GB2352172A - Orally administered dose unit comprising a drug with an outer coating of an enteric polymer, which allows co-administered food to separate from the dose unit - Google Patents
Orally administered dose unit comprising a drug with an outer coating of an enteric polymer, which allows co-administered food to separate from the dose unit Download PDFInfo
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- GB2352172A GB2352172A GB0011232A GB0011232A GB2352172A GB 2352172 A GB2352172 A GB 2352172A GB 0011232 A GB0011232 A GB 0011232A GB 0011232 A GB0011232 A GB 0011232A GB 2352172 A GB2352172 A GB 2352172A
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- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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
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Abstract
An orally administrable pharmaceutical dose unit, such as a tablet or capsule, has a size greater than 7 mm and comprises a drug and an outer coating, which coating comprises a polymer material that is insoluble in aqueous solutions with a pH below 4.0 (ie under the acid conditions present in the human stomach). By appropriate selection of the components and thickness of the coating, it is possible for such dose units to be retained intact within the stomach, following their co-administration with a meal, with the dose unit only breaking up to release the drug contained therein when the bulk of the food has emptied into the small intestine. The coating is thus adapted to provide a separation of the dose unit from co-administered food material and disintegration of the dose unit in the stomach, thereby reducing adverse interaction between drug and food. A fail-safe mechanism is provided when the polymer begins to dissolve at a higher pH that is typical of the small intestine (ie pH 5.0 and above). Prefered polymers are enteric polymers such as cellulose acetate trimellitate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), ethyl cellulose and enteric methacrylic acid copolymers (such as 1: 1 copolymer of methacrylic acid and ethyl acrylate). Suitable drugs for use in the dose units include amoxicillin, ampicillin, antipyrine, clodronate and other similar bisphosphonates, ACE inhibitors such as captopril, cilazipril, enalapril, fosinopril, lisinopril, mocxipril, perindopril, quinapril, ramipril and trandolapril, cephalexin, ketoconazole, oxytetracycline, tetracycline, levodopa, methyldopa, methacycline, nafcillin, penicillamine, rifamycin, theophylline, peptidomimetic thrombin inhibitors, such as sampatrilat, and the peptide inhibitor LY303496.
Description
2352172 ORALLY ADMIMSTRABLE DOSE UNITS The present invention relates
generally to orally administrable dose units. More specifically, the present invention relates to orally administrable dose units which comprise a drug and an outer coating that is adapted to provide for separation of the dose unit from co-administered food material and disintegration of the dose unit in the stomach.
The oral administration of drugs is a popular means of therapy. Many io drugs are well absorbed from the small intestines as well as the large intestines and such absorption is unaffected by the co-admirlistration of foods. However, the absorption of certain drugs is affected by the presence of food that is administered either with the dosage form or immediately after or before dosage form administration. These food effects have been well documented in the scientific literature (see Welling, J. Pharmacokinet. Biopharm., 5, 291, 1977; Welling, Pharmac. Ther., 43, 425, 1989; Williams et al., Eur. J. Drug Metab. Pharmacokin., 21, 201, 1996).
For some drugs the presence of food can increase the absorption of the drug into the systemic circulation, whereas for other drugs the food effect is associated with a reduction in absorption. Various mechanisms are known to be responsible for such food effects.
The effect of food increasing drug absorption may be caused by improved dissolution of the drug, which is promoted by a longer residence time in the stomach as well as the stimulation of bile which acts as a surface 1 active agent. The increase may also be due to the preferential transport of the drug into the lymphatic system in the presence of fats and fatty acids. Certain food substances, notably components of grapefruit juice are able to inhibit a metabolic enzyme found in the small intestine and this is 5 known to enhance the absorption of drugs such as cyclosporin.
The opposite effect of food reducing drug absorption can be caused by a variety of different mechanisms. For example, some drugs physically interact or complex with food. This is a well known phenomena for the io bisphosphonates and tetracyclines which can interact with calcium present in dairy products. Drugs can also be physically or chemically attached to food through physical or chemical absorption processes. The drug and food (or digestion products thereof) can also compete for the same absorption pathway. Some drugs are transported in the gastrointestinal tract, not by a process of passive diffusion, but by the exploitation of the pathways responsible for the absorption of dietary peptides. Drugs in this class include the beta-lactam antibiotics and drugs useful in the treattment of cardiovascular diseases, such as the angiotensin converting enzyme (ACE) inhibitor captopril. For example, it is well known that the adsorption of captopril and other ACE inhibitors is reduced in the presence of food (Martindale, 32' Edn., K. Parfitt (ed), Pharmaceutical Press, London, 1999). Another category of drugs for which adsorption is reduced by food are the peptide thrombin inhibitors.
