WO1999038496A1

WO1999038496A1 - Fast dissolving pharmaceutical products

Info

Publication number: WO1999038496A1
Application number: PCT/GB1999/000317
Authority: WO
Inventors: Harry Seagar
Original assignee: R.P. Scherer Corporation
Priority date: 1998-01-30
Filing date: 1999-01-29
Publication date: 1999-08-05
Also published as: AU2291899A; GB9802088D0

Abstract

A dosage form for oral administration comprises a solid, fast-dispersing or fast-dissolving matrix carrying a drug of the kind not generally effectively absorbed after conventional oral ingestion. These drugs are referred to as 'non-absorbed drugs'. The dosageform provides for rapid release of the drug and its even distribution over mucosal surfaces in the mouth, pharynx and oesophagus. The drug is particularly adapted for absorption at these sites. The fast-dispersing carrier ensures that the drug is irrevocably dispersed in a patient's mouth, and in active contact with these target sites, enabling its absorption pre-gastrically.

Description

1

FAST DISSOLVING PHARMACEUTICAL PRODUCTS

This invention relates to pharmaceutical products, and particularly to such products suitable for oral ingestion and capable of rapid disintegration in the oral cavity.

A large variety of dosage forms for oral ingestion are known and readily available . Some such dosage forms are used for the controlled delivery and absorption of medicaments to different sites in the gastro-intestinal tract, the requisite control being achieved by the rate at which the carrier for the medicament breaks down and releases it. Thus, fast dispersing carriers are used for such products in which the medicament is to be quickly released. Slower dispersing carriers and carriers resistant to digestion in the gastro-intestinal tract can be used where it is intended that release of the medicament is to be delayed, for example until the product has itself reached the upper or lower intestine. Some drugs are administered orally in the form of a tablet designed to be swallowed whole or a measured amount of a conventional syrup designated to be swallowed rapidly. Drugs administered in this way are absorbed from the gastrointestinal tract, that is, the stomach, the small intestine and the proximal large intestine (colon) , into the hepatic portal system and are presented to the liver before reaching the systemic circulation. The liver is known to be the principal site for conversion of drugs into metabolites, some of which are unwanted. Consequently, this first pass of absorbed drug through the liver results in extensive metabolism of the drug and a significant proportion of the absorbed dose never reaches the systemic circulation. This phenomenon is known as the "first pass effect" and results in a decrease in the bioavailability of drugs administered in this way (see Heinonen et al, Clinical Pharmacology & Therapeutics, 2

Vol . 56 , No . 6 , ( 1994 ) , pp . 742 - 749 ) .

Certain drugs are hydrophobic and exhibit poor bioavailability when taken orally. Some other drugs, and particularly peptide and proteinaceous drugs, mucopolysaccharides, carbohydrates and lipids, are unsuitable for conventional oral delivery for the reason that they would be subject to cleavage by acids and enzymes in the gastrointestinal tract prior to absorption. The present invention is concerned particularly with such drugs; ie, those not generally effectively absorbed after conventional oral ingestion. These drugs will be referred to hereinafter as "non- absorbed drugs" .

