PUBLICATION NUMBER: WO/2010/149230

International Application No.: PCT/EP2009/058122
Publication Date: 29.12.2010
International Filing Date: 29.06.2009

IPC: A61K 9/20 (2006.01), A61K 31/785 (2006.01)
A61K 9/20 (2006.01), A61K 31/785 (2006.01)(en) -->
A HUMAN NECESSITIES
61 MEDICAL OR VETERINARY SCIENCE; HYGIENE
K PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
9 Medicinal preparations characterised by special physical form
20 Pills, lozenges or tablets
A HUMAN NECESSITIES
61 MEDICAL OR VETERINARY SCIENCE; HYGIENE
K PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31 Medicinal preparations containing organic active ingredients
74 Synthetic polymeric materials
785 Polymers containing nitrogen

Applicants:
COMBINO PHARM, S.L. [ES/ES]; Fructu-s Gelabert, 6-8
E-08970 Sant Joan Desp' (ES) (For All Designated States Except US).LLORET PƒREZ, Sergio [ES/ES]; (ES) (For US Only).DAZ GUASCH, Laura [ES/ES]; (ES) (For US Only)

Inventors:
LLORET PƒREZ, Sergio; (ES).DAZ GUASCH, Laura; (ES)

Agent:
ILLESCAS TABOADA, Manuel; C/ Recoletos, 13 51/4Izda
28001 Madrid (ES)

Priority Data:
P200930368 26.06.2009 ES

TITLE & ABSTRACT:
(EN) NOVEL PHARMACEUTICAL COMPOSITION COMPRISING POLY (ALLYLAMIN-CO-N,N'-DIALLYL- 1,3-DIAMINO-2-HYDROXYPROPANE) HYDROCHLORIDE
(FR) NOUVELLE COMPOSITION PHARMACEUTIQUE COMPRENANT DU CHLORHYDRATE DE POLY(ALLYLAMINE-CO-N,N'-DIALLYL-1,3-DIAMINO-2-HYDROXYPROPANE)

Abstract:
(EN)Novel pharmaceutical composition comprising poly (allylamin-co-n,n'-diallyl- 1,3- diamino-2-hydroxypropane) hydrochloride. The invention solves the problem related to the high hygroscopicity of active principle sevelamer hydrochloride, which becomes even more serious if the formulation contains it at high concentrations, particularly if said formulation is a tablet. For solving this problem the formulations of the invention comprise an excipient pharmaceutically acceptable which acts as diluent, preferably a pregelatinized starch.
(FR)L'invention porte sur une nouvelle composition pharmaceutique comprenant du chlorhydrate de poly(allylamine-co-N,N'-diallyl-1,3-diamino-2-hydroxypropane). L'invention rŽsout le problme liŽ au caractre hygroscope ŽlevŽ du principe actif chlorhydrate de sevelamer, qui devient encore plus important si la formulation le contient ˆ des concentrations ŽlevŽes, en particulier si ladite formulation est un comprimŽ. Pour rŽsoudre ce problme les formulations de l'invention comprennent un excipient pharmaceutiquement acceptable qui sert de diluant, de prŽfŽrence un amidon prŽgŽlatinisŽ.

Designated States:
AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.African Regional Intellectual Property Org. (ARIPO) (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW)Eurasian Patent Organization (EAPO) (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM)European Patent Office (EPO) (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR)African Intellectual Property Organization (OAPI) (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).

Publication Language:
English (EN)
Filing Language:
English
(EN)

DETAILED DESCRIPTION:





NOVEL PHARMACEUTICAL COMPOSITION COMPRISING POLY (ALLYLAMIN-CO-N^'-DIALLYL- 1,3-DIAMINO-I-HYDROXYPROPANE)

HYDROCHLORIDE

FIELD OF THE INVENTION

The present invention relates to a novel pharmaceutical composition comprising poly(allylamin-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride in solid dosage forms in amount from about 80% to about 94% by weight including the water of hydration, and to processes for the preparation and utilization thereof.

BACKGROUND OF THE INVENTION

Hyperphosphatemia plays a role in the development of secondary hyperparathyroidism in renal insufficiency. Treatment of hyperphosphatemia includes reduction in dietary intake of phosphate, inhibition of intestinal phosphate absorption with phosphate binders, and removal of phosphate with dialysis.

Poly(allylamine-co-N,N'-diallyl- 1 ,3-diamino-2-hydroxypropane) hydrochloride, commonly known as sevelamer hydrochloride (see formula below) is a non-absorbed binding crosslinked polymer. It contains multiple amines separated by one carbon from the polymer backbone. These amines exist in a protonated form in the intestine and interact with phosphate molecules through ionic and hydrogen bonding. By binding phosphate in the dietary tract and decreasing absorption, sevelamer hydrochloride lowers the phosphate concentration in the serum.

a.b: number of primary amine groups c: number of crosslinking groups m: number to indicate extended polymer network n: fraction of protonated amines