One simple strategy for avoiding food effects is to provide labeling for the patient, which directs that the drug should not be taken together with food and should be preferably administered on a well-fasted stomach. While 2 this may be possible in some clinical situations, it does cause problems in certain patient groups and limits the utility of certain therapeutic products.
For many drugs that suffer from food effects, it would be advantageous if 5 the release of the drug were to occur in the stomach when the food has reached the small intestines. This is particularly the case for those drugs that exploit the di- and tri- peptide absorption pathway, which is known to be located in the upper regions of the small intestine. In this case, it would be greatly advantageous for the food to have passed the preferred io absorption site in the intestines and for the dose unit, e.g. capsule or tablet, to break up in the stomach thereby releasing the drug above the preferred absorption site.
Thus, from the standpoint of patient compliance, marketing and the 15 avoidance of reduced or increased levels of drugs, there is a need for a dosage form that can be administered with a food, or shortly before or after a meal, and subsequently separated from the food, so that a known food effect can be avoided.
The present applicant has found that, in human subjects, it is possible to retain coated dose units, such as tablets and capsules, intact within the stomach following their co-administration with a meal. The dose unit only breaks up to release the drug contained therein when the bulk of the food has emptied into the small intestine.
According to the present invention, there is provided an orally administrable pharmaceutical dose unit of a size greater than 7 mm 3 comprising a drug and an outer coating which comprises a polymer material that is insoluble in aqueous solutions with a pH below 4.0 and that is adapted to provide a separation of the dose unit from coadministered food material and disintegration of the dose unit in the 5 stomach.
The present invention also provides a method for separating a drug from co-administered food which comprises formulating the drug into an orally administrable pharmaceutical dose unit having a size greater than 7 mm io and comprising an outer coating which comprises a polymer material that is insoluble in aqueous solutions with a pH below 4.0 and that is adapted to provide a separation of the dose unit from co-administered food material and disintegration of the dose unit in the stomach.
In a further aspect, the present invention provides for the use of a drug and a coating composition which comprises a polymer material that is insoluble in aqueous solutions with a pH below 4.0 in the manufacture of an orally administrable pharmaceutical dose unit having a size greater than 7 mm and an outer coating comprising the polymer material, wherein the outer coating is adapted to provide a separation of the dose unit from coadministered food material and disintegration of the dose unit in the stomach.
By the term "a size greater than 7 mm", we mean that the dose unit has at least one dimension (e.g. length, width, depth or diameter) of a size greater than 7 mm. Preferably, the dose unit is of a size greater than 10 mm and the largest dimension of the dose unit is of a size less than 20 4 mm. Dose units that have a largest dimension of greater than 30 mm are often unsuitable for oral delivery.
The dose unit can be any shape. Preferably, the dose unit has a conventional shape and is typically a tablet or capsule.
The dose unit of the invention is retained in the stomach while food passes from the stomach into the lower regions of the gastrointestinal tract. In the normal process of digestion, food is mixed with the acid and enzymes io present in the stomach and broken down into small particles. These small particles of food are then expelled through the pylorus into the small intestine. A large intact single dose unit of a size greater than 7 mm will not be removed from the stomach in the fed condition because the pylorus is in a constricted state, and the pylorus will remain in such a constricted state until the bulk of the food has been removed from the stomach and the stomach again reaches a fasted state. Thus, the dose unit can be effectively separated from co-administered food by the stomach provided that the unit survives disintegration within the stomach for a period of time that exceeds the gastric residence time of the food. This allows the known effect of food on the absorption of certain important pharmacological agents to be minimised, which in turn allows drugs whose absorption is affected by the presence of food to be coadministered with food.
In man, the process of emptying foods from the fed stomach into the intestine and the lack of emptying of large non-disintegrating single units from the fed stomach is controlled by a physiological process known as the migrating myoelectric complex (see Szurszewski, Am. J. Physiol., 217, 1757, 1969). After the stomach is empty of food, there is a period of approximately 1 to 1.5 hours before phase 3 of the migrating myoelectric complex removes an intact coated tablet or capsule into the 5 intestines (the so called house-keeper wave).
