NOVEL DOSAGE FORM

Abstract: 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. Preferably, the pharmaceutical dose unit is in the form of a coated tablet or capsule. Conveniently, the outer coating is a polymer. In addition, the invention relates to a method for separating an orally administrable pharmaceutical dose unit from co-administered food, and to the use of said pharmaceutical dose units in medicine.

Description: NOVEL DOSAGE FORM 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 oral route of administration of drugs is a popular means of therapy. Many drugs are well absorbed from the small intestines as well as the large intestines, and such absoφtion is unaffected by the co-administration of foods. However, the absorption of a number of drugs is affected by the presence of food that is administered either with the dosage form or immediately after or before dosage form administration. Such food effects have been well documented in the scientific literature, particularly by Welling and colleagues (e.g. Welling 1977, J. Pharmacokinet. Biopharm. 5, 291-334; Welling 1989, Pharmac. Ther. 43, 425-41; Williams et al. 1996, Eur. J. Drug Metab. Pharmacokin. 21, 201-11). 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. Several different mechanisms are known to be responsible for such food effects. For example, food may increase the absoφtion 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 absoφtion of drugs such as cyclosporin in the presence of grapefruit juice. The opposite effect, i.e. food causing a reduction in drug absoφtion, can also occur through a number of different mechanisms. For example, 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 absoφtion processes. In addition, the drug and food (or digestion products thereof) may compete for the same absoφtion 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 absoφtion of dietary peptides. Drugs in this class include the β-lactam antibiotics and several drugs useful in the treatment of cardiovascular diseases, such as captopril. For the latter example, it has been clearly shown that if 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 absoφtion 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 absoφtion 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 absoφtion of said drug. In particular, 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. We have found that coating 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. Thus, 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. By this means, 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 absoφtion of important pharmacological agents. Accordingly, 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. By "a pharmaceutical dose unit" we include the meaning of a pharmaceutical formulation or system containing a known amount of a drug. Preferably, the pharmaceutical dose unit is in the form of a tablet or capsule. 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. 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. When the drug is filled into a capsule, 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). By "starch capsules" we include capsules made from starch as well as capsules made from modified starches or starch derivatives. By the term "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. We have found that in human subjects it is possible to retain coated dose units intact within the stomach following their co-administration with a meal. The tablet or capsule only breaks up to release the drug contained therein when the bulk of the food material within the stomach has emptied into the small intestine. 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. around pH 2.0), but are insoluble or dissolve more slowly in the presence of food, where the pH of the stomach is increased to about pH 4.5 to 5.5 due to the slight buffering effect of food material. Since the coating material does not dissolve, or dissolves slowly, in the fed stomach, the coated dose unit (tablet or capsule) retains its integrity, and does not break up and disperse its contents in the presence of food. Conveniently, the coating material is a polymer, preferably a methacrylate polymer. In a preferred embodiment of the present invention, 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. Separation of an orally-administered pharmaceutical dose unit from co- administered food can be achieved for pharmaceutical dose units greater than about 7 mm in size. By "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. During the normal process of digestion, food is mixed with acid and enzymes present in the stomach, and is subsequently broken down into small particles. These small particles of food are expelled through the pylorus into the small intestine. In contrast, a dose unit in the form of a coated capsule or tablet greater than 7 mm in size is not removed from the stomach in the fed condition because the pylorus is in a constricted state. The pylorus remains in a constricted state until the bulk of the food has been removed from the stomach such that the stomach again reaches a fasted state. The mechanisms involved in emptying food from the fed stomach into the intestine and preventing the emptying of large, intact single units from the fed stomach have been well discussed in the literature. It is known, for example, that an indigestible single unit will remain in the stomach until the food has been removed to the small 7 intestine. In man, a physiological process known as the migrating myoelectric complex is known to control this process (Szurszewski 1969, Am. J. Physiol. 