The aim of the present invention is to provide a means by which non-absorbed drugs can be taken orally, and targeted to appropriate sites to obtain their absorption pre-gastrically. The target sites for drugs provided in dosage forms according to the invention are the mucosal surfaces in the mouth, pharynx and oesophagus. If a drug can achieve absorption at the pre-gastric target sites, then it avoid the destructive "first pass" via the liver. By achieving pre-gastric absorption they also avoid the stomach, and go straight to the circulatory tissue. According to the invention, a dosage form comprises a solid, fast-dispersing or fast-dissolving matrix carrying a non-absorbed drug. This form provides for rapid release of the drug and its even distribution over the target sites. The drug is particularly adapted for absorption at these sites. The adapted drug can be borne in a fast-dispersing carrier, thereby taking advantage of such carriers, and ensuring that the drug is irrevocably dispersed in a patient's mouth, and in active contact with the target sites. There are various means by which non-absorbed drugs can be adapted for pre-gastric absorption. A principal step in one such adaptation is to provide the drug in 3 particulate form, and with a very low average particle size. In such embodiments of the invention a typical maximum particle size is 400 nanometers, although an average particle size of no greater than 100 nanometers would be preferred. The particle surfaces may themselves be modified to improve the bioavailability of the drug, and examples of means by which the particle surfaces can be so modified are given in PCT Patent Publication Nos. O93/25190; W096/22766; 096/25921; and O97/04756. The nanoparticle technology disclosed in these publications provides means by which the bioavailability of the drugs disclosed can be improved. We have found that by providing them in a dosage form comprising a fast-dispersing or fast-dissolving matrix, the adapted drug can disperse more uniformly and rapidly in the mouth and promote pre-gastric absorption.

Another means by which drugs can be adapted for use in dosage forms according to the invention, is encapsulation in proteinoid microspheres . This microsphere technology is itself known, and reference is directed to U.S. Patent No. 5540939, and PCT Publication Nos. WO94/23702; W094/28878; and WO96/09813. This microsphere encapsulation option can also be taken up when the drug is provided in nanoparticulate form, as described above.

A third option for adapting drugs for incorporation into dosage forms of the invention is to convert the drug into a form which has better absorption characteristics, the drug adapting after the converted form has been absorbed, thereby releasing the drug at the target sites in its native form. Typically, the converted form is an intermediate conformational state between its native and denatured state, in a supramolecular non-covalently bonded complex. Certain drugs can be so converted by exposure to a complexing perturbant, as is described in PCT Publication No. W096/12475, to which once again, reference is directed. 4

This option has the additional advantage that in its converted form the drug can be more stable and better resist enzymatic degradation.

Coated microemulsions or microemulsion preconcentrates or liposomes can also be used to protect drugs from enzymatic degradation, and/or to enhance absorption of the drug in the target sites. It is preferred that dosage forms of the invention disintegrate within 1 to 60 seconds, more preferably 1 to 30 seconds, especially 1 to 10 seconds and particularly 2 to 8 seconds, of being placed in the oral cavity.

With the rapid and frequent clearance of material from the gastrointestinal tract also being a factor, drugs and dosage forms according to the invention will also normally include a mucoadhesive element or substance. Mucoadhesive technology is well established, and some suitable polymeric mucoadhesives are disclosed in PCT Publication No. WO94/20070. Fast-dispersing dosage forms, delivered orally, have been demonstrated to rapidly disperse and coat the mucosal surfaces in the mouth, pharynx and oesophagus. In this respect reference is directed to a paper by Wilson et al published in the International Journal of Pharmaceutics, 40 (1997) pages 119-123. Figure 1 in that paper shows the results of a gamma scintigraphic study. Dosage forms which dissolve rapidly in saliva, without the aid of water, have also been demonstrated to increase the time in which the rapidly dispersed contents are in contact with the target sites within the buccopharyngeal area and increase the time taken to reach the stomach, when compared to tablets and capsules. Reference is directed to a further paper by Wilson et al published in the International Journal of Pharmaceutics, 46 (1998) pages 241-246) ; see particularly Figure 1.

Reference is also directed to a paper by Burton et 5 al published in J. Pharm. Pharmacol 1995. Vol 47, pp 901 - 906. The paper considers the effects of drug adaptation and particular dosage forms on the retention of the respective drug in the oesophagus and in the stomach.

The use of a fast-dispersing dosage form, delivered orally, improves the targeting of drugs to mucous membranes in the mouth, the pharynx and the oesophagus and in turn, the concentration of drug making contact with these tissues. Fast-dispersing dosage forms increase the contact time with the target tissue in the buccopharyngeal and oesophagal area. Furthermore, where drugs are appropriately protected from digestion in the stomach and gut, rapidly dispersed materials will further promote absorption of any drug which reaches the small intestine.

