WO2001000177A1 - Retard formulation of amoxicillin for oral administration - Google Patents

Retard formulation of amoxicillin for oral administration Download PDF

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Publication number
WO2001000177A1
WO2001000177A1 PCT/IB2000/000851 IB0000851W WO0100177A1 WO 2001000177 A1 WO2001000177 A1 WO 2001000177A1 IB 0000851 W IB0000851 W IB 0000851W WO 0100177 A1 WO0100177 A1 WO 0100177A1
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WO
WIPO (PCT)
Prior art keywords
amoxicillin
pharmaceutical formulation
formulation according
oral administration
surfactant
Prior art date
Application number
PCT/IB2000/000851
Other languages
French (fr)
Inventor
Vincenzo De Tommaso
Original Assignee
Micio Pharma Chemical Aktiengesellschaft
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Filing date
Publication date
Application filed by Micio Pharma Chemical Aktiengesellschaft filed Critical Micio Pharma Chemical Aktiengesellschaft
Priority to AU52412/00A priority Critical patent/AU5241200A/en
Publication of WO2001000177A1 publication Critical patent/WO2001000177A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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

Definitions

  • the present invention refers to a retard pharmaceutical formulation of amoxicillin.
  • Amoxicillin is a semi-synthetic, widely used, penicillin especially for oral administration, having a broad-spectrum of activity.
  • the orally administered amoxicillin is rapidly adsorbed, reaching, 2 hours after the administration of 250 mg, a peak concentration in the plasma of about 5 ⁇ m/ml.
  • amoxicillin The daily dose of amoxicillin is generally of 3 g for adults and of 100 mg for children per kg of body weight, divided into three administrations.
  • the present invention refers to a retard pharmaceutical formulation of amoxicillin for oral administration, comprising a homogeneous mixture of amoxicillin and one or more polysaccharides.
  • Amoxicillin may be in any state of hydration.
  • the polysacchande is chosen from the group consisting of regenerated cellulose, cellulose ethers or esters, xanthan gum or carrageenan.
  • the cellulose ethers or esters are preferably methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose.
  • amoxicillin trihydrate The ratio between amoxicillin trihydrate and the polysacchande may vary from
  • the formulation may contain a clavulanic acid salt, preferably the potassium salt.
  • the formulation may contain a surfactant, for example a phospholipid, natural or synthetic (hydrogenated phospholipid).
  • a surfactant for example a phospholipid, natural or synthetic (hydrogenated phospholipid).
  • phospholipids are phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine and their hydrogenated forms. Particularly preferred is the hydrogenated phosphatidylcholine.
  • excipients such as stabilizing agents, preservatives, antioxidants, flavouring agents, sweeteners, suspension agents, binders, lubricants and the like, may be present in the formulation.
  • the pharmaceutical preparations may be in the form of tablets, capsules, granules in monodose sachets, or multidose granules.
  • the tablets may be film-coated.
  • a method for the preparation of the formulation of the invention comprises the preparation of granules by mixing, in a suitable mixer, all the raw materials previously sieved and weighted.
  • the thus obtained granules can be: a) directly compressed, for example with oblong pressing punches, in order to obtain tablets to be directly swallowed, or b) compressed, for example with circular pressing punches having a large diameter, and then sieved, and the thus obtained granules can be used in the other forms of pharmaceutical preparations.
  • the thus obtained tablets are then sieved to obtain granules which will be used in the production of the other forms of pharmaceutical preparations.
  • the pharmaceutical formulations according to the present invention provide therapeutic levels of amoxicillin in the blood for 12 hours, therefore two administrations of amoxicillin per day being sufficient. This fact considerably improves the compliance of patients especially in the case of children. Furthermore the levels of amoxicillin in the blood are maintained constant in the course of the time without the sharp variations of concentration stemming from the repeated administrations of amoxicillin
  • Fig.1 shows a graph reporting the plasma concentration of amoxicillin (mg/l), at Example 1 , to five adults.
  • the tablets were obtained according to the method of Example 1 and then coated with a film having the above reported composition.
  • the granules obtained were then mixed with the other excipients.
  • Amoxicillin trihydrate 287 mg (corresponding to 250 mg of amoxicillin)
  • the formulation was prepared according to the method reported for Example 3.
  • Amoxicillin trihydrate 287 mg (corresponding to 250 mg of amoxicillin)
  • the formulation was prepared according to the method reported for Example 3.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention refers to a pharmaceutical formulation of amoxicillin for oral administration, comprising a homogeneous mixture of amoxicillin and one or more polysaccharides, wherein the polysaccharide is selected from the group consisting of regenerated cellulose, cellulose ethers or esters, xanthan gum or carrageenan.

