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IE902629A1 - New oral pharmaceutical dosage form improving¹bioavailability - Google Patents

New oral pharmaceutical dosage form improving¹bioavailability

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Publication number
IE902629A1
IE902629A1 IE262990A IE262990A IE902629A1 IE 902629 A1 IE902629 A1 IE 902629A1 IE 262990 A IE262990 A IE 262990A IE 262990 A IE262990 A IE 262990A IE 902629 A1 IE902629 A1 IE 902629A1
Authority
IE
Ireland
Prior art keywords
pharmaceutical composition
composition according
oxodipine
prosobel
natural proteins
Prior art date
Application number
IE262990A
Original Assignee
Delagrange Lab
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 Delagrange Lab filed Critical Delagrange Lab
Publication of IE902629A1 publication Critical patent/IE902629A1/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
    • A61K31/33—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

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates to a novel pharmaceutical dosage form improving the bioavailability of a medicament. The insertion of natural proteins into the formula brings about a controlled release of the active principle. It enables single-dose forms to be obtained which are applicable, in particular, to dihydropyridines possessing calcium-antagonist properties. These particular forms are useful for producing a daily therapeutic intake.

Description

NEW ORAL PHARMACEUTICAL DOSAGE FORM IMPROVING BIOAVAILABILITY APPLICATION Mo ΐ UNDER ί o^QTION 69 AND RULE 11 / t \ OIL. NO. OF Τ-Ί /ί /hi LABORATOIRES DELAGRANGE, a body corporate organised under the laws of France, of 1, avenue Pierre Brossolette, 91380 CHILLY-MAZARIN, France.
The invention relates to a new pharmaceutical dosage form enabling the bioavailability of medicinal products, and especially those belonging to the category of calcium inhibitors, to be controlled.
Among these inhibitors, dihydropyridine derivatives endowed with valuable cardiovascular properties are limited in their use by problems of dissolution in vivo, and consequently in an aqueous medium.
The Applicant has hence endeavoured to obtain a 10 special pharmaceutical dosage form to match the in vivo release of such active principles to the production of plasma levels sufficient for one daily dose, irrespective of the solubility of these active principles.
The essence of the invention lies in the choice 15 of a specific protein substrate enabling this objective to be attained.
It is known to combine an active principle with a water-soluble crystalline substrate, such as polyethylene glycol or polyvinylpyrrolidone, in the form of a dispersant agent, to obtain sustained release forms as is described, for example, in French Patent 2,565,822. However, the resulting dispersion, converted into tablets or hard gelatin capsules with conventional excipients, undergoes, as stated in the abovementioned patent, 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, blotches, and the like.
Experience showed that the production of these dispersions under known physicochemical conditions generally led to a product in the form of solid lumps which were difficult to grind. Since grinding causes a heating effect, the active principle becomes unstable and runs the risk of an at least partial decomposition. In other cases, sticky substances, difficult to recover and hence incapable of industrial exploitation, are obtained (Stability Problems under special consideration of solid dispersion of drugs, S.T.P. Pharma 1 (7) 660-665 - 2 (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.
The subject of this invention is to propose an oral dosage form of such medicinal products, offering 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.
The example which follows illustrates its practi15 cal importance.
Oxodipine (or methyl ethyl l,4-dihydro-4-(2,3methylenedioxyphenyl)-3,5-pyridinedicarboxylate), 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 low solubility in water appeared to limit its possibilities of use in pharmaceutical compositions.
Now, the use of common means of solubilization, such as non-aqueous 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 an improvement was already obtained by using an oxodipine/polyvinylpyrrolidone coprecipitate, compared with pure oxodipine whose dissolution is slow and limited, thereby resulting 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 good control of the bioavailability over the course of a day. - 3 Figure 1 shows the kinetics of intestinal dissolution in vivo in man of two oxodipine preparations administered orally, namely powder of pure oxodipine and solid solution of oxodipine in polyvinylpyrroli5 done, relative to a reference oral aqueous-alcoholic solution giving 100% absorption, each dosage form containing 20 mg of active principle. It is seen that the powder releases at most 20% of the 20 mg administered, while the solid solution releases 100% of it, which is totally absorbed, almost immediately.
