ZA200506710B

ZA200506710B - Formulations comprising tolterodine and cocoa powder and use thereof

Info

Publication number: ZA200506710B
Application number: ZA200506710A
Authority: ZA
Inventors: Kristina Maarit Thyresson; Nils-Olof Lindberg; Katarina Eva Anette Lindell; Alice C Nicklasson Fredrik Per Martino
Original assignee: Pfizer Health Ab
Priority date: 2003-03-26
Filing date: 2005-08-22
Publication date: 2006-11-29
Also published as: CN1764441A; CL2004000625A1; AR043773A1; CA2519119A1; BRPI0408743A; MXPA05010314A; EP1605920A1; SE0300830D0; AU2004224556A1; WO2004084864A1; JP2006521347A

Description

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FORMULATIONS COMPRISING TOLTERODINE AND COCOA POWDER AND USE THEREOF

Field of the Invention

This invention relates to novel orally administered pharmaceutical formulations of tolterodine, optionally comprising salts, complexes, prodrugs and metabolites there- of, to the use of tolterodine, optionally comprising salts, prodrugs and metabolites thereof, for the manufacturing of a medicament to be administered orally for achieving an effect against overactive bladder, and to methods of treating overactive bladder by oral administration of tolterodine, optionally comprising salts, prodrugs and metabolites thereof.

Backgroynd

Tolterodine is an effective and safe compound for treatment of overactive blad- der. The synthesis of tolterodine and its utility for the treatment of overactive bladder is disclosed in US 5,382,600 (Pharmacia & Upjohn AB). An optimal efficacy/side effect profile is obtained at an oral dosage of 1 or 2 mg twice daily.

Tolterodine has a molecular weight of 325.0 and 475.6 as the tartrate salt. The enantiomeric purity is > 99 %. The pKa value is 9.87 and the solubility in water is about 11 mg/ml at room temperature. The partition coefficient (Log P) between n-octanol and phosphate buffer at pH 7.32 is 1.83.

OH Y Tolterodine, PNU-200583

Ns N.N-diiso-propyl-3-(2-hydroxy-5-methylphenyl)-3- phenylpropanamine.

The major metabolic pathway for the metabolism of tolterodine is mediated by cytochrome P450 2D6 leading to the formation of a 5-HM metabotite, (R)-N,N- diisopropyl-3-(2-hydroxy-5 -hydroxymethylphenyl)-3-phenylpropanamine. This meta- bolite has a similar pharmacological profile as tolterodine - see Nilvebrant L, Gillberg

P-G, Sparf B. “Antimuscarinic potency and bladder selectivity of PNU-200577, a major metabolite of tolterodine.” Pharmacol. Toxicol. (1997) 81: 195-207. For the similarity to tolterodine in pharmacological profile, see Brynne N, Dalén P, Alvin G, Bertilssora L and Gabrielsson J, Clin Pharmacol Ther 1998 (63): 529-39.

A N-dealkylated metabolite is mediated by CYP3A and may be further meta- bolized to a N-dealkylated 5-hydroxymetabolite. See the below scheme.

Yo T

Toltwrodine N-dealkylated tolterodine

OH ~ OH H 0 5-HM N-deskylated 5-HM

One further metabolite is formed when a carboxylic acid group is formed at the

CH,OH group of the 5-HM metabolite. Still one further metabolite is formed when a 5 carboxylic acid group is formed at the CH, OH group of the N-dealkylated 5-HM metabolite.

Tolterodine of the present invention encompasses the R-isomer, the S-isomer and the racemic mixture as well as salts, complexes, prodrugs and metabolites thereof.

Major effects are obtained from the R-isomer and the racemic mixture as well as from salts, complexes, prodrugs and metabolites thereof. Examples of salts are tolterodine 1- tartrate and tolterodine mesylate. Examples of complexes are complexes between tolterodine and beta-cyclodextrine and tolterodine and jon exchange compositions, such as ion exchange resinates.