Description

RETARD FORMULATION OF AMOXICILLIN FOR ORAL ADMINISTRATION
The present invention refers to a retard pharmaceutical formulation of amoxicillin.
Amoxicillin is a semi-synthetic, widely used, penicillin especially for oral administration, having a broad-spectrum of activity.
The orally administered amoxicillin is rapidly adsorbed, reaching, 2 hours after the administration of 250 mg, a peak concentration in the plasma of about 5 μm/ml.
The daily dose of amoxicillin is generally of 3 g for adults and of 100 mg for children per kg of body weight, divided into three administrations. Amoxicillin, as the other penicillins, has a relatively short half-life (0.9-2.5 hours) and it is therefore necessary to undertake three administrations per day, regularly spaced out, in order to maintain the therapeutic levels of the antibiotic in the blood.
Obviously, the fact that the antibiotic has to be taken every 8 hours, especially in the case of children, is very inconvenient. Furthermore, the concentration of the antibiotic in the blood widely varies in correlation to the three administrations.
The present invention refers to a retard pharmaceutical formulation of amoxicillin for oral administration, comprising a homogeneous mixture of amoxicillin and one or more polysaccharides.
Amoxicillin may be in any state of hydration.
The polysacchande is chosen from the group consisting of regenerated cellulose, cellulose ethers or esters, xanthan gum or carrageenan.
The cellulose ethers or esters are preferably methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose.
The ratio between amoxicillin trihydrate and the polysacchande may vary from
100:1 to 100:40, preferably from 100:7 to 100:9.
Furthermore the formulation may contain a clavulanic acid salt, preferably the potassium salt.
The formulation may contain a surfactant, for example a phospholipid, natural or synthetic (hydrogenated phospholipid). Examples of phospholipids are phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine and their hydrogenated forms. Particularly preferred is the hydrogenated phosphatidylcholine.
Other excipients, such as stabilizing agents, preservatives, antioxidants, flavouring agents, sweeteners, suspension agents, binders, lubricants and the like, may be present in the formulation.
The pharmaceutical preparations, suitable for oral use, may be in the form of tablets, capsules, granules in monodose sachets, or multidose granules.
The tablets may be film-coated.
The pharmaceutical formulations according to the present invention may be obtained by the methods known to the persons skilled in the art. For example, a method for the preparation of the formulation of the invention, comprises the preparation of granules by mixing, in a suitable mixer, all the raw materials previously sieved and weighted. The thus obtained granules can be: a) directly compressed, for example with oblong pressing punches, in order to obtain tablets to be directly swallowed, or b) compressed, for example with circular pressing punches having a large diameter, and then sieved, and the thus obtained granules can be used in the other forms of pharmaceutical preparations.
In the case of a), wherein the powder is used in order to produce tablets of 1 g of amoxicillin, it is necessary to optimize the compression conditions for obtaining tablets with a hardness of from 7 to 10 kg and an average weight of about 1.4 g ( variable according the title of the active principle). Said tablets may be coated with a film of an aqueous suspension of ethylcellulose, titanium dioxide, polyethylene glycol 4000, polyethylene glycol 6000. In the case of b), wherein the granulate is intended for the production of other forms of oral pharmaceutical preparations, said granules must be compressed, for example with circular pressing punches, by optimizing the compression conditions so as to obtain tablets having a hardness of from 8 to 12 kg. The thus obtained tablets are then sieved to obtain granules which will be used in the production of the other forms of pharmaceutical preparations. The pharmaceutical formulations according to the present invention provide therapeutic levels of amoxicillin in the blood for 12 hours, therefore two administrations of amoxicillin per day being sufficient. This fact considerably improves the compliance of patients especially in the case of children. Furthermore the levels of amoxicillin in the blood are maintained constant in the course of the time without the sharp variations of concentration stemming from the repeated administrations of amoxicillin