According to the United States Food & Drug Administration information, sevelamer hydrochloride is a phosphate binder in the dosage and form of 400 mg and 800 mg film-coated tablets for oral administration, marketed under the trade name Renagel¨, indicated for the control of serum phosphorus in patients with chronic kidney disease on dialysis. The recommended starting dose of Renagel is 800 mg to 1600 mg, which can be administered as one to two 800 mg Renagel¨ Tablets or two to four 400 mg Renagel¨ Tablets, with meals based on serum phosphorus level. EP 1 239 837 Bl discloses a tablet, which composition comprises an aliphatic amine polymer what includes sevelamer hydrochloride, in amount at least 95% by weight of the core, assuring minimum amount of excipients in the pharmaceutical composition to provide a tablet that is as small as possible and easy to administer. This patent also describes that for sevelamer the compressibility is strongly dependent upon the degree of hydration (moisture content), therefore the process of preparation of the pharmaceutical composition requieres hydrating or drying sevelamer in order to achieve the required degree of hydration in order to achieve optimal compression.

EP 1 304 104 Bl discloses a tablet which comprises a phosphate-binding polymer what includes sevelamer hydrochloride, together with crystalline cellulose and/or low substituted hydroxypropylcellulose, what ensures sufficient hardness and shows rapid dispersibility. This patent further indicates difculties that can occure during development of the pharmaceutical composition comprising sevelamer, which are caused by the hygroscopic nature of the active ingredient and the high dose of the active principle in the tablet core. Therefore there is a need to provide alternative pharmaceutical compositions which might be easy to manufacture, may have a broad range of compressibility and rapid disintegration time, independently of the water content of sevelamer hydrochloride. This means that the process for preparing said formulations had not to comprise any hydrating/dehydrating or drying step of the active principle sevelamer.

DESCRIPTION OF THE INVENTION

The invention provides an alternative pharmaceutical composition which is easy to manufacture, have a broad range of compressibility and rapid disintegration time, and is independent on the water content of sevelamer hydrochloride.

In an aspect, the invention provides a novel solid pharmaceutical composition for oral administration comprising from about 80% to about 94% by weight of sevelamer hydrochloride including the water of hydration, and at least one pharmaceutical acceptable excipient, which is useful for the therapeutic treatment of mammals, including humans.

Preferably the novel solid dosage form composition of the invention comprises from about 84% to about 90% by weight of sevelamer hydrochloride including the water of hydration.

The solid composition of the invention preferably includes a therapeutically acceptable quantity of sevelamer hydrochloride (e.g. 400 mg and/or 800 mg) and further includes one or more pharmaceutically acceptable carriers and/or excipients.

At least one pharmaceutical acceptable excipient of the solid pharmaceutical composition of the invention is a diluent, preferably is a pharmaceutically acceptable starch, for example pregelatinized starch, corn starch, wheat starch, rice starch, potato starch. Even more preferably, the diluent of the pharmaceutical composition of the invention is pregelatinized starch. For the purpose of present invention the term "pregelatinized starch" is defined as a starch that has been chemically and/or mechanically processed to rupture all or part of the starch granules and so render the starch flowable and directly compressible. Partially pregelatinized grades are also commercially available. Typically, pregelatinized starch contains 5% of free amylose, 15% of free amylopectin and 80% unmodified starch. In present invention the commercially available "Starch 1500¨" has been used. Aanother commercially available trade marks according to "Pharmaceutical excipients" are the following:

- "Sepistab¨ ST 200"

- "Instastarch¨"

- "Lycatab¨ PGS" - "National 78-1551¨"

- "Pharma-Gel"

- "Prejel

The applicants have surprisingly found that the use of a pharmaceutically acceptable starch in the pharmaceutical composition of the invention stabilizes and facilitates the manufacturing process of said pharmaceutical composition. Namely, the combination of sevelamer hydrochloride with a pharmaceutically acceptable starch in the formulations of present invention avoids the need for controlling the water content in the active ingredient, which advantageously saves time, energy and resources. The pharmaceutical acceptable starches are characterized by having high water content up to about 20%. It has been found in present invention that this water can migrate and be absorbed by the hygroscopic sevelamer hydrochloride assuring the desired properties for the final pharmaceutical composition.

In a preferred embodiment of present invention the solid pharmaceutical composition further comprises a pharmaceutical acceptable excipient selected from the following group: one or more binding agent, one or more disintegrant, one or more surfactant, one or more stabilizing agent, one or more lubricant, one or more glidant (improving fluidity), and mixtures thereof. Optionally, the pharmaceutical compositions of the present invention may further comprise a coating layer.

In another aspect, the present invention relates to a process for preparing the solid pharmaceutical compositions of the invention, said process comprising blending the sevelamer hydrochloride with the at least one pharmaceutically acceptable excipient.

The solid pharmaceutical composition of the invention may be in any known solid dosage form such as, for example, tablets, coated tablets, orodispersible tablet, mini-tablets in capsules, pills and the like.

Preferably, the solid pharmaceutical composition of the invention is in the form of tablets or coated tablets. It has also been found in present invention that the use of a pharmaceutically acceptable starch in the solid pharmaceutical composition of the invention is especially advantageous when producing tablets or coated tables. Precisely, the use of pharmaceutically acceptable starch facilitates the manufacturing process as it does not require a previous hydrating or drying step of the active ingredient, while providing a tablet with excellent hardness and fast disintegration time.