By appropriate selection of the components making up the dose unit, particularly those making up the coating, as well as the thickness of the coating, it is possible to obtain a dose unit which has a time-dependent io failure in the acidic conditions prevailing in the stomach and which is retained as a single intact unit for a suitable period of time. Thus, break up of the intact dose unit predominantly in the stomach, during the period between the emptying of the food and the onset of the clearance mechanism of the migrating myoelectric complex, can be achieved.
With regard to the coating, despite the insoluble nature of the polymer in aqueous environments having a pH of below 4.0, the coating will tend to exhibit a degree of water permeability. This is true even for coatings made of enteric polymers. The water permeability can be due to the inherent physical/chemical properties of the polymer and/or a result of the structure of the coating. The water permeability of the coating can be controlled by a number of factors, which include the chemical nature of the coating polymer, the type and amount of additives, for example water soluble, pore forming materials may be used, and the thickness of the coating. The technique used to apply the coating may also have an affect. For example, coatings applied using spray apparatus may inherently have a degree of porosity.
6 By exercising control over the degree of water permeability of the coating, it is possible to obtain a coating that will provide for separation of the dose unit from co-administered food material in the stomach as well as disintegration of the dose unit within the stomach before the onset of the clearance mechanism of the migrating myoelectric complex.
Once the food has substantially left the stomach, the dose unit breaks up in the stomach.
Preferably, the polymer coating material is selected from the group consisting of enteric polymers and polymers that are insoluble in aqueous environments at pH values below 4.0 and which can form water permeable coatings which disintegrate at an appropriate rate.
By the term "enteric polymers", we mean materials that are insoluble in the acid conditions present in the human stomach but begin to dissolve at a higher pH that is typical of the small intestine (i.e. pH 5.0 and above).
Enteric polymers are particularly suitable for providing a coated dose unit that resists disintegration in the stomach for a sufficient period of time so that it remains intact in the stomach while much of the food contained in the stomach passes into the small intestine and yet disintegrates in the stomach following the egress of the food to release the drug predominantly in the stomach.
7 By the use of an enteric coating, a fail-safe mechanism is provided, such that if disintegration of the coating is incomplete when the dose unit leaves the stomach, the coat will rapidly dissolve when exposed to the higher pH intestinal fluid. In this way, if the dose unit fails to release the entire amount of drug when in the stomach, it,will still be released in the upper small intestine where absorption can take place.
Enteric coating polymers that are suitable for use in the present invention include cellulose acetate trimellitate (CAT), hydroxypropylmethyl io cellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP) and enteric methacrylic acid copolymers, such as EudragitsO L and S, e.g. EudragitO L 30D (the 1:1 copolymer of methacrylic acid and ethyl acrylate) which begins to dissolve at a pH of 5.6. Preferred enteric coating polymers include methacrylic acid copolymers, hydroxypropylmethyl cellulose phthalate and cellulose acetate phthalate. An especially preferred enteric coating polymer is hydroxypropylmethyl cellulose phthalate.
Another suitable coating polymer is ethyl cellulose.
The coating may optionally contain further ingredients, which may also affect water permeability. Optional ingredients that may be included in the dose unit coating include plasticisers, such as dibutyl sebacate and triacetin, anti-tack agents, such as talc and magnesium stearate, and water soluble pore-forming agents. Suitable pore-forming materials include polyethylene glycols (PEGs), celluloses such as hydroxypropy1cellulose and hydroxypropyhnethy1cellulose and sugars such as lactose, mannitol 8 and dextrose. The nature and amounts of optional ingredients primarily depend on the properties of the enteric polymer and are well known to those skilled in the art. For example, hydroxypropylmethylcellulose phthalate generally requires no additional additives, whereas methacrylic acid copolymers typically require the addition of both a plasticiser and anti-tack agent.
A preferred coating comprises, by weight, 20-100% enteric polymer, 050% plasticiser, 0-80% anti-tack agent and 0-40% pore former. An io especially preferred coating comprises 40-100% enteric polymer, 0-25% plasticiser, 0-60 % anti-tack agent and 0-25 % pore former.
