containing a rapid-release loading 15 dose and the other layer being slow-release.
17. A pharmaceutical composition according to Claim 4 substantially as hereinbefore described in Example 2 or 3.
Published 1991 at The Patent Office, State House, 66/71 High Holbom. IA)ndonWC I R47?.FurLher copies may be obtained from.Sales Branch. Unit 6. Nine Mile Point Cwmfehnfach. Cross Keys. Newport. NPI 7HZ. Printed by Multiplex techniques lid, St Mary Cray. Kent
GB9017144A 1989-08-07 1990-08-03 Oral pharmaceutical dosage form improving bioavailability Withdrawn GB2234898A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR8910605A FR2650502B1 (en) 1989-08-07 1989-08-07 NEW ORAL GALENIC FORM IMPROVING BIOAVAILABILITY

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GB9017144D0 GB9017144D0 (en) 1990-09-19
GB2234898A true GB2234898A (en) 1991-02-20

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KR (1) KR910004181A (en)
CN (1) CN1049455A (en)
AU (1) AU631235B2 (en)
CA (1) CA2022447A1 (en)
CS (1) CS276556B6 (en)
DD (1) DD297332A5 (en)
DE (1) DE4023136A1 (en)
FI (1) FI903885A0 (en)
FR (1) FR2650502B1 (en)
GB (1) GB2234898A (en)
HU (1) HU204997B (en)
IE (1) IE902629A1 (en)
IL (1) IL95105A0 (en)
IN (1) IN170789B (en)
LU (1) LU87777A1 (en)
MA (1) MA21923A1 (en)
NO (1) NO903442L (en)
NZ (1) NZ234593A (en)
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DE4221880A1 (en) * 1992-07-03 1994-01-05 Alfatec Pharma Gmbh Solid and liquid solutions of poorly water-soluble drugs
KR20030089147A (en) * 2002-05-16 2003-11-21 슈라펫 주식회사 Water bottle for pet

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EP0219076A2 (en) * 1985-10-11 1987-04-22 Sumitomo Pharmaceuticals Company, Limited Sustained release composition
EP0235363A2 (en) * 1986-03-03 1987-09-09 Yissum Research Development Company Of The Hebrew University Of Jerusalem Sustained release tablets of theophylline
EP0276674A1 (en) * 1987-01-24 1988-08-03 Bayer Ag Parenteral solution
EP0326618A1 (en) * 1987-03-04 1989-08-09 Nippon Hypox Laboratories Incorporated Medicinal composition containing albumin as carrier and process for its preparation

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CA2022447A1 (en) 1991-02-08
TNSN90111A1 (en) 1991-03-05
CS383890A3 (en) 1992-06-17
KR910004181A (en) 1991-03-28
NO903442D0 (en) 1990-08-06
AU6023990A (en) 1991-02-07
LU87777A1 (en) 1990-12-11
IE902629A1 (en) 1991-02-27
NZ234593A (en) 1993-04-28
IN170789B (en) 1992-05-23
DD297332A5 (en) 1992-01-09
CN1049455A (en) 1991-02-27
FI903885A0 (en) 1990-08-06
PT94823A (en) 1991-04-18
CS276556B6 (en) 1992-06-17
AU631235B2 (en) 1992-11-19
HU204997B (en) 1992-03-30
HU904909D0 (en) 1991-01-28
DE4023136A1 (en) 1991-02-14
IL95105A0 (en) 1991-06-10
JPH0377819A (en) 1991-04-03
OA09301A (en) 1992-09-15
NO903442L (en) 1991-02-08
EP0412877A1 (en) 1991-02-13
PE491A1 (en) 1991-01-26
ZA905886B (en) 1991-04-24
GB9017144D0 (en) 1990-09-19
FR2650502A1 (en) 1991-02-08
HUT55230A (en) 1991-05-28
FR2650502B1 (en) 1994-05-27
MA21923A1 (en) 1991-04-01

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