Fig.1 shows a graph reporting the plasma concentration of amoxicillin (mg/l), at Example 1 , to five adults.
EXAMPLE 1
1g AMOXICILLIN TABLETS (not coated)
Amoxicillin trihydrate 1148 mg (corresponding to 1g of amoxicillin)
Hydroxypropyl methylcellulose 90 mg
Soybean hydrogenated phosphatidylcholine 70 mg
Sodium carboxymethylcellulose 90 mg
Magnesium stearate 20 mg
2296 g trihydrate amoxicillin, 180 g hydroxypropyl methylcellulose (Methocel K 4M), 140 g soybean hydrogenated phosphatidylcholine (Epikuron 200 SH), 180 g sodium carboxymethylcellulose (Pharmacel XL), 40 g magnesium stearate, previously sieved through a sieve having a hole of 1 mm as net aperture, were placed in a conical mixer.
The thus obtained granules were compressed with oblong pressing punches to obtain tablets to be swallowed.
EXAMPLE 2
1g AMOXICILLIN TABLETS (coated)
Amoxicillin trihydrate 1148 mg (corresponding to 1g of amoxicillin)
Hydroxypropyl methylcellulose 90 mg
Soybean hydrogenated phosphatidylcholine 70 mg Sodium carboxymethylcellulose 90 mg
Magnesium stearate 20 mg
COATING* 32 mg
* Ethylcellulose-titanium dioxide-polyethylene glycol 4000- polyethylene glycol
6000 in the weight ratio 14:14:2:2.
The tablets were obtained according to the method of Example 1 and then coated with a film having the above reported composition.
EXAMPLE 3
AMOXICILLIN GRANULES IN 1 g MONODOSE SACHETS (for adults)
Amoxicillin trihydrate 1148 mg (corresponding to 1g of amoxicillin)
Hydroxypropyl methylcellulose 90 mg
Soybean hydrogenated phosphatidylcholine 70 mg
Sodium carboxymethylcellulose 90 mg
Magnesium stearate 20 mg
Xanthan gum 6 mg
Raspberry flavour 71 mg
Strawberry flavour 25 mg
Sucrose 2498 mg
2296 g trihydrate amoxicillin, 180 g hydroxypropyl methylcellulose (Methocel K
4M), 140g soybean hydrogenated phosphatidylcholine (Epikuron 200 SH), 180 g sodium carboxymethyl cellulose (Pharmacel XL), 40 g magnesium stearate, previously sieved through a sieve having a hole of 1 mm as net aperture, were placed in a conical mixer.
The thus obtained granules were compressed with circular pressing punches, obtaining tablets which were then sieved throuth a sieved having a hole of 0.66 mm as net aperture.
The granules obtained were then mixed with the other excipients.
EXAMPLE 4 AMOXICILLIN GRANULES IN 250 mg MONODOSE SACHETS (for children)
Amoxicillin trihydrate 287 mg (corresponding to 250 mg of amoxicillin)
Hydroxypropyl methylcellulose 22.5 mg
Soybean hydrogenated phosphatidylcholine 17.5 mg
Sodium carboxymethylcellulose 22.5 mg
Magnesium stearate 5 mg
Xanthan gum 3 mg
Raspberry flavour 71 mg
Strawberry flavour 25 mg
Sucrose 3059 mg
The formulation was prepared according to the method reported for Example 3.
EXAMPLE 5
AMOXICILLIN GRANULES TO BE DOSED, 250 mg amoxicillin/3 g granules (bottle containing 50 g)
Amoxicillin trihydrate 287 mg (corresponding to 250 mg of amoxicillin)
Hydroxypropyl methylcellulose 22.5 mg
Soybean hydrogenated phosphatidylcholine 17.5 mg
Sodium carboxymethylcellulose 22.5 mg
Magnesium stearate 5 mg
Xanthan gum 3 mg
Raspberry flavour 71 mg
Strawberry flavour 25 mg
Sucrose 2562 mg
The formulation was prepared according to the method reported for Example 3.
EXAMPLE 6 Dissolution test
The dissolution test was performed according to USP XXIII. The results of the test are reported in the following table, as release percentages at different times, for six tablets (A-F) obtained as reported in the Example 1.
Figure imgf000008_0001