217, 1757-63). Hence, after the stomach is empty of food, there will be a period of approximately \ - V- hours before phase 3 of the migrating myoelectric complex removes an intact coated tablet or capsule into the intestines. Thus, provided the drug is contained in a non- disintegrating single unit for a suitable period of time, the stomach will effectively permit separation of the encapsulated drug from the co- administered food. For many drugs that are vulnerable to food effects, it would be advantageous if 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 absoφtion site in the intestines and for the capsule or tablet to break up in the stomach, thereby releasing the drug upstream from the preferred absoφtion site. We have found that this break up 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 by the careful choice of size of the administered single unit and the coating polymer. We have particularly found that a polymer coating that is soluble within the pH range 2.5 - 4.0 can provide the desired effect. We believe that this effect is achieved because die polymer is poorly soluble in the stomach contents when in food is present. However, as the food is removed from the stomach, the pH decreases and the polymer therefore begins to dissolve. 8 By using a coating thickness of a suitable size, it is possible to achieve the desired release of the drug in the stomach when the food is in the small intestine. 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 μm, and more preferably between 40 and 100 μm. As a further consequence of the pH buffering effect of food, in the event that the patient takes a second meal shortly after the first, then the capsule will not release its contents until the second meal has also been discharged into the small intestine. In effect, the tablet or capsule is able to discriminate as to whether it is in the presence of food in the stomach or not. 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. We believe the invention to be especially useful for the administration of drugs that are negatively influenced by the presence of food; that is, the absoφtion is decreased in the presence of food. These include, but are not limited due, the β-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. Thus, 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. The invention is now described, but not limited, with reference to the following examples: Example 1 - Preparation of coated starch capsules 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 γ-emitting material in a nuclear reactor. The contents of each capsule were: 10 227 mg captopril 66.5 mg microcrystalline cellulose (Avicel PH 102) 5.5 mg erbium oxide 5.0 mg magnesium stearate The preparation of the Eudragit El 00 coating solution was as follows: 50 g Eudragit E100 25 g talc 20 ml water 730 ml isopropanol Initially, 50 g of Eudragit E100 was weighed into a plastic weighing boat. A solvent mixmre comprising 730 ml of isopropanol and 20 ml of ultrapure water was prepared in a 1 litre measuring cylinder. Into a 1 litre glass bottle was transferred 600 ml of the isopropanol/water solution (130 ml of the ispropanol/ water mixmre was retained in the measuring cylinder). The Eudragit El 00 was then slowly added to the isopropanol/water solution while mixing vigorously with an overhead stirrer. 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: 11 Into the chamber of the Aeromatic STREA-1 coater (standard column) (available from Niro Limited) were placed 55 dmg-containing capsules and 450 g of placebo capsules. The Eudragit ElOO coating solution was applied to the starch capsules using the following coating conditions, with minor modifications as appropriate: Drying temperature 250°C Fan speed 6 Atomisation pressure 1 bar Pump speed Start at 1 , increase to 2 as run proceeds To determine the weight gain of the capsules at intervals throughout the coating process, 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: (i) The surface area of the capsule was calculated according to the equation: Surface area (cm 2 ) = π x diameter (cm) x length (cm) For capsules of size 0, the surface area is 5 cm 2 . 12 (ii) Given that 1 mg of Eudragit ElOO coating solution applied to a surface area of 1 cm 2 yields a layer of 8 μm in thickness, a coat thickness was calculated using the weight gain of the capsule according to the equation: Coat thickness (μm) = weight gain [mg] x 8 surface area (cm 2 ) Hence, in the present example: Coat thickness = (65/5) x 8 = 104 μm Dissolution testing: Three 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. 13 Example 2 - Preparation of coated gelatin capsules 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. Example 3 - Preparation of a coated tablet 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. An increase in weight of the tablets of 55 mg was used as an indication of suitable coating thickness. 