EP1059918A1 - Neue dosierungsform - Google Patents

Neue dosierungsform

Info

Publication number
EP1059918A1
EP1059918A1 EP99901758A EP99901758A EP1059918A1 EP 1059918 A1 EP1059918 A1 EP 1059918A1 EP 99901758 A EP99901758 A EP 99901758A EP 99901758 A EP99901758 A EP 99901758A EP 1059918 A1 EP1059918 A1 EP 1059918A1
Authority
EP
European Patent Office
Prior art keywords
dose unit
pharmaceutical dose
drug
food
coating
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99901758A
Other languages
English (en)
French (fr)
Inventor
Peter James Watts
Lisbeth Illum
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kyowa Kirin Services Ltd
Original Assignee
West Pharmaceutical Services Drug Delivery and Clinical Research Center Ltd
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 West Pharmaceutical Services Drug Delivery and Clinical Research Center Ltd filed Critical West Pharmaceutical Services Drug Delivery and Clinical Research Center Ltd
Publication of EP1059918A1 publication Critical patent/EP1059918A1/de
Withdrawn legal-status Critical Current

Links

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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells

Definitions

  • This invention relates to means for oral delivery of a drug, and specifically to means of avoiding changes in the rate of absorption of an orally-delivered drug in the gastrointestinal tract due to the presence of co- administered food material.
  • 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.
  • food may increase the abso ⁇ tion of certain drugs due to improved dissolution of the drug, an effect which is promoted by a longer residence time of the drug in the stomach, and by stimulation of bile which acts as a surface active agent thereby improving drug dissolution.
  • Alternative mechanisms include the preferential transport of a drug into the lymphatic system in the presence of fats and fatty acids, and the inhibition or reduction of efflux systems, in particular /?-glycoprotein, by specific food materials.
  • An example of this latter case is the enhanced abso ⁇ tion of drugs such as cyclosporin in the presence of grapefruit juice.
  • the opposite effect i.e. food causing a reduction in drug abso ⁇ tion
  • food causing a reduction in drug abso ⁇ tion can also occur through a number of different mechanisms.
  • some drugs physically interact or complex with particular food types. This phenomenon is well known for the bisphosphonates and tetracyclines, which can interact with calcium present in dairy products. Drugs can also be physically or chemically attached to food through various abso ⁇ tion processes. In addition, the drug and food (or digestion products thereof) may compete for the same abso ⁇ tion pathway. Indeed, 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 abso ⁇ tion of dietary peptides.
  • Drugs in this class include the ⁇ -lactam antibiotics and several drugs useful in the treatment of cardiovascular diseases, such as captopril.
  • captopril is administered with foodstuffs high in protein, then the amount of drug reaching the systemic circulation can be greatly reduced.
  • Another category of drugs known to be affected by foods is the peptidic thrombin inhibitors.
  • One simple strategy for avoiding food effects on drug abso ⁇ tion is to provide labelling for the patient that directs that the drug should not be taken together with food, and preferably should be administered on a well- fasted stomach. While this may be possible in some clinical situations, it creates problems in certain patient groups and limits the utility of certain therapeutic products. From the standpoint of patient compliance, marketing and the avoidance of inappropriate levels of drugs, it would be advantageous if a drug could be adrriinistered with a food, or shortly before or after a meal, without the rate of drug abso ⁇ tion being altered.
  • the present invention seeks to provide a means of orally administering a drug which avoids or reduces the effects of co-administered food material on the rate of abso ⁇ tion of said drug.
  • the present invention provides an orally administrable pharmaceutical dose unit of a size greater than 7 mm comprising a drug and an outer coating which is adapted to prevent release of said drug into the stomach or the small intestine when the pharmaceutical dose unit is in the presence of food.
  • the present invention further provides an orally administrable pharmaceutical dose unit of a size greater than 7 mm which comprises a drug and an outer coating wherein the coating is made of a material that is soluble at pH values below 5.0 and is adapted to provide a separation of the pharmaceutical dose unit from co-administered food material.
  • the pharmaceutical dose unit with a suitable material which is insoluble or only sparingly soluble at pH values above 5.0 can allow for retention of the intact dose unit in the upper regions of the gastrointestinal tract, thereby resulting in its separation from co- administered food material.
  • the co-administered food is permitted to proceed along the gastrointestinal tract and so becomes located in the distal regions of the intestine, while the dose unit is retained in the stomach or proximal small intestines where it is subsequently broken down to release its contents.
  • the system provides effective separation of the dose unit from co-administered food, thereby minimising any effect of such food material on the rate of abso ⁇ tion of important pharmacological agents.