Claims

1) A pharmaceutical formulation of amoxicillin for oral administration, comprising a homogeneous mixture of amoxicillin and one or more polysaccharides.
2) A pharmaceutical formulation according to claim 1 , wherein the polysacchande is selected from the group consisting of regenerated cellulose, cellulose ethers or esters, xanthan gum or carrageenan.
3) A pharmaceutical formulation according to claim 2, wherein the cellulose ethers or esters are methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose.
4) A pharmaceutical formulation according to any one of the preceding claims further containing a clavulanic acid salt.
5) A pharmaceutical formulation according to claim 4 wherein the clavulanic acid salt is the potassium salt.
6) A pharmaceutical formulation according to any one of the preceding claims further containing a surfactant.
7) A pharmaceutical formulation according to claim 6, wherein the surfactant is a phospholipid natural or synthetic (hydrogenated phospholipide).
8) A pharmaceutical formulation according to claim 7 wherein the surfactant is a phospholipid selected from a group consisting of phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine and their hydrogenated forms.
9) A pharmaceutical formulation, according to claim 8, wherein the surfactant is hydrogenated phosphatidylcholine.
10)A pharmaceutical formulation according to any one of the preceding claims further containing one or more excipients. 11)A pharmaceutical formulation according to any one of the preceding claims for oral use.
PCT/IB2000/000851 1999-06-29 2000-06-26 Retard formulation of amoxicillin for oral administration WO2001000177A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU52412/00A AU5241200A (en) 1999-06-29 2000-06-26 Retard formulation of amoxicillin for oral administration

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH120699 1999-06-29
CH1206/99 1999-06-29

Publications (1)

Publication Number Publication Date
WO2001000177A1 true WO2001000177A1 (en) 2001-01-04

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6660299B2 (en) 1999-04-13 2003-12-09 Beecham Pharmaceuticals Limited Modified release pharmaceutical formulation comprising amoxycillin
WO2004019901A2 (en) * 2002-08-30 2004-03-11 Orchid Chemicals & Pharmaceuticals Ltd. Sustained release pharmaceutical composition
US6746692B2 (en) 1999-04-13 2004-06-08 Beecham Pharmaceuticals (Pte) Limited Modified release pharmaceutical formulation comprising amoxycillin
US6756057B2 (en) 2000-10-12 2004-06-29 Beecham Pharmaceuticals (Pte) Limited Amoxicillin and potassium clavulanate dosage form
US6783773B1 (en) 1999-04-13 2004-08-31 Beecham Pharmaceuticals (Pte) Limited Composition comprising amoxicillin and potassium clavulanate
RU2627464C2 (en) * 2010-10-12 2017-08-08 Футамура Кагаку Кабусики Кайся Medical adsorbent and method for its obtaining