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: For circular (discoidal) tablets: Surface area (cm 2 ) = (π x diameter (cm) x height (cm)) + (π x radius 2 (cm 2 )) For oblong tablets: Surface area (cm 2 ) = π x diameter (cm) x length (cm) 14 Example 4 - In vivo evaluation In order to demonstrate the utility of the invention, a group of healthy volunteers was selected and requested to fast overnight. On the study day, they were given radiolabelled, coated capsules (as described in Example 1) together with a meal containing a second radiolabel in the form of technetium-99m. The meal comprised scrambled eggs in which was incoφorated technetium sulphur colloid, labelled with technetium-99m according to the procedure described by Knight et al. (1981), J. Nucl. Med. 23, 21. Using this dual label approach, it was possible to distinguish between the position (and integrity) of the coated capsule and the position (and spreading) of the meal. This was achieved by placing the subject in front of 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. By this method it was possible to ascertain when the capsules broke up and whether they broke up in the stomach or in the small intestines. At the time-point at which the capsules broke up, it was also possible to ascertain the location of the food within the gastrointestinal tract. The results for nine subjects are shown in Table 1. It can be seen that in all but one case the capsules were retained in the stomach where they broke up, releasing their contents. In contrast, the technetium-labelled food was found to be in the distal small intestine or in the colonic region. Interestingly, in the one subject where the capsule was not retained in the stomach, it broke up in the upper regions of the small intestines (probably 15 close to the preferred absoφtion site for drugs exploiting the di- and tri- pedtide pathway) while the food had reached the colon or was located largely at the ileocecal junction. Thus, in all cases, it was demonstrated that effective separation of the drug delivery system from the co- administered food was achieved. 16 TABLE 1 •o 5 --I Separation of Delivery System from Food t*J Dual Isotope Scintigraphy Study - Labelled capsule and labelled food Subject Position of capsule Time (h) Position of Food disintegration (erbium-171 label) (technetium labe -j STO 6.4 dSI/AC 2 STO 2.5 SI 3 STO 2.5 SI 4 SI 6.4 ICJ/AC 5 STO 3.5 SI 6 STO 3.5 SI 7 STO 3.0 SI 8 STO 2.9 SI 9 STO 4.5 SI o H STO - Stomach: SI - small intestine: ICJ - ileocaecal junction: AC - ascending colon: d - distal: O 03 o ©

Claims: Claims: 1. 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. 2. 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. 3. A pharmaceutical dose unit according to claim 1 or 2 in the form of a coated tablet or capsule. 4. A pharmaceutical dose unit according to claim 3, wherein the capsule is fabricated from gelatin, starch or hydroxypropylmethyl cellulose. 5. A pharmaceutical dose unit according to any one of claims 1 to 4, wherein the coating is soluble within the pH range 2.5 to 4.0. 6. A pharmaceutical dose unit according to any one of claims 1 to 5, wherein the coating is a polymer. 7. A pharmaceutical dose unit according to claim 6, wherein the polymer is Eudragit ElOO. 18 8. A pharmaceutical dose unit according to any one of the preceding claims, wherein the size is between 10 mm and 20 mm. 9. A pharmaceutical dose unit according to any one of the preceding claims, wherein the coating has a thickness of between 20 μm and 200 μm. 10. A pharmaceutical dose unit according to claim 9, wherein the coating has a thickness of between 40 and 100 μm. 11. A pharmaceutical dose unit according to any one of the preceding claims, wherein the drug is one whose absoφtion is impaired in the presence of food material. 12. A pharmaceutical dose unit according to claim 11, wherein the drug is a peptidic thrombin inhibitor. 13. A pharmaceutical dose unit according to any one of claims 1 to 10 wherein the drug is selected from a group consisting of amoxicillin, ampicillin, antipyrine, clodronate, bisphosphonates, captopril, cephalexin, ketoconazole, lysinopril, oxytetracycline, tetracycline, levodopa, methyldopa, methacycline, nafcillin, penicillamine, rifamycin, theophylline, and Sampatrilat. 14. A method for separating an orally administrable pharmaceutical dose unit from co-administered food comprising coating said 19 pharmaceutical dose unit with a material that is soluble at pH values below 5.0. 15. A pharmaceutical dose unit according to any one of claims 1 to 13 for use in medicine. 16. The use of a drug and a coating material that is soluble at pH values below 5.0 in the manufacture 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. 20

Inventors: ILLUM LISBETH, WATTS PETER JAMES, ILLUM, LISBETH, WATTS, PETER, JAMES
Applicants: DANBIOSYST UK, ILLUM LISBETH, WATTS PETER JAMES, DANBIOSYST UK LIMITED, ILLUM, LISBETH, WATTS, PETER, JAMES
Application year: 1999
Main classification: A61K9
IPC codes: A61K9, A61K31, A61K47