WO2013059768A1

WO2013059768A1 - Therapeutic agents for treating gastrointestinal disorders associated with inflammation of the gastrointestinal tract

Info

Publication number: WO2013059768A1
Application number: PCT/US2012/061265
Authority: WO
Inventors: Stephen Perrett; Fredric Jay Cohen
Original assignee: Aptalis Pharma U.S., Inc.
Priority date: 2011-10-20
Filing date: 2012-10-22
Publication date: 2013-04-25

Abstract

A solid pharmaceutical composition for treatment of gastrointestinal disorders comprising less than or equal to 2 g of a mesalamine or a mesalamine pro-drug wherein the composition demonstrates superior spreading, coverage or absorption at the intended delivery site.

Description

THERAPEUTIC AGENTS FOR TREATING GASTROINTESTINAL DISORDERS ASSOCIATED WITH INFLAMMATION OF THE GASTROINTESTINAL TRACT

TECHNICAL FIELD OF THE INVENTION

This invention relates to therapeutic agents administered for the treatment of gastrointestinal disorders associated with inflammation of the gastrointestinal tract.

BACKGROUND OF THE INVENTION

The drug treatment of first line for ulcerative colitis, a type of inflammatory bowel disease, is 5- amino salicylic acid which is known as mesalamine and mesalazine. The drug is formulated and used as oral, enema, rectal foam, rectal gel and suppository formulations. The oral formulations are generally formulated as delayed release forms with the intention of a preferential drug delivery to the lower gastrointestinal tract. Pro-drug forms of mesalamine, such as balsalazide, sulfasalazine and dipentum are also available as oral formulations, in this case the mesalamine moiety is released through cleavage of an azo bond by gut bacteria. The 4-amino derivative of salicyclic acid has also been studied for use in inflammatory bowel disease, but at present is only indicated for tuberculosis.

Mesalamine is a zwitterion and exhibits a pH-dependent solubility; however, at pH levels relevant to the site of its physiological action, colon pH of approximately 5.3-8.5, its solubility is relatively low - approximately 7.0 mg/ml [Fadda et. al. 2010, Drug Solubility in Luminal Fluids from Different Regions of the Small and Large Intestine of Humans. Molecular Pharmaceutics Vol. 7, No. 5 (2010), 1527-1532]. The dose of mesalamine is relatively high and ranges from 1 ,6g to 4.8g per day by the oral route and from 1 g-4g via the rectal route. Owing to the high dose and tolerability issues associated with the inactive moiety of the first therapeutic compound developed, sulfasalazine, dosing was set at 3 or 4 times per day. More recent products such as Lialda and Apriso, which contain mesalamine only, are dosed once a day at levels of up to 4.8 g. Recent studies have shown that other mesalamine products can also be given in one large dose for the same therapeutic effect as divided dosing. This means that drug solubility may be a limiting factor regarding efficacy when these doses are given as a single bolus; for example,

l there was no apparent difference in the disease response between the 2.4g and 4.8g does of Lialda [Lialda, Prescribing Information].

The action of mesalamine is also thought to be largely topical and typically less than 30% of the oral dose is absorbed [Asacol HD; Prescribing Information]. When delivered by the rectal route, absorption is in the region of an enema form is in the region of 10-30%% [Rowasa Prescribing Information ]; a foam formulation has been shown to have approximately 25% lower absorption than an oral form [Salofalk U.K. Prescribing Information] and ; absorption from the suppository form is variable and by the urinary route at steady state ,≤ 1 1 % of the dose was eliminated as unchanged 5-ASA and 3-35% as N-acetyl-5-ASA [Canasa; Prescribing Information]. There is also no apparent difference in dose response between 1 g and 4g of drug delivered using an enema formulation [S. Hanauer, Dose-ranging study of mesalamine (PENTASA) enemas in the treatment of acute ulcerative proctosigmoiditis: results of a multicentered placebo-controlled trial. The U.S. PENTASA Enema Study Group. Inflamm Bowel Dis. ; 4(2):79-83, May 1998], The combination of the limited solubility of mesalamine and the limited amounts of available water in the colon, particularly when delivered rectally, have an affect particularly relative to therapeutic action.

No strategies are disclosed relative to mesalamine in such products as delivered to reduce its particle size to an increase in surface area to increase in the rate of dissolution in an aqueous environment. There are also no strategies disclosed relative to mesalamine in such products as delivered to increase the solubility of mesalamine, such as by combining it with buffering agents to adjust or control pH may be of value owing to the pH-dependent solubility profile of mesalamine. Lastly, there are no strategies disclosed relative to mesalamine in such products as delivered whereby solid solutions of amorphous forms of the drug or carrier molecules such as cyclodextrins or emulsified systems are used to enhance its solubility.