  • a preferred embodiment of the present invention provides a pharmaceutical dose unit for oral delivery of a drug comprising said drug and an outer coating wherein the pharmaceutical dose unit has a size greater than 7 mm and wherein the coating is insoluble at pH values above 5.0.
  • a pharmaceutical dose unit we include the meaning of a pharmaceutical formulation or system containing a known amount of a drug.
  • the pharmaceutical dose unit is in the form of a tablet or capsule.
  • the single dose unit When the single dose unit is a tablet, it will have a core comprising the drug and typically one or more further ingredients of the type that are conventionally blended with drugs, such as an excipient, and an outer coating or layer which surrounds the core and comprises a material which prevents release or any substantial release of the drug when the dose unit is in the presence of food, e.g. a material which is insoluble at pH values above 5.0.
  • a core comprising the drug and typically one or more further ingredients of the type that are conventionally blended with drugs, such as an excipient, and an outer coating or layer which surrounds the core and comprises a material which prevents release or any substantial release of the drug when the dose unit is in the presence of food, e.g. a material which is insoluble at pH values above 5.0.
  • the single dose unit When the single dose unit is a capsule, it will have a casing which encloses a compartment containing the drug and typically one or more further ingredients of the type that are conventionally blended with drugs, such as an excipient, and a barrier coating or layer on the outer surface of the casing which comprises a material which prevents release or any substantial release of the drug when the dose unit is in the presence of food, e.g. a material which is insoluble at pH values above 5.0.
  • a barrier coating or layer on the outer surface of the casing which comprises a material which prevents release or any substantial release of the drug when the dose unit is in the presence of food, e.g. a material which is insoluble at pH values above 5.0.
  • any of the capsules which have been fabricated to deliver medicaments to the human body may be employed.
  • Suitable capsules include those made of hard gelatin, starch or hydroxypropylmethyl cellulose.
  • Starch capsules e.g. as described in the United States Pharmacopoeia (USP), are preferred since these offer advantages in coating, i.e. in the storage and stability of the coating layer (PCT/GB95/01458).
  • starch capsules we include capsules made from starch as well as capsules made from modified starches or starch derivatives.
  • derivatives we particularly mean esters and ethers of the parent compound that can be unfunctionalised or functionalised to contain, for example, ionic groupings.
  • Suitable starch derivatives include hydroxyethyl starch, hydroxypropyl starch, carboxymethyl starch, cationic starch, acetylated starch, phosphorylated starch, succinate derivatives of starch and grafted starches.
  • Such starch derivatives are well known and described in the art (for example Modified Starches: Properties and Uses, O. B. Wurzburg, CRC Press Boca Raton (1986)).
  • the starches used should be of food or pharmaceutical quality.
  • the starch capsules can be made by an injection moulding process and typically comprise a body and a cap. The body is filled with the drug and the cap is then attached and sealed. Methods for making starch capsules are well known and are described, for example, in EP-A-118240, WO- 90/05161, EP-A-0304401, WO-92/04408 and GB-2187703.
  • the coating material selected for the invention is not an enteric material.
  • Enteric coatings are defined as those 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 6.0 and above).
  • Suitable coating materials for use in the present invention are those that dissolve in the acid conditions of the fasted stomach (i.e.
  • the coated dose unit (tablet or capsule) retains its integrity, and does not break up and disperse its contents in the presence of food.
  • the coating material is a polymer, preferably a methacrylate polymer.
  • the coating is Eudragit El 00, a polymer of butylmethacrylate, (2-dimethyl aminoethyl) methacrylate, and methylmethacrylate in the weight ratio 1:2: 1 (available from Rohm Pharma, Darmstadt, Germany), which dissolves when the pH falls below 5.
  • Other polymers that would be suitable for use in the present invention include, but are not limited to, polyamino acids and polymeric materials, such as chitosan and poly- galactosamine, the solubility of which increase with a decrease in pH.
  • a size greater than 7 mm we mean that the unit can be of any shape, preferably a conventional shape for a pharmaceutical dose unit (such as a tablet or capsule), which has at least one linear dimension (i.e. length, width or depth) of greater than 7 mm, for example over 10 mm. Conveniently, the largest linear dimension is less than 20 mm. Units having a largest dimension of over 30 mm are generally unsuitable for oral delivery.
  • the food were to be removed to the small intestines and for release of the drug to occur in the stomach. This is particularly the case for those drugs that exploit the di- and tri-peptide pathway, which is known to be located in the upper regions of the small intestine. In this case it would be most advantageous for the food to have passed the preferred abso ⁇ tion site in the intestines and for the capsule or tablet to break up in the stomach, thereby releasing the drug upstream from the preferred abso ⁇ tion site.