The Applicant discovered, continuing his investigations, that the combination of a solid solution (of oxodipine with polyvinylpyrrolidone, for example) and proteins enabled a satisfactory therapeutic system, ensuring the control of absorption and bioavailability, to be obtained. Among these proteins, two were specifically distinguished since they make it possible to attain, within this combination, the following objectives : - bringing the insoluble matter into solution controlling the release of the soluble matter making available to the body a rapid (loading) dose and a controlled dose improving the dissolution, absorption and bio25 availability 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 Preparation of an oxodipine/polwinvlpvrrolidone coprecipitate ,800 ml of absolute ethanol were introduced into a 20-litre reactor, followed by the portionwise addition, with stirring, of 2,600 g of polyvinylpyrrolidone. The - 4 10 mixture was heated to approximately 30 C to effect complete dissolution and 650 g of oxodipine were added. The mixture was heated gently to approximately 80°C 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 80°C in order to dissolve the product. The mixture was left standing for 24 hours at room temperature (approximately 20°C) and the solution was then evaporated. The product obtained was dried for several hours at 80°C and ground, then sieved through a 400^(sieve.
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 Turbula mixer and homogenized for 10 minutes.
The preparation is mixed with the lubricating components (B) and No. 1 hard gelatin capsules are filled with this mixture.
Reference capsules F (A) Oxodipine coprecipitate 0.050 g (containing 20% or 10 mg of oxodipine) HPMC 15000 0.018 g (hydroxypropylmethylcellulose) PROSOBEL - L 60 0.113 g Maize starch 0.014 g Lactose 0.032 g 0.227 g (B) Talc (2301 - ZA) 0.0022 g Mg stearate (2493-SW) 0.0022 g Per hard gelatin capsule containing 0.2314 g - 5 Reference capsule 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 the physical combination (bonding) of two sub-tablets, (C) rapid-release and (D) slow-release, containing the active principle combined with common excipients, and with PROSOBEL - L85 or - L60 (which give similar results).
The whole constitutes a therapeutic system which permits 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 23.4 ELCEMA - G250 70.1 PRIMOJEL (carboxymethylstarch) 6.5 100 sub-tablet 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 1 100 By way of example, the sub-tablet C contains 5 mg 35 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 - 6 studies .
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 the 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% absorption is not exceeded, which is insufficient.
The hard gelatin capsules F and G (according to Example 2) were administered to 6 healthy volunteers, and the plasma oxodipine levels as well as the percentages of absorbed oxodipine were monitored throughout the 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 corresponding to 3 20 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, 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 6 healthy volunteers. Figure 4 and Table I show the changes in the plasma concentrations, monitored throughout the twentyfour-hour period. The results are compared with those obtained after oral administration of the powder and of the coprecipitate.
Table I -mg tablet 20-mg tablet 25-mg tablet Time (h) Concentration in ng/ml Concentration in ng/ml Concentration 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). - 8 Table II mg powder 20 mg coprecipitate 20-mg tablet Time (h) Concentration in ng/ml Concentration in ng/ml Concentration 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 ng/ml of serum, and that the corresponding curve is - 9 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 TIME (h) 20 rag POWDER COFRECIPITATE 15-mg TABLET 20-mg TABLET ZS-mg 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 BIOAVAILABILITY COMPARED WITH THE SOLUTION 31% 100 86% 92% 88% - 10 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 confirmed by those obtained by the Applicant with other dihydropyridines, and in particular NIFEDIPINE.
Figure 7 shows the parallel behaviour between 10 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 intro30 duced, 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 (18)