The thickness of the coating is also important to ensure that a controllable rate of water permeation is achieved. If the enteric coating is thin, the rate of water ingress into the dose unit could be too rapid and could result in disintegration of the dose unit and/or significant release of drug before the food has emptied from the stomach.
By using a coating of suitable thickness, it is possible to achieve the 2o desired release of the drug in the stomach when the food is in the lower small intestine. The thickness of the coating layer is preferably between 10 and 200 microns and is more preferably between 20 and 100 microns. An especially preferred coating thickness is between 30 and 90 microns.
The thickness of the coating can be measured by sectioning the dose unit and measuring the layer by light or electron microscopy or by use of a sensitive micrometer to measure dose unit dimensions. In practice, 9 thickness is often determined from the weight gain during the coating process. For example, a coat thickness of approximately 50 to 90 microns is equivalent to a weight gain of 35 to 50 mg per tablet, as measured on a tablet weighing approximately 1 g and of capsule shape 8.5 5 mm width x 21.7 mm length.
Although the composition of the coating and its thickness are the most important considerations when formulating a dose unit which has the required time dependent integrity, the nature of the core or interior of the io dose unit has some relevance. Preferably, the core or interior of the dose unit is not so water sensitive that the integrity of the unit is compromised before the significant proportion of the food has passed from the stomach into the small intestine.
Excipients which can be combined with the drug and used in the manufacture of the dose unit core are those typically used in tablet and capsule formulations and will be known to those skilled in the art. Excipients include diluents, fillers and compression aids, such as microcrystalline cellulose, dicalcium phosphate and lactose, disintegrants such as cross-linked carboxymethy1cellulose, cross-linked povidone and pregelatinised starch, binders such as polyvinylpyrrolidine, gelatin, starch and acacia, and lubricants such as magnesium stearate.
The drug and excipients may be compressed into a tablet or filled into a 25 hard capsule. The hard capsule shell may be made from a pharmaceutically acceptable material, such as gelatin, starch or hydroxypropylmethylcellulose. The preferred composition of the tablet or capsule core is, by weight, 1-90 % drug, 5-95 % diluent/filler/compression aid, 0- 10 % binder, 0. 5-20 % disintegrant and 0. 5-5 % lubricant.
The dose units of the present invention may comprise a variety of drugs that suffer from known food effects. Suitable drugs for use in the present invention include arnoxicillin, ampicillin, antipyrine, clodronate and other similar bisphosphonates, ACE inhibitors such as captopril, cilazipril, enalapril, fosinopril, lisinopril, mocxipril, perindopril, quinapril, ramipril i o and trandolapril, cephalexin, ketoconazole, oxytetracycline, tetracycline, levodopa, methyldopa, methacycline, nafcillin, penicillamine, rifamycin, theophylline and peptidomimetic thrombin inhibitors, such as sampatrilat and the peptide inhibitor LY303496.
The dose units of the present invention are believed to be especially useful for the administration of drugs that are negatively influenced by the presence of food; that is the absorption is decreased in the presence of food. Therefore, drugs that are especially preferred for use in the dose units of the present invention include beta-lactam, antibiotics, peptide-like 2o drugs such as lisinopril and captopril as well as the peptidornimetic thrombin inhibitors. Examples of the latter can be found in the article by Bernatowicz et al., J. Med. Chem., 39, 4879, 1996.
The present invention is now illustrated but not limited with reference to 25 the following Examples.
Example I
Preparation of coated tablets:
LY303496 (Eli Lilly), a thrombin inhibitor, was sieved to a particle size of less than 0.71 mm and 140 g was blended with 69.9 g of microcrystalline cellulose (Avicel PH102) (FMC Corporation) using a Kenwood food mixer. The powder blend was granulated by slowly io adding a solution containing 4 g Kollidon 30 (Povidone-l-vinyl-2 Pyrrolidinone polymer BASF) in 80 ml ethanol. The wet granules were passed through a 1.4 mm sieve, dried at 40C and screened through a 0.25 nun sieve. 135.1 9 of granules were blended with 52.9 g of Avicel, 8 g of Ac-Di-Sol (Croscarmellose Sodium) (FMC Corporation) and 4 g of magnesium stearate (BDH).