  • Coating thickness may be determined by known methods, such as by sectioning dose units and measuring the coat thickness by light or electron microscopy. In practice, coat thickness may be determined by measuring dose unit weight gain during or following the coating process and calculating the coat thickness therefrom.
  • a preferred thickness for the coating is between 20 and 200 ⁇ m, and more preferably between 40 and 100 ⁇ m.
  • a further aspect of the present invention provides a method for separating an orally administrable pharmaceutical dose unit from co-administered food comprising coating said pharmaceutical dose unit with a material that is soluble at pH values below 5.0.
  • An additional aspect of the present invention provides pharmaceutical dose units for use in medicine.
  • the present invention may be used to orally deliver a variety of drugs that suffer from food effects on administration. These include, but are not limited to, the following examples; amoxicillin, ampicillin, antipyrine, clodronate and other similar bisphosphonates, captopril, cephalexin, ketoconazole, lysinopril, oxytetracycline, tetracycline, levodopa, methyldopa, methacycline, nafcillin, penicillamine, rifamycin, theophylline, peptidic thrombin inhibitors and Sampatrilat.
  • the invention is especially useful for the administration of drugs that are negatively influenced by the presence of food; that is, the abso ⁇ tion is decreased in the presence of food.
  • drugs that are negatively influenced by the presence of food; that is, the abso ⁇ tion is decreased in the presence of food.
  • drugs include, but are not limited due, the ⁇ -lactam antibiotics, peptide-like drugs such as lysinopril and captopril, as well as the peptidic thrombin inhibitors. Examples of the latter class of drug can be found in Bernatowicz et al. (1996), J. Med. Chem. 39, 4879.
  • the invention further provides the use of a drug and a coating material that is soluble at pH values below 5.0 in the preparation of an orally administrable pharmaceutical dose unit of a size greater than 7 mm which is adapted to prevent release of the drug into the stomach or the small intestine when the pharmaceutical dose unit is in the presence of food.
  • Starch capsules (size 0) were obtained from Capsugel (Switzerland) and were filled with pharmaceutical excipients together with a radiolabelled marker used to demonstrate capsule break up.
  • the marker chosen was erbium oxide, that can be converted to a ⁇ -emitting material in a nuclear reactor.
  • the contents of each capsule were:
  • microcrystalline cellulose (Avicel PH 102)
  • the preparation of the Eudragit El 00 coating solution was as follows:
  • talc Into a 250 ml beaker was weighed 25 g of talc, to which 80 ml of the retained isopropanol/water solution was added while mixing with a glass rod until a smooth paste was formed. The talc paste was then added to the Eudragit solution, and the remaining isopropanol/water solution was used to rinse the beaker before being added to the Eudragit/talc mixmre.
  • the capsules were then coated with Eudragit E100 solution using an Aeromatic STREA-1 fluidised bed coater, as follows:
  • the dmg-containing capsules were weighed and the amount of Eudragit ElOO coating applied per capsule was calculated. This weight gain figure was then used to calculate the coat thickness on the capsule. When the capsules had gained 65 mg/capsule in weight, the coating process was terminated and the capsules were allowed to dry overnight.
  • Coating thickness can be calculated from the weight gain as follows:
  • the surface area is 5 cm 2 .
  • Coat thickness ( ⁇ m) weight gain [mg] x 8 surface area (cm 2 )
  • Eudragit ElOO-coated capsules were dissolution tested using the Van Kel dissolution apparatus (United States Pharmacopoeia dissolution method 2, using a basket) prior to neutron irradiation. A further five Eudragit ElOO coated capsules were dissolution tested after neutron irradiation.
  • Eudragit ElOO-coated capsules were dissolution tested in pH 5 citric acid-disodium hydrogen phosphate buffer (Mcllvaine's buffer). Dissolution buffer samples (5 ml) were withdrawn at 15-minute intervals for a duration of 180 minutes. Each dissolution sample was placed in a 10 ml screw-top glass bottle for analysis of captopril content by HPLC, as described in Kirschbaum and Perlman (1984) J. Pharm. Sci. 73, 686-7. Results indicated that the capsules did not dissolve at pH 5.0 and that neutron irradiation did not affect the solubility of the Eudragit ElOO coating.
  • Example 1 The procedure described in Example 1 for preparation of starch coated capsules may also be used to coat capsules made from gelatin.
  • Suitable gelatin capsules (size 0) include those obtained from Capsugel, Switzerland.
  • a tablet was prepared from microcrystalline cellulose, containing the same radiolabel (erbium oxide) as described in Example 1 , and 250 mg of captopril.
  • the tablets were circular with a diameter of 15 mm, and were made by compression using the Manesty F3 machine with concave puncmres.
  • the tablets were coated using a solution of polymer Eudragit ElOO, as described in Example 1.
  • Tablet coating thickness can be calculated using the same method as that described in Example 1 , with the following equations being used to calculate surface area:
  • a gamma camera for example a General Electric Maxi camera, field of view 40 cm.
  • the break up of the capsules can be visualised on the camera and representative pictures obtained using a data capture method such as magnetic tape.
  • a data capture method such as magnetic tape.