The invention herein combines with techniques that will allow the drug to contact a greater surface area through increasing spreading of the drug over the diseased tissue surface. This may be achieved by incorporating surface active agents that will spread at interfaces or reduce surface tension effects. Similarly agents that will promote a physical disintegration and movement of a dosage form such as disintegrants and effervescent capsules may also be employed.

The topical nature of drug action also means that materials that will promote persistence and/or penetration into the tissues of the Gl tract, particularly the colon, may also be effective in increasing therapeutic efficacy. Of particular interest in this regard are materials that may have more than one action. Soya bean lecithin derived phospholipids, when delivered alone as a high dose enterically-coated formulation have been shown to offer benefit in the treatment of ulcerative colitis [Stremmel et. al. Phosphatidylcholine for steroid-refractory chronic ulcerative colitis: a randomized trial. Ann Intern Med.; 147(9):603-10, Nov 6, 2007; US6677319] through a postulated restoration of the barrier function of mucus in the colon. [Liposome encapsulated mesalamine has been shown to promote tissue accumulation of mesalamine in comparison to free drug [Kesisoglou, et. al. , Liposomal Formulations of Inflammatory Bowel Disease Drugs: Local versus Systemic Drug Delivery in a Rat Model. Pharmaceutical Research, Vol. 22, No. 8, August 2005, 1320-1330] when delivered to the lumen of rats. These formulations differ from the present invention in a number of key aspects. Dose levels were very high, when lecithin is delivered alone levels of 4g were dosed 4 times per day. When used as a liposomal formulation a weight ratio of 50 mg lipid to 7.5 mg was used in an aqueous volume of 1 ml; a typical therapeutic level of mesalamine ranges between 1 and 4.8g, equating to a daily lipid level of 6.7 g - 32 g. In the first instance no drug is included and in the second drug and lipid is delivered in a iiposomally-encapsulated form. In the present invention essential features of the invention are the presence of both phospholipid and drug and either a level of water in the formulation which is insufficient to form a substantially aqueous liposomal formulation and/or which is insufficient to substantially dissolve the drug substance.

Phospholipids are also well known for their effects in interfacial spreading and surface tension reduction and also have the advantage of being a foodstuff with GRAS status. Phospholipids would therefore be an effective means to deliver and stabilize an improved form of a therapeutic agent such as mesalamine. Such formulations could also be delivered by the oral or by the rectal route and relatively high level of phospholipids could be included in these formulations. There are no reports of phospholipids being used in combination with mesalamine that has been formulated to improve its ability to cover a diseased tissue surface or to enhance its solubility.

Studies have been carried out in which enema formulations have been compared as to their retention. There are however no studies which have demonstrated an improved therapeutic efficacy. In addition there are no reports of studies in which strategies to increase drug efficacy through increasing mesalamine solubilization or increasing mesalamine surface area have been applied to oral, suppository or rectal foam formulation. In particular, suppository formulations have not been changed other than to modify the size of the dosage since their first introduction into commerce.

SUMMARY OF THE INVENTION

In one embodiment, the present invention is directed to a solid pharmaceutical composition comprising less than or equal to 2.0 g of a mesalamine or a mesalamine pro-drug wherein the composition demonstrates superior spreading, coverage or absorption at the intended delivery site when compared to formulations of the prior art.

In another embodiment, the present invention is directed to a suppository formulation comprising drug of a reduced particle size with the optional inclusion of agents that will aid spreading of the drug and/or formulation, such as surfactants, e.g., phospholipids, and materials that aid disintegration such as disintegrants and effervescent capsules.

In another embodiment, the present invention is directed to a suppository formulation comprising drug formulated to enhance drug solubilization, such as a solid solution, and/or with buffering agents and the like. The suppository may also optionally contain agents that will aid spreading of the drug and/or formulation, such as surfactants, e.g., phospholipids, and materials that aid disintegration such as disintegrants and effervescent capsules.

In another embodiment, the present invention is directed to other rectal delivery forms, e.g., enemas, which incorporate the technologies described for the suppository forms above.

In another embodiment, the present invention is directed to an oral delayed-reiease formulation comprising drug of a reduced particle size with the optional inclusion of agents that will aid spreading of the drug and/or formulation in the lower Gl tract, such as surfactants and materials that aid disintegration such as disintegrants and effervescent couples.