0.4 g of Amberlite IRP69 ion-exchange resin (Sodium Polystyrene Sulphonate) (Rohm & Haas) was radiolabelled by adding In-111 chloride solution followed by drying in an oven. To prepare a batch of 30 tablets, the radiolabelled Amberlite was blended with 39.6 g of the LY303496 granules prepared above.
An IR press was set up with capsule-shaped tablet tooling (8.5 mm width x 21.7 mm length). To make each tablet, 1. 1 to 1. 2 g of powder blend was weighed into the tablet die. The tablet was then pressed by hand.
The tablet, weighing 1 g, contained 438 mg of LY303496.
12 The tablets were then mixed with 340 g of similar-shaped placebo tablets and coated with hydroxypropy1methyl cellulose phthalate HPMCP (Shin-Etsu Chemical Co) as follows.
HPMCP (20 g) was dispersed into acetone (220 ml). Ethanol (72 ml) was added and the dispersion was stirred until the HPMCP had dissolved completely.
The coating solution was applied to the tablets using an Aeromatic io STREA-1 (Niro Limited) under the following conditions.
Drying temperature 250C Fan Speed 5 Atomisation pressure I bar To determine the weight gain of the tablets, at intervals throughout the coating process, the drug containing tables were weighed and the amount of (HPMCP) coating applied per tablet was calculated during the process. When the tablets had gained 40 to 45 mg each, they were allowed to dry overnight.
Example In vivo evaluation using gamma scintigraph In order to demonstrate the utility of the invention, a group of I I healthy volunteers was selected and were asked to fast overnight. On the study day they were given the radiolabelled coated tablets (containing 1 MBq Indium- I 11 as label) as described in Example 1, together with a meal 13 containing a radiolabel in the form of technechium-99m. This radiolabel was incorporated into the meal. The meal comprised scrambled eggs containing technetium sulphur colloid labeled with technetium-99m 5 according to the procedure described by Knight et al., J. Nucl. Med., 23 21 (1981). By the use of a dual label it is possible to distinguish between the position and integrity of the coated tablet and the position and spreading of the meal. This was achieved by placing the subject in front of a gamma camera (General Electric Maxi camera) with a field of view lo of 40 cm. The break up of the tablet was visualised on the camera and representative pictures obtained using a data capture method in the form of magnetic tape. By this method it was possible to ascertain when the tablets broke up and whether they broke up in the stomach or in the small intestines. When the tablets broke up it was also possible to ascertain where the food was within the gastrointestinal tract. The results for the 11 subjects are shown in Table 1. It can be seen that in all but one case the tablets were retained in the stomach and the tablets broke up in the stomach releasing their contents. In contrast, the food was found to be largely in the distal small intestine.
14 Table I Scintigraphic evaluation of gastrointestinal transit of food and a HPMCP coated tablet formulation using a dual isotope technique.
Volunteer Position of tablet Time of tablet Position of food at Number disintegration disintegration time of disintegration (indium. label) (hours) (techneflum, label) 1 Stomach 3.05 Small intestine 2 Stomach 3.65 Small intestine (some in stomach) 3 Stomach 3.10 Small intestine (some in stomach) 4 Stomach 4.25 Small intestine Stomach 3.733 Small intestine 6 Stomach 3.183 Small intestine (trace in stomach) 7 Stomach 4.217 Small intestine and stomach 8 Stomach 2.783 Small intestine and stomach 9 Small intestine 3.183 Small intestine Stomach 4.767 Small intestine 11 Stomach 4.15 Small intestine
Claims (15)
1. An orally administrable pharmaceutical dose unit of a size greater than 7 mm comprising a drug and an outer coating which comprises a polymer material that is insoluble in aqueous solutions with a pH below 4. 0 and that is adapted to provide a separation of the dose unit from coadministered food material and disintegration of the dose unit in the stomach.
2. A pharmaceutical dose unit according to Claim 1, which is a tablet or capsule.
3. A pharmaceutical dose unit according to Claim 1 or Claim 2, wherein the polymer material is an enteric polymer.
4. A pharmaceutical dose unit according to Claim 3, wherein the enteric polymer is selected from cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate and methacrylic copolymers.
5. A pharmaceutical dose unit according to Claim 4, wherein the enteric polymer is hydroxypropylmethyl cellulose phthalate.