Prior Art

Above-mentioned US 5,382,600 does not disclose any formulation similar to the ones of the present invention.

WO 98/03067 discloses transdermal administration of the S-isomer of toltero- dine.

WO 00/12070 discloses transdermal administration of the R-isomer and of the racemate of tolterodine.

No prior arton tolterodine-containing formulations similar to the ones of the present invention has been found.

Chocolate, which is different from cocoa powder as such, is very rarely used as an ingredient in pharmaceutical products, hitherto only in laxatives. One example is Ex-

Lax® being chocolated laxative pieces marketed by Novartis comprising sennosides.

Purex, a laxative wherein phenolphthalein was formulated with chocolate, was mar- keted in the 1950s. It is not known any compositions comprising tolterodine and chocolate.

It has now surprisingly been found that an orally administered pharmaceutical formulation of tolterodine, which may be administered without liquid, having sufficient taste masking of badly tasting ingredients, such as tolterodine and optional buffering agents, is obtained by tolterodine-containing formulations comprising cocoa powder as taste masker and texturizer. No similar formulations have been disclosed hitherto and the skilled person would not without inventive efforts have conceived the formulations of the present invention.

Hence the present invention, as further described below, is both new and inven- tive.

Summary of the invention

The present invention provides an orally administered pharmaceutical formu- lation of tolterodine, optionally comprising salts, prodrugs and metabolites thereof for achieving an effect against overactive bladder, comprising detrusor instability, detrusor hyperreflexia, urinary frequency, urinary urgency and urge incontinence. The admini- stration can be to a human being or to an animal.

The administration may be accomplished without the addition of liquid. Admini- stration without added liquid is a big advantage in all those situations where e g clean water or other suitable liquid is not available, such as on travel. Also the administration is discreet being a big advantage e g at lectures and on the theatre. Further, use of the present formulation, which should melt in the mouth rather than be swallowed, is ofa great advantage to all those persons having difficulties in swallowing a traditional tablet. A particularly useful dosage form of the present invention is thus a formulation that disintegrates or mels in the mouth without need for drinking water or other fluid.

The formulation is a dosage form comprising a therapeutically effective amount of tolterodine. A “therapeutically effective amount” herein is an amount sufficient to achieve an effect against overactive bladder, comprising detrusor instability, detrusor hyperreflexia, urinary frequency, urinary urgency and urge incontinence. By “urinary frequency” is primarily meant a need to urinate more than 8 times over 24 hours or more than 2 times per night. By “urinary urgency” is primarily meant frequent, strong and sudden needs to urinate. By “urge incontinence” is primarily meant involuntary urination after a sudden need to urinate.

It is preferred that the amount of tolterodine be lower than an amount causing significant side effects.

The invention is adapted for discreet self-administration. By “discreet self- administration” herein is meant self-administration that does not draw attention to the existence of a need for therapy.

Also provided by the present invention are methods of use of formulations of the present invention for treatment of overactive bladder, and a method of use of a formu- lation of the invention for preparing a medicament. Other features of this invention will be in part apparent and in part pointed out hereinafter.

An object of the invention is to provide novel orally administered pharmaceu- tical formulations of tolterodine comprising cocoa powder.

A second object of the invention is to provide methods for preparing said for- mulations.

A third object of the invention is methods for using said formulations therapy for treating overactive bladder.

Further objects of the invention will become apparent to one skilled in the art, and still other objects will become apparent hereinafter from the specification and claims. :

The main advantages provided by a formulation according to the present invention are: 1) The formulation provides for adequate taste masking; 2) The formulation does not require any added liquid at the time of administration; 3) By not adding liquid at administration use of the formulation does not increase the need for therapy, as there is no increase in the urinary burden — in comparison with conventional tablets being administered together with liquid. 4) The formulation provides for discreet self-administration; 5) The formulation does not give an immediate patient-perceived association with medicines, as do traditional tablets.

6) The formulation may provide for rapid transmucosal absorption, especially when buffering agents are added.