In another embodiment, the present invention is directed to an oral delayed-release formulation comprising drug formulated to enhance drug solubilization, such as a solid solution, and/or with buffering agents and the like. The formulation may also optionally contain agents that will aid spreading of the drug and/or formulation, such as surfactants, e.g., phospholipids, and materials that aid disintegration such as disintegrants and effervescent couples.

In another embodiment of the invention the formulations contain phospholipid in combination with a therapeutic agent.

In another embodiment, the present invention is directed to a method for treating an

inflammatory condition of the gastrointestinal tract. The method comprises administering to an individual in need thereof a pharmaceutical composition of the present invention.

In yet another embodiment, the present invention provides a method of treating a

gastrointestinal disorder comprising administering to a patient in need thereof a dosage form comprising a composition comprising mesalamine with a mean particle size of below 2,000 nm further comprising at least one excipient.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the present invention, a dosage form is provided that is suitable for use in a mammal comprising mesalamine with a mean particle size of below 2,000 nm as will be described in more detail herein.

In another embodiment of the present invention, a dosage form is provided that is suitable for use in a mammal comprising mesalamine with a mean particle size of below 2,000 nm further comprising at least one excipient. In one preferred embodiment, the excipient is glyceride. In another preferred embodiment, the excipient is at least one film-forming polymer capable of delaying the release of the mesalamine into the body. Preferably, the polymer is water-soluble. In preferred embodiments of the invention, the mesalamine is milled to a mean particle diameter of between 100 and 2000 nm with optional stabilizers to prevent aggregation, e.g., lecithin, sodium dodecylsulfate, polysorbate, lactose and combined in a weight ratio of between 1 :0.5 to 1 :5 with hard fat, USP to form a suppository formulation.

In preferred embodiments, the mesalamine is milled to a mean particle diameter of below 2000 nm. In other preferred embodiments, the mesalamine is milled to a mean particle diameter of below 1000 nm. In other preferred embodiments, the mesalamine is milled to a mean particle diameter of below 500 nm. In still other preferred embodiments, the mesalamine is milled to a mean particle diameter of below 250 nm. In still other preferred embodiments, the mesalamine is milled to a mean particle diameter of below 150 nm.

In another embodiment hard fat USP is combined with phospholipid in weight ratios of between 20: 1 and 1 :2 by heating the hard fat above its melting point and above the phase transition temperature of the phospholipid. This base is used to form suppositories containing an antiinflammatory drug, e.g., mesalamine, in a weight ratio between 1 :0.5 to 1 :5 drug:base. In cases where a highly potent drug is used drug to base ratios may range from 1 : 10 to 1 :5000.

In another embodiment the mesalamine is milled to a mean particle diameter of between 100 and 2000 nm and used for the formation of suppositories using the hard fat/phospholipid base in the manner described above. In other preferred embodiments, the mesalamine is milled to a mean particle diameter of below 1000 nm. In other preferred embodiments, the mesalamine is milled to a mean particle diameter of below 500 nm. In still other preferred embodiments, the mesalamine is milled to a mean particle diameter of below 250 nm. In still other preferred embodiments, the mesalamine is milled to a mean particle diameter of below 150 nm.

In another embodiment the hard fat USP of the embodiments described above is replaced with polyethylene glycol with a molecular weight in excess of 1000.

In another embodiment the hard fat of the embodiments described above is replaced with substantially aqueous fluid, such that the drug:fluid weight ratio is between 1 :3 and 1 :500 or 1 :3 to 1 :50000 in the case of highly potent drugs. The formulation may also optionally include a suitable polymer to form a gel formulation. In another embodiment the embodiments described above, with the optional removal of the hard fat or the polyethylene glycol, a suitable propellant is included such that the drug:propellant weight ratio is between 1 :3 and 1 :500 or 1 :3 to 1 :50000 in the case of highly potent drugs.

In another embodiment the embodiments described above which do not have an aqueous component also contain an effervescent couple such that the weight ratio of drug to effervescent couple is between 1 :2 and 10: 1 or between 1 : 100 and 1 : 1 in the case of highly potent drugs.

In another embodiment the hard fat of the embodiments described above is replaced with an excipient blend suited to the formation of tablets or pellets. Pressed tables or pellets are coated with suitable excipients, e.g., pH sensitive polymers, to create delayed release formulations. Pellet formulations may optionally be filled into capsules. The formulations of this embodiment are suited to oral delivery.

In another embodiment the only one component of the effervescent couple is used, such that the solubility of mesalamine is increased owing to the buffering effect of the alkaline component.