In yet another aspect, the invention relates to a process for preparing the solid pharmaceutical composition of the invention in the form of tablets or coated tablets, said process comprising the steps of blending the sevelamer hydrochloride with the at least one pharmaceutically acceptable excipient to obtain a blend, compressing the blend to obtain a tablet, and optionally coating the tablet to obtain a coated tablet.

Preferably, the compressing the blend to obtain a tablet of the process above is carried out by means of a direct compression process, which is easier to control, and saves time and energy.


EXAMPLES
EXAMPLE 1

Preparation of sevelamer hydrochloride tablets wherein the used sevelamer hydrochloride had a water content of 4.90%

This example shows a tablet composition comprising from about 84% to about 90% by weight of sevelamer hydrochloride, and pharmaceutically acceptable excipients, wherein one of these excipients was pregelatinized starch, which stabilized the pharmaceutical composition and facilitated its manufacturing process. This example further shows a process for preparing a solid pharmaceutical in accordance with an embodiment of the invention.

The tablets were prepared using the materials listed in table 1.

Table 1

Tablets were manufactured using the following procedure comprising the following steps: i) blending sevelamer hydrochloride with pregelatinized starch and colloidal silicon dioxide, ii) the blend of step i) was lubricated with stearic acid, iii) the resultant mixture was compressed into sevelamer hydrochloride tablets of appropriate weight and hardness, iv) the tablet cores of step iii) could be optionally coated. Obtained tablets had 5min 44sec of disintegration time and 293.6 N of hardness.

EXAMPLE 2

Preparation of sevelamer hydrochloride tablets wherein the used sevelamer hydrochloride had a water content of 6.90%

This example shows a tablet composition comprising from about 84% to about 90% by weight of sevelamer hydrochloride, and pharmaceutically acceptable excipients, wherein one of these excipients was pregelatinized starch, which stabilized the pharmaceutical composition and facilitated its manufacturing process.

This example further shows a process for preparing a solid pharmaceutical in accordance with an embodiment of the invention.

The tablets were prepared using the materials listed in table 2.

Table 2

Tablets were manufactured using the following procedure comprising the following steps: i) blending sevelamer hydrochloride with pregelatinized starch and colloidal silicon dioxide, ii) the blend of step i) was lubricated with stearic acid, iii) the resultant mixture was compressed into sevelamer hydrochloride tablets of appropriate weight and hardness, iv) the tablet cores of step iii) could be optionally coated. Obtained tablets had 3min 22sec of disintegration time and 239.4 N of hardness.

EXAMPLE 3

Preparation of sevelamer hydrochloride tablets wherein the used sevelamer hydrochloride had a water content of 7.43%

This example shows a tablet composition comprising from about 84% to about 90% by weight of sevelamer hydrochloride, and pharmaceutically acceptable excipients, wherein one of these excipients was pregelatinized starch, which stabilized the pharmaceutical composition and facilitated its manufacturing process. This example further shows a process for preparing a solid pharmaceutical in accordance with an embodiment of the invention.

The tablets were prepared using the materials listed in table 3.

Table 3

Tablets were manufactured using the following procedure comprising the following steps: i) blending sevelamer hydrochloride with pregelatinized starch and colloidal silicon dioxide, ii) the blend of step i) was lubricated with stearic acid, iii) the resultant mixture was compressed into sevelamer hydrochloride tablets of appropriate weight and hardness, iv) tablet cores of step iii) could be optionally coated. Obtained tablets had 3min 09sec of disintegration time and 185.1 N of hardness.

EXAMPLE 4

Preparation of sevelamer hydrochloride tablets wherein the used sevelamer hydrochloride had a water content of 8.10%

This example shows a tablet composition comprising from about 84% to about 90% by weight of sevelamer hydrochloride, and pharmaceutically acceptable excipients, wherein one of these excipients was pregelatinized starch, which stabilized the pharmaceutical composition and facilitated its manufacturing process.

This example further shows a process for preparing a solid pharmaceutical in accordance with an embodiment of the invention. The tablets were prepared using the materials listed in table 3.

Table 3

For the purpose of present invention the term "Dextrates" is defined as a purified mixture of saccharides resulting from the controlled enzymatic hydrolysis of starch. It is either anhydrous or hydrated. In addition to dextrose, dextrates contains 3-5% maltose and higher polysaccharides. In present invention the commercially available trade mark of dextrates Emdex¨, has been used.

Tablets were manufactured using the following procedure comprising the following steps: i) blending sevelamer hydrochloride with pregelatinized starch, dextrates and colloidal silicon dioxide, ii) the blend of step i) was lubricated with stearic acid, iii) the resultant mixture was compressed into sevelamer hydrochloride tablets of appropriate weight and hardness, iv) the tablet cores of step iii) could be optionally coated. Obtained tablets had lmin 47sec of disintegration time and 293 N of hardness.
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