6. A pharmaceutical dose unit according to any one'of Claims 1 to 5, wherein the coating thickness is between 10 and 200 microns.
7. A pharmaceutical dose unit according to Claim 6, wherein the coating thickness is between 30 and 90 microns.
16
8. A pharmaceutical dose unit according to any one of Claims I to 7, wherein the drug is selected from the group consisting of amoxicillin, ampicillin, antipyrine, clodronate and other similar bisphosphonates, ACE inhibitors, such as captopril, cilazipril, enalapril, fosinopril, lisinopril, mocxipril, perindopril, quinapril, ramipril and trandolapril, cephalexin, ketoconazole, oxytetracycline, tetracycline, levodopa, methyldopa, methacycline, nakillin, penicillamine, rifamycin, theophylline and peptidomimetic thrombin inhibitors.
9. A pharmaceutical dose unit according to Claim 8, wherein the drug is a peptidomimetic thrombin inhibitor.
10. A pharmaceutical dose unit according to Claim 9, wherein the peptide inhibitor is LY303496.
11. A pharmaceutical dose unit according to Claim 8, wherein the drug is an ACE inhibitor.
12. A pharmaceutical dose unit according to Claim 11, wherein the ACE inhibitor is captopril.
13. A method for separating a drug from co-administered food which comprises formulating the drug into an orally administrable pharmaceutical dose unit having a size greater than 7 mm and comprising an outer coating which comprises a polymer material that is insoI uble in aqueous solutions with a pH below 4.0 and that is adapted to provide a separation of the dose unit from co-administered food material and disintegration of the dose unit in the stomach.
17
14. The use of a composition according to any one of Claims 1 to 12, to provide separation of a single unit dose form from food after their coadministration, where the single unit disintegrates in the stomach.
15. The use of a drug and a coating composition which comprises a polymer material that is insoluble in aqueous solutions with a pH below 4.0 in the manufacture of an orally administrable pharmaceutical dose unit having a size greater than 7 mm and an outer coating comprising the material, wherein the outer coating is adapted to provide a separation of the dose unit from co-administered food material and disintegration of the dose unit in the stomach.
18
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GBGB9910773.2A GB9910773D0 (en) | 1999-05-11 | 1999-05-11 | Novel single unit coated dosage forms that can be used to minimise the effect of food on the absorption of drugs from the gastrointestinal tract |
Publications (2)
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GB0011232D0 GB0011232D0 (en) | 2000-06-28 |
GB2352172A true GB2352172A (en) | 2001-01-24 |
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GBGB9910773.2A Ceased GB9910773D0 (en) | 1999-05-11 | 1999-05-11 | Novel single unit coated dosage forms that can be used to minimise the effect of food on the absorption of drugs from the gastrointestinal tract |
GB0011232A Withdrawn GB2352172A (en) | 1999-05-11 | 2000-05-11 | Orally administered dose unit comprising a drug with an outer coating of an enteric polymer, which allows co-administered food to separate from the dose unit |
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GBGB9910773.2A Ceased GB9910773D0 (en) | 1999-05-11 | 1999-05-11 | Novel single unit coated dosage forms that can be used to minimise the effect of food on the absorption of drugs from the gastrointestinal tract |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002051407A1 (en) * | 2000-12-26 | 2002-07-04 | Les Laboratoires Servier | Thermoformable solid pharmaceutical composition for controlled release of perindopril |
FR2841140A1 (en) * | 2002-06-24 | 2003-12-26 | Servier Lab | MICROCAPSULES FOR DELAYED AND CONTROLLED RELEASE OF PERINDOPRIL |
WO2004073747A1 (en) * | 2003-02-24 | 2004-09-02 | Lg Life Sciences Ltd. | Orally administrable pharmaceutical compositions and methods for preventing food-dr ug interaction |
WO2006003043A1 (en) * | 2004-06-25 | 2006-01-12 | Cosmo Technologies Ltd. | Oral antimicrobial pharmceutical compositions |