One example of a fast-dispersing dosage form is described in U.S. Patent No. 4855326 in which a melt spinnable carrier agent, such as sugar, is combined with an active ingredient and the resulting mixture spun into a "candy-floss" preparation. The spun "candy-floss" product is then compressed into a rapidly dispersing, highly porous solid dosage form.

U.S. Patent No. 5120549 discloses a fast-dispersing matrix system which is prepared by first solidifying a matrix-forming system dispersed in a first solvent and subsequently contacting the solidified matrix with a second solvent that is substantially miscible with the first solvent at a temperature lower than the solidification point of the first solvent, the matrix- forming elements and active ingredient being substantially insoluble in the second solvent, whereby the first solvent is substantially removed resulting in a fast-dispersing matrix. U.S. Patent No. 5079018 discloses a fast-dispersing dosage form which comprises a porous skeletal structure of a water soluble, hydratable gel or foam forming 6 material that has been hydrated with water, rigidified in the hydrated state with a rigidifying agent and dehydrated with a liquid organic solvent at a temperature of about 0°C or below to leave spaces in place of hydration liquid.

Published International Application No. WO 93/12769 (PCT/JP93/01631) describes fast-dispersing dosage forms of very low density formed by gelling, with agar, aqueous systems containing the matrix-forming elements and active ingredient, and then removing water by forced air, vacuum drying, or other drying systems. U.S. Patent No. 5298261 discloses fast-dispersing dosage forms which comprise a partially collapsed matrix network that has been vacuum-dried above the collapse temperature of the matrix. However, the matrix is preferably at least partially dried below the equilibrium freezing point of the matrix.

U.S. Patent No. 5587180 discloses a particulate support matrix for a tablet, and method for making same, which disintegrates or dissolves in just a few seconds once placed in the oral cavity. The particulate support matrix comprises a first polymeric component which may be a polypeptide, a second polymeric component which may be a different polypeptide, and may be a hydrolyzed gelatin, and a bulking agent.

Published International Application No. WO 91/04757 (PCT/US90/05206) discloses fast-dispersing dosage forms which contain an effervescent disintegration agent designed to effervesce on contact with saliva to provide rapid disintegration of the dosage form and dispersion of the active ingredient in the oral cavity.

The term "fast-dispersing dosage form" therefore encompasses all the types of dosage form described in the preceding paragraphs. However, it is particularly preferred that the fast-dispersing dosage form is of the type described in U.K. Patent No. 1548022, that is, a solid fast-dispersing dosage form comprising a network 7 of the active ingredient and a water-soluble or water- dispersible carrier which is inert towards the active ingredient , the network having been obtained by subliming solvent from a composition in the solid state, that composition comprising the active ingredient and a solution of the carrier in a solvent.

In the case of the preferred type of fast- dispersing dosage form described above, the composition will preferably contain, in addition to the active ingredient, matrix forming agents and secondary components. Matrix forming agents suitable for use in the present invention include materials derived from animal or vegetable proteins, such as the gelatins, dextrins and soy, wheat and psyllium seed proteins; gums such as acacia, guar, agar, and xanthan; polysaccharides; alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and polypeptide/protein or polysaccharide complexes such as gelatin-acacia complexes.

Other matrix forming agents suitable for use in the present invention include sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminium silicates; and amino acids having from 2 to 12 carbon atoms such as a glycine, L-alanine, L-aspartic acid, - glutamic acid, L-hydroxyproline, L-isoleucine, -leucine and L-phenylalanine . One or more matrix forming agents may be incorporated into the solution or suspension prior to solidification. The matrix forming agent may be present in addition to a surfactant or to the exclusion of a surfactant. In addition to forming the matrix, the matrix forming agent may aid in maintaining the dispersion of any active ingredient within the solution or suspension. This is especially helpful in the case 8 of active agents that are not sufficiently soluble in water and must, therefore, be suspended rather than dissolved.