Detailed Description of the Invention

It is the primary object of the present invention to provide pharmaceutical 5 tolterodine-containing formulations useful for treatment of overactive bladder, com- prising detrusor instability, detrusor hyperreflexia, urinary frequency, urinary urgency and urge incontinence.

More specifically it is the object of the invention to provide such a tolterodine- containing formulation, for transmucousal delivery, that mainly disintegrates and/or melts in the oral cavity with or without the aid of salivary fluid or mechanical erosion, or a combination thereof, after which the formulation may show adhesiveness towards tissues in the oral cavity.

Preferably the formulation is such that it does not require addition of liquid at the time of administration. By not adding liquid at administration use of the formulation does not increase the need for therapy, as there is no increase in the urinary burden — in comparison with conventional tablets being administered together with liquid. No additional urine is produced.

Optional addition of buffering agents provides for a transient change in local pH of the saliva. Thereby a higher fraction of tolterodine is transformed into its less ionized form. Thereupon the transmucousal permeation is facilitated, which enhances the absorption of the active agent. For those skilled in the art it is evident that the choice of the buffering system is dependent on the one or more pK.s of the active agent.

It has surprisingly been found that a sufficient taste masking of badly tasting ingredients, such as tolterodine itself and/or buffering agents, is achieved through the use of cocoa powder. The cocoa powder acts as taste masker and texturizer.

Cocoa powder is defined as cocoa nib with some fat removed and ground into a powder. Cocoa nib is defined as cocoa beans with the shell removed. Cocoa butter is defined as fat expelled from the center (kernels or nib) of cocoa beans.

Cocoa powder is prepared from roasted cocoa beans. It is a complex compound, which consists of starch, cocoa butter, amino acids, proteins, xanthines, amines, mono- and polysaccharides, phospholipids, flavonoids, pyrazines, etc.

A preferred embodiment is a formulation, weighing around 400 mg, having the following preferred formulation (w/w):

w a LI La ingredient

Cocoa powder 18,00 Taste masker/ ——

EC Lu LCR

EC Lis Ll

Eo CR

Titanium dioxide Coloring —

Voge [00 | Teed

Mint and vanilla flavors 3,00 Flavoring

PR

Soya [100 [Emile

Examples

Below follows non-limiting examples on preparation of embodiments of the pre- sent invention.

Example 1: Preparation of a preferred embodiment

A formulation, weighing around 400 mg, is prepared with the following pre- ferred composition (w/w): o

Eel ll hE

Jee

ER Lc Li

EC LE LL

LU Ce

Titanium dioxide 2,00 Coloring

Jo oom [00 | Teenie]

Mint and vanilla flavors 3,00 Flavoring

A

ER LJ

Cocoa powder may be used in a non-alkalized form and in an alkalized form.

Both are useful in the present formulations. Alkalized cocoa powder is preferred when a somewhat milder taste is desirable.

A part of the hydrogenated soybean oil is melted. The solid components, i e tolterodine 1-tartrate, cocoa powder, mannitol, maize starch, aspartame, acesulfame-K, titanium dioxide, monosodium glutamate and the flavoring agents if solid, are added and mixed. A reduction of particle size of the solid components is performed by milling in a roll-refiner. If the solid components have already got the required particle size, € § by milling before the mixing with the fatty components, roll refining is dispensed with.

Afier treatment in the roll-refiner the mixture is mixed with the rest of the melted fatty components or remelted, if solidified, and mixed with the rest of the melted hydro- genated soybean oil. A mixing of the melt is performed in a suitable mixer. The liquid components, i e soy lecithin and the flavoring agents if liquid, are added. Tablets or 1S other solid dosage forms are subsequently made using suitable techniques, such as molding, extrusion or congealing, including pastillation, when necessary after suitable preconditioning. Also other suitable manufacturing methods may be used.