CN107875136A (en) * | 2017-12-27 | 2018-04-06 | 广州白云山医药集团股份有限公司白云山制药总厂 | A kind of Amoxicillin pharmaceutical preparation and preparation method thereof |
US11458104B1 (en) * | 2018-06-21 | 2022-10-04 | Mission Pharmacal Company | Enteric coated tiopronin tablet |
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EP0460921A2 (en) * | 1990-06-04 | 1991-12-11 | Aicello Chemical Company Limited | Large intestinal dissociative hard capsules |
WO1997037641A1 (en) * | 1996-04-10 | 1997-10-16 | Merck & Co., Inc. | Oral coated active drugs |
WO1999037290A1 (en) * | 1998-01-22 | 1999-07-29 | West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited | Novel dosage form |
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1999
- 1999-05-11 GB GBGB9910773.2A patent/GB9910773D0/en not_active Ceased
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2000
- 2000-05-11 GB GB0011232A patent/GB2352172A/en not_active Withdrawn
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EP0122815A1 (en) * | 1983-04-18 | 1984-10-24 | Sankyo Company Limited | Enteric-soluble preparations and a process for their production |
EP0460921A2 (en) * | 1990-06-04 | 1991-12-11 | Aicello Chemical Company Limited | Large intestinal dissociative hard capsules |
WO1997037641A1 (en) * | 1996-04-10 | 1997-10-16 | Merck & Co., Inc. | Oral coated active drugs |
WO1999037290A1 (en) * | 1998-01-22 | 1999-07-29 | West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited | Novel dosage form |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002051407A1 (en) * | 2000-12-26 | 2002-07-04 | Les Laboratoires Servier | Thermoformable solid pharmaceutical composition for controlled release of perindopril |
CZ297796B6 (en) * | 2000-12-26 | 2007-03-28 | Les Laboratoires Servier | Heat moldable solid pharmaceutical composition with controlled release of perindopril |
HRP20050055B1 (en) * | 2002-06-24 | 2013-11-08 | Les Laboratoires Servier | Microcapsules for the delayed, controlled release of perindopril |
FR2841140A1 (en) * | 2002-06-24 | 2003-12-26 | Servier Lab | MICROCAPSULES FOR DELAYED AND CONTROLLED RELEASE OF PERINDOPRIL |
WO2004000286A1 (en) * | 2002-06-24 | 2003-12-31 | Les Laboratoires Servier | Microcapsules for the delayed, controlled release of perindopril |
EA007571B1 (en) * | 2002-06-24 | 2006-12-29 | Ле Лаборатуар Сервье | Microcapsules for the delayed, controlled release of perindopril |
AP2029A (en) * | 2002-06-24 | 2009-08-24 | Servier Lab | Microcapsules for the delayed, controlled release of perindopril |
WO2004073747A1 (en) * | 2003-02-24 | 2004-09-02 | Lg Life Sciences Ltd. | Orally administrable pharmaceutical compositions and methods for preventing food-dr ug interaction |
WO2006003043A1 (en) * | 2004-06-25 | 2006-01-12 | Cosmo Technologies Ltd. | Oral antimicrobial pharmceutical compositions |
US8263120B2 (en) | 2004-06-25 | 2012-09-11 | Cosmo Technologies Ltd. | Oral antimicrobial pharmaceutical compositions |
US8486446B2 (en) | 2004-06-25 | 2013-07-16 | Cosmo Technologies Ltd. | Oral antimicrobial pharmaceutical compositions |
US8529945B2 (en) | 2004-06-25 | 2013-09-10 | Cosmo Technologies Ltd. | Oral antimicrobial pharmaceutical compositions |
CN1976685B (en) * | 2004-06-25 | 2011-05-18 | 科斯莫科技有限公司 | Oral antimicrobial pharmaceutical compositions |
US8741948B2 (en) | 2004-06-25 | 2014-06-03 | Cosmo Technologies Ltd. | Oral antimicrobial pharmaceutical compositions |
CN107875136A (en) * | 2017-12-27 | 2018-04-06 | 广州白云山医药集团股份有限公司白云山制药总厂 | A kind of Amoxicillin pharmaceutical preparation and preparation method thereof |
CN107875136B (en) * | 2017-12-27 | 2021-03-05 | 广州白云山医药集团股份有限公司白云山制药总厂 | Amoxicillin medicinal preparation and preparation method thereof |
US11458104B1 (en) * | 2018-06-21 | 2022-10-04 | Mission Pharmacal Company | Enteric coated tiopronin tablet |
Also Published As
Publication number | Publication date |
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GB9910773D0 (en) | 1999-07-07 |
GB0011232D0 (en) | 2000-06-28 |
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