1. Process for controlling the bioavailability of an oral medicinal product, which consists in incorporating 10 to 70% by weight of natural proteins into the inactive excipients .
2. Process according to Claim 1, in which the natural proteins are extracted from milk.
3. Process according to one of Claims 1 and 2, in which the natural proteins are PROSOBEL.
4. Pharmaceutical composition having controlled bioavailability, comprising at least one active principle acting as a calcium inhibitor, common excipients and natural proteins .
5. Pharmaceutical composition according to Claim 4, in which the calcium inhibitor is a dihydropyridine.
6. Pharmaceutical composition according to either of Claims 4 and 5, in which the active principle is oxodipine .
7. Pharmaceutical composition according to either of Claims 4 and 5, in which the active principle is nifedipine .
8. Pharmaceutical composition according to any one of Claims 4 to 7, in which the natural proteins are extracted from milk. 9. Pharmaceutical composition according to any one of Claims 4 to 8, in which the natural proteins are
PROSOBEL.
10. Pharmaceutical composition according to any one of Claims 4, 5, 6, 8 and 9, characterized in that it contains oxodipine and PROSOBEL L60.
11. Pharmaceutical composition according to any one of Claims 4, 5, 6, 8 and 9, characterized in that it contains oxodipine and PROSOBEL L85.
12 . Pharmaceutical composition according to any one of Claims 4, 5, 7, 8 and 9, characterized in that it contains nifedipine and PROSOBEL L60.
13. Pharmaceutical composition according to any one of Claims 4, 5, 7, 8 and 9, characterized in that it contains nifedipine and PROSOBEL L85. - 12
14. Pharmaceutical composition according to any one of Claims 4 to 13, characterized in that it is contained in a hard gelatin capsule containing a daily unit dose.
15. Pharmaceutical composition according to any one of Claims 4 to 13, characterized in that it is in the form of a tablet containing a daily unit dose.
16. Pharmaceutical composition according to Claim 15, characterized in that the tablet is bilayer, one of the layers containing the rapid-release loading dose and the other layer being slow-release.
17. A process according to claim 1, substantially as hereinbefore described and exemplified.
18. A pharmaceutical composition according to claim 4, substantially as hereinbefore described and exemplified.
IE262990A 1989-08-07 1990-07-18 New oral pharmaceutical dosage form improving¹bioavailability IE902629A1 (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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IE902629A1 true IE902629A1 (en) 1991-02-27

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EP (1) EP0412877A1 (en)
JP (1) JPH0377819A (en)
KR (1) KR910004181A (en)
CN (1) CN1049455A (en)
AU (1) AU631235B2 (en)
CA (1) CA2022447A1 (en)
CS (1) CS383890A3 (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)
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NO (1) NO903442L (en)
NZ (1) NZ234593A (en)
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KR20030089147A (en) * 2002-05-16 2003-11-21 슈라펫 주식회사 Water bottle for pet

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DK179687D0 (en) * 1987-04-08 1987-04-08 Farma Food As PREPARATION
EP0307097B1 (en) * 1987-09-08 1993-06-09 Takeda Chemical Industries, Ltd. Water-insolubilized cytokines

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PE491A1 (en) 1991-01-26
NO903442D0 (en) 1990-08-06
KR910004181A (en) 1991-03-28
CS276556B6 (en) 1992-06-17
IL95105A0 (en) 1991-06-10
FR2650502B1 (en) 1994-05-27
FR2650502A1 (en) 1991-02-08
HUT55230A (en) 1991-05-28
IN170789B (en) 1992-05-23
MA21923A1 (en) 1991-04-01
LU87777A1 (en) 1990-12-11
HU204997B (en) 1992-03-30
PT94823A (en) 1991-04-18
NZ234593A (en) 1993-04-28
GB9017144D0 (en) 1990-09-19
EP0412877A1 (en) 1991-02-13
ZA905886B (en) 1991-04-24
OA09301A (en) 1992-09-15
JPH0377819A (en) 1991-04-03
CN1049455A (en) 1991-02-27
TNSN90111A1 (en) 1991-03-05
AU631235B2 (en) 1992-11-19
AU6023990A (en) 1991-02-07
GB2234898A (en) 1991-02-20
NO903442L (en) 1991-02-08
CA2022447A1 (en) 1991-02-08
FI903885A0 (en) 1990-08-06
HU904909D0 (en) 1991-01-28
DD297332A5 (en) 1992-01-09
CS383890A3 (en) 1992-06-17
DE4023136A1 (en) 1991-02-14

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