Landscapes

  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP99901758A 1998-01-22 1999-01-20 Neue dosierungsform Withdrawn EP1059918A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9801363.4A GB9801363D0 (en) 1998-01-22 1998-01-22 Novel dosage form
GB9801363 1998-01-22
PCT/GB1999/000193 WO1999037290A1 (en) 1998-01-22 1999-01-20 Novel dosage form

Publications (1)

Publication Number Publication Date
EP1059918A1 true EP1059918A1 (de) 2000-12-20

Family

ID=10825713

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99901758A Withdrawn EP1059918A1 (de) 1998-01-22 1999-01-20 Neue dosierungsform

Country Status (9)

Country Link
EP (1) EP1059918A1 (de)
JP (1) JP2002501016A (de)
AR (1) AR014467A1 (de)
AU (1) AU2176099A (de)
CA (1) CA2318257A1 (de)
GB (1) GB9801363D0 (de)
NO (1) NO20003640L (de)
WO (1) WO1999037290A1 (de)
ZA (1) ZA99454B (de)

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Also Published As

Publication number Publication date
WO1999037290A1 (en) 1999-07-29
JP2002501016A (ja) 2002-01-15
ZA99454B (en) 2000-10-23
NO20003640D0 (no) 2000-07-14
AU2176099A (en) 1999-08-09
GB9801363D0 (en) 1998-03-18
AR014467A1 (es) 2001-02-28
NO20003640L (no) 2000-09-12
CA2318257A1 (en) 1999-07-29

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