Example 2: Preparation of another embodiment

In essentially the same way as in Example 1 is manufactured a formulation, weighing around 500 mg, having the following preferred composition (wiw):

Ingredient Amount (%)

Cocoa powder Taste masker/ texturizer

Hydrogenated soybean oil 44,00 Lipid ingredient am CC a]

Ce CC Ce

Vanilla flavour Flavoring agent

CE CO

Example 3: Preparation of further embodiments

In essentially the same way as in Example 1 are manufactured formulations with a weight from around 200 mg to around 1000 mg having the below composition (wiw):

Ingredient Amount (%)

Tolterodine (base, prodrug, metabolite, salt or complex)

Cocoa butter equivalents (CBEs) Lipid ingredient

Cocoa powder Taste masker/ texturizer

Water-soluble or dispersible diluents, preferably as fine particulate powder

[0 [ee

EE Li Li

Ee LN Lia

Coloring agent 0-3 Coloring i i a

Example 4: Preparation of alternative embodiments

Useful embodiments are obtained by exchanging some of the excipients in the

Ss embodiments of the above examples for equivalently functioning alternative com- pounds.

The cocoa powder may be used in its pon-alkalized form, its alkalized form or in a mixture thereof.

The diluents may be selected from one or more of the compounds sucrose, fruc- tose, glucose, galactose, lactose, maltose, invert sugar, a pharmaceutically acceptable polyol such as xylitol, sorbitol, maltitol, mannitol, isomalt and glycerol, or polydex- trose, or starch, or any mixture thereof, but only to such an extent that the taste-masking effect of the cocoa-powder remains sufficient.

The lipid ingredient, being fatty components, may be chosen from one or more of the following compounds: - cocoa butter and cocoa butter alternatives, including cocoa butter equivalents (CBE), cocoa butter substitutes (CBS), cocoa butter replacers (CBR) and cocoa butter improvers (CBD), - coconut, palmkernel oil and other similar oils characterized by being predomi- nantly based on lauric and myristic acids, ) - palm oil, shea butter, karite butter, illipe butter, mango kernel oil, sal fat and other similar fats characterized by being predominantly based on palmitic. oleic and stearic acids, - corn oil, sunflower oil, hybrid sunflower oil, soybean oil, rapeseed oil, canola oil, olive oil, ricebran oil, cottonseed oil, arachis (peanut, groundnut) oil and other oils characterized by being predominantly based on oleic, linoleic and linolenic acids and hydrogenated to a suitable melting point,

- fish oil, tallow, lard, butterfat and other animal derived fats, and - synthetic fats, reesterified fats, hard fats obtained by a chemical reaction of fatty acids with glycerol using 00, acidic, alkaline or enzymatic catalysis, whereby said compound/s is/are used as a single component or mixed with each other, being either crude or refined using physical or alkaline refining, or being subject- ted to further processing including catalytic hydrogenation, interesterification, tran- sesterification and fractionation.

The optional buffering agent/s may be selected from one or more of carbonates, bicarbonates, acetates, gluconates, glycerophosphates, phosphates or glycinates of sodium, potassium or ammonium, of mixtures thereof. Most phosphates are though less suitable because their taste usually is disagreeable and difficult to mask. Addition of buffering agents/s may increase the uptake through the buccal mucosa.

The sweetener may selected from one or more artificial sweeteners, such as sucrose, aspartame, acesulfame potassium, saccharine, sodium saccharine, cyclamate, glycyrhizine, thaumatin (talin), sucralose, dihydrochalcone (neohesperidin dihydro- chalcone), alitare, miraculin (miracle fruit), monellin (serendipity berry), stevside and/or salts thereof.

The emulsifier is preferably soy lecithin and/or egg lecithin, but may be exchanged for - a nonionic surfactant, such as poloxamer, polyoxyethylene alkyl ether, poly- oxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, monoglyce- ride, diglyceride and esther thereof, polyoxyethylene stearate, polyglycerolester of fatty acids, including polyglycerolpolyricinoleic acid (PGPR), sorbitan fatty acid ester, - an anionic surfactant, such as fatty acid, soap of fatty acid, lactylate, especially sodium and/or calcium stearoyllactylate, sodium lauryl sulfate and latanol, - a zwitterionic surfactant, such as zwitterionic phospholipid, such as phosphati- dylcholine and phosphatidylethanolamine, or mixtures, fractions or derivatives thereof or with lecithin.