In another embodiment, the present invention provides a method of treating a gastrointestinal disorder comprising administering to a patient in need thereof a dosage form comprising a composition comprising mesalamine with a mean particle diameter of below 2,000 nm further comprising at least one excipient.

EXAMPLES

Example 1 (Prior art)

Preparation of 1000 mg Mesalamine Suppositories.

1000 mg mesalamine suppositories are prepared using the following procedure. Add 200.0 kg of hard fat NF (Witepsol® 15) to a mix tank. Begin heating the batch to 58-62 °C by recirculating steam through the tank jacket. The target temperature is 60 °C. Begin mixing with the sweeps at 12 Hz as the product begins to melt. Continue heating to 58-62 °C (target 60 °C). Mix until the product is completely molten, increasing the sweeps to 60 Hz as the product melts. Mix for a minimum of 30 minutes, maintaining the temperature at 58-62 °C using the hot box (target 60 °C). Adjust the temperature of the batch to 40-44 °C by re-circulating tap water at approximately 34-40 °C through the jacket. Maintain the batch at this temperature using the hot box (target 42 °C). While adjusting the temperature, shut off the sweeps, install the prop mixer with one 7" x 7" blade and restart the sweeps to 60 Hz. Begin mixing with the prop at 12 Hz and adjust the sweeps to 30 Hz.

Slowly add 100.0 kg of mesalamine powder USP to the mix tank. During the addition of the powder, slowly increase the sweeps to 35 Hz and the prop to 35 Hz as the product level in the tank increases, minimizing aeration. The addition of the powder is to be performed over a 35 to 60 minute interval. The powder is to be completely dispersed prior to mixing.

Mix for a minimum of 60 minutes. During the mix period, flush product through the bottom valve using a large pot. Continue flushing throughout the mixing interval until product appears visually uniform. Return the product to the mix tank.

Adjust the temperature of the batch to 43-45 °C. by recirculating tap water at approximately 50- 55 °C. through the tank jacket or use the hot box, if necessary. Perform in-process sampling from the bottom valve of the tank taking approximately 600 g in a plastic beaker. Hook up the hot box and set it to hold the temperature of the batch at 43-45 °C. Adjust the sweeps to 30-36 Hz and prop to 20-30 Hz to prevent aeration of the product.

Fill each mould. Remove 1 suppository per filling head (14 consecutive suppositories) every 25- 35 minutes of operation. Fill weights of individual suppositories should be between 2.85 and 3.15 g.

Example 2

Mesalamine powder is milled using an air jet mill to a mean particle diameter of about 2000 nm and used to prepare suppositories as described in Example 1 .

Example 3 Mesalamine powder is milled, using a microfluidizer to a mean particle size of less than 1000 nm and used to prepare suppositories as described in example 1. Milling is carried out in water and in the molten wax used to form the suppositories.

Example 4

1000g of mesalamine is intimately mixed with 250g of sodium bicarbonate and 150 g of ascorbic acid. This mixture is combined with 2,000g of hard fat using the procedures described in example 1 . In other examples, the milled mesalamine of examples 2 and 3 is used.

Example 5

1000 g of hard fat is combined with 1000 g of phospholipid by heating the hard fat above its melting point and above the phase transition temperature of the phospholipid. The temperature is maintained, with optional mixing, until the two components have formed an intimate mixture/solution. 1000 g of mesalamine is then combined with the lipid mixture to form suppositories as described in example 1 . In other examples the milled mesalamine of examples 2 and 3 is used. In other examples the sodium bicarbonate and optionally the ascorbic acid of example 4 are also included.

Example 6

In other examples the hard fat component of the formulation is substituted for by polyethylene glycol with an average molecular weight of above 1 ,000.

Example 7

Gel formulation presentations of the suppository formulations described in examples 2 through 6 are constructed through the substitution of the hard fat component with a gel consisting of 1 part hyroxypropylmethylcellulose: 1 part propylene glycol: 1 part water with suitable preservatives.

Example 8

Enema formulations were also prepared in which the hard fat component was substituted with 50 mis of a 10% solution of hyroxypropylmethylcellulose in water. Example 9

Mesalamine powder is milled using an air jet mill to a mean particle diameter of about 2000 nm and used to prepare a pellet dosage through suspending the drug particles in ethanol containing 10% phospholipid. This suspension is sprayed on to the surface of non-pareil sugar spheres to a total drug loading of 35 %. The spheres are further spray coated with the enteric polymer, Eudragit S, to a total polymer level of 10% (wt). The pellets are then filled into capsules.

