Sustained release formulation comprising octreotide and three linear polylactide-co-glycolide polymers   

The present invention relates to sustained release formulations comprising as active ingredient octreotide or a pharmaceutically-acceptable salt thereof and three different linear polylactide-co-glycolide polymers (PLGAs).

These pharmaceutical compositions according to the present invention are indicated for inter alia long-term maintenance therapy in acromegalic patients, and treatment of severe diarrhea and flushing associated with malignant carcinoid tumors and vasoactive intestinal peptide tumors (vipoma tumors).

Peptide drugs are usually administerd systemically, e.g. parenterally. However, parenteral administration may be painful and cause discomfort, especially for repeated daily administrations. In order to minimize the number of injections to a patient, the drug substance should be administered as a depot formulation. A common drawback with injectable depot formulations is the fluctuation in plasma levels such as high peak levels together with plasma levels close to zero during the entire release periode.

Sustained release formulations comprising as active ingredient octreotide or a pharmaceutically acceptable salt thereof and two or more different polylactide-co-glycolide polymers (PLGAs) have, for instance, been also disclosed in WO2007/071395.

The present invention discloses a sustained release formulation comprising as active ingredient (drug substance) octreotide or a pharmaceutically-acceptable salt thereof. Octreotide is a somatostatin analog having the following formula:

The active ingredient may be in the form of a pharmaceutically acceptable salt of octreotide, such as an acid addition salt with e.g. inorganic acid, polymeric acid or organic acid, for example with hydrochloric acid, acetic acid, lactic acid, citric acid, fumaric acid, malonic acid, maleic acid, tartaric acid, aspartic acid, benzoic acid, succinic acid or pamoic (embonic) acid. Acid addition salts may exist as mono- or divalent salts, e.g. depending whether 1 or 2 acid equivalents are added. Preferred is the pamoate monosalt of octreotide.

The particle size distribution of the drug substance influences the release profile of the drug from the depot form. The drug substance which is used to prepare the depot formulation is crystalline or in the form of an amorphous powder. Preferred is an amorphous powder which has a particle of a size of about 0.1 microns to about 15 microns (99%>0.1 microns, 99%<15 microns), preferably from 1 to less than about 10 microns (90%>1 microns, 90%<10 microns). The drug substance preferentially undergoes a micronization process to present the required particle size distribution.

The present invention further provides a sustained release pharmaceutical composition (depot) comprising as active ingredient octreotide or a pharmaceutically-acceptable salt thereof incorporated in blends or mixtures of poly(lactide-co-glycolide)s (PLGAs), for instance in form of microparticles, implants or semisolid formulations.

Alternatively to blends of PLGAs, in another aspect of the present invention the pharmaceutical composition comprises a mixture of PLGA polymers containing the active ingredient; i.e. the active ingredient may be incorporated into one or more PLGAs in form of microparticles, implants or semisolid formulations and is then mixed with another microparticle or implant or semisolid formulation also comprising the active ingredient and one or more PLGAs.

The pharmaceutical composition according to the present invention allows a sustained release of the active ingredient over a period of more than three month, preferentially between three and six months. During the release of the active ingredient the plasma levels of octreotide are within the therapeutic range. It is understood that the exact dose of octreotide will depend on a number of factors, including the condition to be treated, the severity of the condition to be treated, the weight of the subject and the duration of therapy.

Surprisingly fluctuations in plasma levels can significantly be reduced by using a suitable combination of three different linear PLGAs in the pharmaceutical composition according to the present invention.

The drug substance is incorporated into a biodegradable polymer matrix consisting of three different linear polylactide-co-glycolide polymers (PLGAs). The PLGAs have a lactide: glycolide monomer ratio of 100:0 to 40:60, preferably 90:10 to 40:60, more preferably 85:15 to 65:35.

The PLGAs according to the present invention have a molecular weight (Mw) ranging from 1,000 to 500,000 Da, preferably from 5,000 to 100,000 Da. The architecture of the polymers is linear.

The inherent viscosity (IV) of the PLGAs according to the present invention is below 0.9 dl/g in CHCl3, preferentially below 0.8 dl/g in CHCl3. The inherent viscosities can be measured by the conventional methods of flow time measurement, as described for example in “Pharmacopoée Européenne”, 1997, pages 17-18 (capillary tube method). Unless stated otherwise, these viscosities have been measured in chloroform at a concentration of 0.5% at 25° C. or in hexaisofluoropropanol at a concentration of 0.5% at 30° C.

End groups of the PLGAs according to the present invention can be but are not limited to Hydroxy, carboxy, ester or the like.

The drug substance content of the depot formulation (the loading) is in a range of 1% to 30%, preferred 10% to 25%, more preferred 15% to 20%. The loading is defined as the weight ratio of drug substance as free base to the total mass of the PLGA formulation.

Suitable polymers are commonly known but not limited to those commercially available as RESOMER® by Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany, LACTEL® by Absorbable Polymers International (API), Pelham, Ala., USA, MEDISORB® by Alkermes, Inc., Cambridge, Mass., USA, PURASORB® by PURAC biochem By, Gorinchem, The Netherlands. Examples of suitable polymers are listed in Table 1.

TABLE 1 Examples of suitable polymers Inherent Producer No Product name Polymer viscosity [dL/g] Supplier 1 Resomer ® R 202 H Linear Poly(D,L-lactide) 0.16-0.241) Boehringer free carboxylic acid end group 2 Resomer ® R 202 S Linear Poly(D,L-lactide) 0.16-0.241) Boehringer 3 Resomer ® R 203 S Linear Poly(D,L-lactide) 0.25-0.351) Boehringer 4 Resomer ® RG 752 H Linear Poly(D,L-lactide-co- 0.14-0.221) Boehringer glycolide) 75:25 free carboxylic acid end group 5 Resomer ® RG 752 S Linear Poly(D,L-lactide-co- 0.16-0.241) Boehringer glycolide) 75:25 6 Resomer ® CR RG Linear Poly(D,L-lactide-co- 0.32-0.441) Boehringer 75:25 or Resomer ® glycolide) 75:25 RG Type 75:25 S/ Resomer ® RG 753 S 7 Lactel ® 100D020A Linear Poly(D,L-lactide) 0.15-0.252) API/Durect free carboxylic acid end group 8 Lactel ® 100D040A Linear Poly(D,L-lactide) 0.26-0.542) API/Durect free carboxylic acid end group 9 Lactel ® 100D040 Linear Poly(D,L-lactide) 0.26-0.542) API/Durect 10 Lactel ® 100D065 Linear Poly(D,L-lactide) 0.55-0.752) API/Durect 11 Lactel ® 85DG040 Linear Poly(D,L-lactide-co- 0.26-0.542) API/Durect glycolide) 85:15 12 Lactel ® 85DG065 Linear Poly(D,L-lactide-co- 0.55-0.752) API/Durect glycolide) 85:15 13 Lactel ® 75DG065 Linear Poly(D,L-lactide-co- 0.55-0.752) API/Durect glycolide) 75:25 14 Lactel ® 65DG065 Linear Poly(D,L-lactide-co- 0.55-0.753) API/Durect glycolide) 65:35 15 Lactel ® 50DG065 Linear Poly(D,L-lactide-co- 0.55-0.753) API/Durect glycolide) 50:50 16

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