Formulations according to the present inventions primarily constitute meltable and/or suckable oral tablets, but also include other suitable dosage forms for oral administration such as buccal patches, buccal paste and buccal sprays.

The present invention also encompasses tolterodine-containing formulations further comprising one or more other active agents having an effect against overactive bladder, such as oxobutynin, emepromium, trospium, propanetheline and darifenacin.

Claims

1. An orally administered pharmaceutical formulation comprising tolterodine, optionally comprising salts, complexes, prodrugs and metabolites thereof, charac - § terized in that it comprises cocoa powder.

2 A formulation according to claim I, characte ri z e d in that tolterodine essentially is in its R-isoreric form.

3. A formulation according to claim 1, haracterized in that tolterodine essentially is in its S-isomeric form.

4. A formulation according to claim 1, characte ri ze d in that tolterodine essentially is in racemic form.

5. A formulation according to claim 1, characte ri zed in that it admini- sters the tolterodine metabolite (R)-N,N-diisopropyl-3 -2-hydroxy-5-hydroxymethyi- phenyl)-3-phenylpropanamine, optionally together with tolterodine.

6. A formulation according to any of the preceding claims, characte- rized in that it further comprises one or more lipid ingredients.

7. A formulation according to claim 6, char acterized in that the one or more lipid ingredients is/are chosen from - cocoa butter and cocoa butter alternatives, including cocoa butter equivalents (CBE), cocoa butter substitutes (CBS), cocoa butter replacers (CBR) and cocoa butter improvers (CBI), - coconut, palmkernel oil and other similar oils characterized by being predomi- nantly based on lauric and myristic acids, - palm oil, shea butter, karite butter, illipe butter, mango kernel oil, sal fat and other similar fats characterized by being predominantly based on palmitic, oleic and stearic acids, - corn oil, sunflower oil, hybrid sunflower oil, soybean oil, rapeseed oil, canola oil, olive oil, ricebran oil, cottonseed oil, arachis (peanut, groundnut) oil and other oils characterized by being predominantly based on oleic, linoleic and linolenic acids and hydrogenated to a suitable melting point, - fish oil, tallow, lard, butterfat and other animal derived fats, and - synthetic fats, reesterified fats, hard fats obtained by a chemical reaction of fatty acids with glycerol using no, acidic, alkaline or enzymatic catalysis, whereby said compound/s is/are used as a single component or mixed with each other, being either crude or refined using physical or alkaline refining, or being subjected to further processing including catalytic hydrogenation, interesterification, transesterification and fractionation.

8. A formulation according to claim 7, characterized in that the one Of more lipid ingredients is/are chosen from cocoa butter equivalents (CBE), cocoa butter substitutes (CBS) and cocoa butter replacers (CBR).

9. A formulation according to any of the preceding claims, ¢ haracte— ri z e d in that it further comprises one or more buffering agents.

10. A formulation according to claim 9, character i z ed in that the one or more buffering agents is/are chosen from carbonates, bicarbonates, acetates, gluconates, glycerophosphates, phosphates or glycinates of sodium, potassium or ammonium, or mixtures thereof.

11. A formulation according to any of the preceding claims, haracte— riz ed in that it further comprises One Or More Sweeteners and optionally one or more : flavoring agents.

12. A formulation according to claim 11,characteriz e d in that the one or more sweeteners is/are sucrose, aspartarne, acesulfame potassium, saccharine, sodium saccharine, cyclamate, glycyrrhizine, thaumatin (talin), sucralose, dihydrochalcone (neohesperidin dihydrochalcone), alitame, miraculin (miracle fruit), monellin (seren- dipity berry), stevside and/or salts thereof.

13. A formulation according to any preceding claim,character izedin that it further comprises one or more emulsifiers/solubilisers.