Example 10

Mesalamine powder is milled, using a microfluidizer to a mean particle diameter of less than 1000 nm and used to prepare a pellet dosage through suspending the drug particles in ethanol containing 10% phospholipid. This suspension is sprayed on to the surface of non-pareil sugar spheres to a total drug loading of 35 %. The spheres are further spray coated with the enteric polymer, Eudragit S, to a total polymer level of 10% (wt). The pellets are then filled into capsules.

Example 11

Mesalamine is combined with sodium bicarbonate in a ratio of 2 parts mesalamine to 1 part sodium bicarbonate through co-granulation. The granules are combined with 2% sodium stearyl fumarate and pressed into tablets containing 800 mg of mesalamine. The tablets are coated with Eudragit S to a total polymer level of 10% (wt). Tablets are also prepared using the mesalamine with reduced particle size used in examples 2 and 3.

The foregoing examples and description of the preferred embodiments should be taken as illustrating, rather than as limiting the present invention as defined by the claims. As will be readily appreciated, numerous variations and combinations of the features set forth above can be utilized without departing from the present invention as set forth in the claims. Such variations are not regarded as a departure from the spirit and scope of the invention, and all such variations are intended to be included within the scope of the following claims.

Claims

We Claim:

1. A dosage form suitable for use in a mammal comprising mesalamine with a mean particle size of below 2,000 nm.

2. A dosage form suitable for use in a mammal comprising mesalamine with a mean particle size of below 2,000 nm further comprising at least one excipient.

3. A dosage form of claim 2 where the excipient is a glyceride.

4. A dosage form of claim 3 where glyceride is Hard Fat NF.

5. A dosage form of claim 2 where the excipient is a water-soluble polymer.

6. A dosage form of claim 2 where the excipients is a film-forming polymer capable of delaying the release of the mesalamine into the body.

7. A composition of claim 1 where the dosage form is a suppository.

8. A composition of claim 1 where the dosage form is an enema.

9. A composition of claim 1 where the dosage form is a gel.

10. A composition of claim 1 where the dosage form is a tablet or capsule.

11 . A composition of claim 2 where the excipient is a surface active agent capable of adsorbing onto the surface of the particles.

12. A composition of claim 2 where the excipient acts as a surface stabilizer on the particles.

13. A composition of claim 2 where the excipient enhances the surface spreading of the particles.

14. A composition of claims 1 1 or 12 where the excipient is a phospholipid.

15. A composition of claim 2 where the excipient is a base.

16. A composition of claim 2 where the excipient is an acid.

17. A composition comprising mesalamine with a mean particle size below 2,000 nm, a glyceride and a surfactant.

18. A composition of claim 16 in the form of a suppository.

19. The composition of claim 1 , wherein the oral dosage form is coated with a pH-sensitive coating that delays dissolution of the mesalamine when administered orally.

20. A substantially anhydrous solid or semi-solid dosage form comprising mesalamine with a mean particle size below 2,000 nm, a glyceride and an acid base couple with some water solubility.

21 . A suppository containing mesalamine with a mean particle diameter below 2,000 nm.

22. A suppository containing mesalamine with a mean particle diameter below 1000 nm.

23. A suppository containing mesalamine with a mean particle diameter below 500 nm.

24. A suppository containing mesalamine with a mean particle diameter below 250 nm.

25. A suppository containing mesalamine with a mean particle diameter below 150 nm.

26. A tablet or capsule containing mesalamine with a mean particle diameter below 2,000 nm.

27. A tablet or capsule containing mesalamine with a mean particle diameter below 1000 nm.

28. A tablet or capsule containing mesalamine with a mean particle diameter below 500 nm.

29. A tablet or capsule containing mesalamine with a mean particle diameter below 250 nm.

30. A tablet or capsule containing mesalamine with a mean particle diameter below 150 nm.

31 . A method of treating a gastrointestinal disorder comprising administering to a patient in need thereof a dosage form comprising a composition comprising mesalamine with a mean particle size of below 2,000 nm further comprising at least one excipient.

32. The method of claim 31 wherein the dosage form is a suppository.

33. The method of claim 31 wherein the suppository comprises mesalamine with a mean particle diameter below 1000 nm.

34. The method of claim 33 wherein the suppository comprises mesalamine with a mean particle diameter below 500 nm.

35. The method of claim 34 wherein the suppository comprises mesalamine with a mean particle diameter below 250 nm.

36. The method of claim 35 wherein the suppository comprises mesalamine with a mean particle diameter below 150 nm.

37. The method of claim 31 wherein the at least one excipient is an acid.

38. A dosage of claim 1 for the use in treating a gastrointestinal disorder.