Secondary components such as preservatives, antioxidants, surfactants, viscosity enhancers, colouring agents, flavouring agents, pH modifiers, sweeteners or taste-masking agents may also be incorporated into the composition. Suitable colouring agents include red, black and yellow iron oxides and FD & C dyes such as FD & C blue No. 2 and FD & C red No. 40 available from Ellis & Everard. Suitable flavouring agents include mint, raspberry, liquorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavours and combinations of these. Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Suitable sweeteners include aspartame, acesulfame K and thaumatic. Suitable taste-masking agents include sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds, adsorbates or microencapsulated actives.

Claims

1. A solid unit oral dosage designed to disperse rapidly in the mouth, comprising a matrix carrying a non-absorbed drug form (as herein defined) adapted for pre-gastric absorption.

2. A dosage form according to Claim 1 wherein the non-absorbed drug is one of an hydrophobic drug, a peptide, and a proteinaceous drug. 3. A dosage form according to Claim 1 or Claim 2 wherein the drug is in particulate form with an average particle size no greater than 400 nanometers. . A dosage form according to Claim 3 wherein the surfaces of the particles have been modified to improve the bioavailability of the drug.

5. A dosage form according to Claim 4 wherein the surface modifier comprises a block copolymer.

6. A dosage form according to Claim 5 wherein the block copolymer is linked to at least one ionic group. 7. A dosage form according to Claim 5 wherein the block copolymer contains at least one polyoxyethylene block and at least one polyoxy (higher alkaline) block.

8. A dosage form according to Claim 7 wherein at least some of the blocks are linked by an oxymethylene linking group.

9. A dosage form according to Claim 1 or Claim 2 wherein the drug is encapsulated in proteinoid microspheres .

10. A dosage form according to Claim 9 wherein the proteinoid microspheres include an amine reactive modifying agent.

11. A dosage form according to Claim 9 or Claim 10 wherein the proteinoid microspheres include at least one amino acid. 12. A dosage form according to Claim 11 wherein the microspheres include a plurality of amino acids.

13. A dosage form according to Claim 11 wherein the microspheres include at least one diketopiperazine 10 or at least one mono or di substituted diketopiperazine. 14. A dosage form according to any of Claims 9 to 13 wherein the microspheres comprise diamide- dicarboxylic acids . 15. A dosage form according to Claim 1 or Claim 2 wherein the drug has been converted for transportation into tissues into a form which adapts to its native state within the tissues.

16. A dosage form according to Claim 15 wherein the drug is in an intermediate conformational state between its native and denatured state in a supramolecular complex.

17. A dosage form according to Claim 16 wherein the drug has been converted to said intermediate state by exposure to a complexing perturbant .

18. A dosage form according to any preceding Claim including a mucoadhesive substance.

19. A dosage form according to any preceding Claim in which the solid dispersing form is a low density matrix tablet or water.

20. A dosage form according to Claim 19 wherein the low density matrix is formed by removal of solvent by lyophilisation from a frozen suspension.

21. A dosage form according to Claim 19 wherein the low density matrix is formed by removal of solvent from a frozen suspension by contact with a second solvent, in which the matrix forming materials are insoluble .

22. A dosage form according to Claim 19 wherein the low density matrix is formed by compacting finely divided extruded materials .

23. A dosage form according to Claim 19 wherein the low density matrix is formed by loosely compacting particles formed by spray-coating, spray-drying, lyophilisation, spray-chilling, coacervation, or fluid- bed drying.

24. A dosage form according to Claim 19 wherein the low density matrix is formed by gelling a suspension 11 and then removing solvent by drying.

25. A dosage form according to any preceding Claim wherein the solid dispensing form disintegrates within 10 seconds in the oral cavity.