14. A formulation according to claim 13, characterize d in that the one or more emulsifiers/solubilisers is/are chosen from - lecithin, preferably soy lecithin and/or egg lecithin, - a nonionic surfactant, such as poloxamer, polyoxyethylene alkyl ether, poly- oxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, monoglyce- ride, diglyceride and esther thereof, polyoxyethylene stearate, polyglycerolester of fatty acids, including polyglycerolpolyricinoleic acid (PGPR), sorbitan fatty acid ester, - an anionic surfactant, such as fatty acid, soap of fatty acid, lactylate, especially sodium and/or calcium stearoyllactylate, sodium lauryl sulfate and latanol, - a zwitterionic surfactant, such as zwitterionic phospholipid, such as phosphati- dyicholine and phosphatidylethanolamine, or mixtures, fractions or derivatives thereof or with lecithin.

15. A formulation according to claim 14,characterized in that the one or more emulsifiers/solubilisers is/are chosen from lecithin, preferably soy lecithin and/or egg lecithin.

16. A formulation according to any preceding claim, character izedin that it further comprises a substance/substances chosen from one or more of the com- pounds Sucrose, fructose, glucose, galactose, lactose, maltose, invert sugar, a pharma- ceutically acceptable polyol such as xylitol, sorbitol, maltitol, mannitol, isomait and glycerol, or polydextrose, Or starch, or any mixture thereof.

17. An orally administered pharmaceutical formulation, ¢ haracterizedin that a unit dose thereof has a weight of around 400 mg and comprises Ingredient Amount Function om Hydrogenated soybean oil 43,55 Lipid i fl Cocoa powder 18,00 Taste masker/ i a == ER LL Lo EE Li Lo ee SN LL i Titanium dioxide Coloring lia a = Er SL hol Mint and vanilla flavors 3,00 Flavoring — me EE LC Lo

18. An orally administered pharmaceutical formulation, characterizedin that 2 unit dose thereof has a weight of around 500 mg and comprises

Ingredient Amount (%) Fo Cocoa powder Taste masker/ texturizer Hydrogenated soybean oil 44,00 Lipid ingredient [TR CON Ceti Vanilla flavour Flavoring Er E

19. An orally administered pharmaceutical formulation comprising tolerodine, optionally comprising salts, complexes, prodrugs and metabolites thereof, ¢ harac- te rized in that aunit dose thereof has a weight of around 200 — 1000 mg and com- § prises Ingredient Amount (% wiw) Tolierodine (base, prodrug, metabolite, salt or complex) 01-2 [Adie Lipid ingredients 35-55 Lipid ingredient Cocoa powder Taste masker/ texturizer Water-soluble or dispersible diluents, preferably as fine particulate powder a LLL Loa Ee A Li Lai agent

20. A formulation according to any preceding claim, character i z ed in that it further comprises one or more other agents having an effect against overactive bladder.

21. A formulation according to claim 20, characterizedin that the one or more other agents is/are chosen from oxobutynin, emepromium, trospium, propan- etheline and darifenacin.

22. A formulation according to any preceding claim which is formulated as an oral dosage form and which provides for delivery of tolterodine mainly through the buccal mucosa and/or other mucosa of the oral cavity.

23. Use of a formulation according to any preceding claim for the manufacture of a medicament useful for treatment of overactive bladder.

24. Method for treating overactive bladder in a subject comprising administra- tion of a tolterodine-containing orally administered pharmaceutical formulation according to anyone of claims 1 — 22 to the subject.

25. Method for treating overactive bladder in a subject comprising administra- tion of a twlterodine-containing orally administered pharmaceutical formulation accor- ding to anyone of claims 1 — 22 to the subject concomitantly with administration of tolterodine and/or one or more other agents having an effect against overactive bladder through one or more other routes of administration.

26. Method for treating overactive bladder in a subject according to claim 25 wherein the one or more other routes are chosen from transdermal and peroral admini- stration, and administration by inhalation and injection.