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0080862A1 (en) * 1981-12-02 1983-06-08 Beecham Group Plc Pharmaceutical formulation comprising beta-lactam antibiotics
US4448769A (en) * 1981-07-15 1984-05-15 Kanebo Ltd. Ester of 1,1-dioxopenicillanic acid, and use thereof as β-lactamase inhibitor
US5478819A (en) * 1993-06-23 1995-12-26 Simo Tarpila Phospholipid composition and use thereof
WO1997009042A1 (en) * 1995-09-07 1997-03-13 Smithkline Beecham Corporation Pharmaceutical formulation
WO1998022091A1 (en) * 1996-11-17 1998-05-28 Yissum Research Development Company Of The Hebrew University Of Jerusalem PHARMACEUTICAL PREPARATIONS FOR THE CONTROLLED RELEASE OF β-LACTAM ANTIBIOTICS
US5851550A (en) * 1991-05-08 1998-12-22 Smithkline Beecham P.L.C. Pharmaceutical formulations of compacted granulates of β-Lactam antibiotics
WO1999003453A1 (en) * 1997-07-14 1999-01-28 Lek, Tovarna Farmacevtskih In Kemic^¿Nih Izdelkov , D.D. Novel pharmaceutical formulation with controlled release of active substances

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4448769A (en) * 1981-07-15 1984-05-15 Kanebo Ltd. Ester of 1,1-dioxopenicillanic acid, and use thereof as β-lactamase inhibitor
EP0080862A1 (en) * 1981-12-02 1983-06-08 Beecham Group Plc Pharmaceutical formulation comprising beta-lactam antibiotics
US5851550A (en) * 1991-05-08 1998-12-22 Smithkline Beecham P.L.C. Pharmaceutical formulations of compacted granulates of β-Lactam antibiotics
US5478819A (en) * 1993-06-23 1995-12-26 Simo Tarpila Phospholipid composition and use thereof
WO1997009042A1 (en) * 1995-09-07 1997-03-13 Smithkline Beecham Corporation Pharmaceutical formulation
WO1998022091A1 (en) * 1996-11-17 1998-05-28 Yissum Research Development Company Of The Hebrew University Of Jerusalem PHARMACEUTICAL PREPARATIONS FOR THE CONTROLLED RELEASE OF β-LACTAM ANTIBIOTICS
WO1999003453A1 (en) * 1997-07-14 1999-01-28 Lek, Tovarna Farmacevtskih In Kemic^¿Nih Izdelkov , D.D. Novel pharmaceutical formulation with controlled release of active substances

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6660299B2 (en) 1999-04-13 2003-12-09 Beecham Pharmaceuticals Limited Modified release pharmaceutical formulation comprising amoxycillin
US6746692B2 (en) 1999-04-13 2004-06-08 Beecham Pharmaceuticals (Pte) Limited Modified release pharmaceutical formulation comprising amoxycillin
US6783773B1 (en) 1999-04-13 2004-08-31 Beecham Pharmaceuticals (Pte) Limited Composition comprising amoxicillin and potassium clavulanate
US6878386B1 (en) 1999-04-13 2005-04-12 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection comprising amoxycillin and potassium clavulanate
US7217430B2 (en) 1999-04-13 2007-05-15 Beecham Pharmaceuticals (Pte) Limited Compositions and methods of treatment comprising amoxicillin and potassium clavulanate with xanthan
US6756057B2 (en) 2000-10-12 2004-06-29 Beecham Pharmaceuticals (Pte) Limited Amoxicillin and potassium clavulanate dosage form
WO2004019901A2 (en) * 2002-08-30 2004-03-11 Orchid Chemicals & Pharmaceuticals Ltd. Sustained release pharmaceutical composition
WO2004019901A3 (en) * 2002-08-30 2005-05-06 Orchid Chemicals & Pharm Ltd Sustained release pharmaceutical composition
RU2627464C2 (en) * 2010-10-12 2017-08-08 Футамура Кагаку Кабусики Кайся Medical adsorbent and method for its obtaining

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