Pharmaceutical oral dosage form containing a synthetic oligosaccharide
The present invention concerns a pharmaceutical formulation intended for oral administration containing a synthetic oligosaccharides containing one to 18 monosaccharide units and having a therapeutical activity or a pharmaceutically acceptable additions salt or solvate thereof wherein the formulation contains: a) the synthetic oligosaccharide (A) in an amount of up to 5% by weight of the total weight of the formulation, advantageously up to 1% by weight of the total weight of the formulation, b), a lipophilic phase (B) consisting of triglyceride of fatty acids in an amount of 50 to 80% by weight of the total weight of the formulation, advantageously of 50 to 70% by weight of the total weight of the formulation, c) at least one lipophilic surfactant (C) with HLB below 7 consisting of partial esters of polyol and fatty acids in an amount of 10 to 30% by weight of the total weight of the formulation, advantageously of 15 to 30% by weight of the total weight of the formulation, d) at least one hydrophilic surfactant (D) with HLB above 7 in an amount of up to 20% by weight of the total weight of the formulation, advantageously up to 15% by weight of the total weight of the formulation, e) optionally, at least one hydrophilic solvent (E) in an amount of up to 15% by weight of the total weight of the formulation, advantageously up to 10% by weight of the total weight of the formulation, (F) between 0 and 30% by weight of the total weight of the formulation of a chemical and/or physical stabilization agent (F), advantageously between 0 and 20% by weight of the total weight of the formulation, wherein when the formulation is in a form of a reverse emulsion or microemulsion and contains at least one hydrophilic solvent (E), the physical stabilization agent is present and is silicon dioxide.
1. A pharmaceutical formulation intended for oral administration containing a synthetic oligosaccharides containing 3 to 18 monosaccharide units and having a therapeutical activity or a pharmaceutically acceptable additions salt or solvate thereof wherein the formulation contains:
a) the synthetic oligosaccharide (A) in an amount of up to 5% by weight of the total weight of the formulation,
b) a lipophilic phase (B) consisting of triglyceride of fatty acids in an amount of 58 to 64% by weight of the total weight of the formulation,
c) at least one lipophilic surfactant (C) with HLB below 7 consisting of partial esters of polyol and fatty acids in an amount of 10 to 30% by weight of the total weight of the formulation,
d) at least one hydrophilic surfactant (D) with HLB above 7 in an amount of up to 20% by weight of the total weight of the formulation,
e) optionally, at least one hydrophilic solvent (E) in an amount of up to 15% by weight of the total weight of the formulation,
f) between 0 and 30% by weight of the total weight of the formulation of a chemical and/or physical stabilization agent (F),
wherein when the formulation is in a form of a reverse emulsion or microemulsion and contains at least one hydrophilic solvent (E), the physical stabilization agent is present and is silicon dioxide.
2. Formulation according to claim 1 wherein the lipophilic phase (B) consists of triglycerides of medium chain fatty acids.
3. Formulation according to claim 1 wherein the hydrophilic surfactant (D) is selected from the group consisting of a polyoxyethylene (20) monooleate, PEG 8 caprylic/capric glycerides, PEG 6 caprylic/capric glycerides, poly(oxyethylene)(4)Lauryl ether and mixtures thereof.
4. Formulation according to claim 1 wherein the hydrophilic solvent (E) is selected from the group consisting of propylene glycol, PEG 400, diethylene glycol monoethyl ether, glycerol triacetate, ethanol, glycerol, dimethylisosorbide, N-methyl-2-pyrrolidone, poloxamers, water and mixtures thereof.
5. Formulation according to claim 1 wherein the lipophilic surfactant (C) consists of a mixture of mono and diglyceride of medium chain fatty acids.
6. Formulation according to claim 1 wherein it contains the hydrophilic solvent (E) and it is in the form of a reverse microemulsion, a reverse emulsion or a micellar solution in oil.
7. Formulation according to claim 1 wherein its extent of digestion after 60 minutes in pancreatin solution containing a pancreatin extract having an activity of approximately 8 Tributyrin Units (TBUs) per milligram of dry powder in distilled water at the dosage of 250 mg/ml at 37.5° C.+/−0.5° C. is such that at least 1 mmol of the total free fatty acid is released/g of the formulation.
8. Formulation according to claim 1 wherein the formulation is homogenous.
9. Formulation according to claim 1 wherein the oligosaccharide is a pentasaccharide.
10. Formulation according to claim 9 wherein the pentasaccharide is a heparin-related pentasaccharide.
11. Enteric pharmaceutical dosage form which contains the formulation according to claim 1 , the enteric dosage form being pH dependent.
12. A method for treating and/or preventing venous thromboembolism, comprising administering to a person in need thereof an effective amount of the formulation according to claim 10 .
13. A method according to claim 12 , wherein:
the synthetic oligosaccharide (A) is in an amount of up to 1% by weight of the total weight of the formulation,
the lipophilic phase (B) in an amount of 50 to 70% by weight of the total weight of the formulation,
the at least one lipophilic surfactant (C) with HLB below 7 consists of partial esters of polyol and fatty acids in an amount of 15 to 30% by weight of the total weight of the formulation,
the at least one hydrophilic surfactant (D) is up to 15% by weight of the total weight of the formulation,
the least one hydrophilic solvent (E) is in an amount of up to 10% by weight of the total weight of the formulation, and
the chemical and/or physical stabilization agent (F) is between 0 and 20% by weight of the total weight of the formulation.
14. A method according to claim 12 , wherein said method is for treating acute coronary syndromes, myocardial infarction, or stroke.
15. A method according to claim 12 , wherein said composition is in an enteric pharmaceutical dosage form.
16. A formulation according to claim 1 , wherein the formulation contains:
a) the synthetic oligosaccharide (A) in an amount of up to 1% by weight of the total weight of the formulation,
b) a lipophilic phase (B) consisting of triglyceride of fatty acids in an amount of 58 to 64% by weight of the total weight of the formulation,
c) at least one lipophilic surfactant (C) with HLB below 7 consisting of partial esters of polyol and fatty acids in an amount of 15 to 30% by weight of the total weight of the formulation,
d) at least one hydrophilic surfactant (D) with HLB above 7 in an amount of up to 15% by weight of the total weight of the formulation,
e) optionally, at least one hydrophilic solvent (E) in an amount of up to 10% by weight of the total weight of the formulation, and
f) a chemical and/or physical stabilization agent (F) between 0 and 20% by weight of the total weight of the formulation.
17. A formulation according to claim 1 , wherein the oligosaccharide is a pentasaccharide in the form of its sodium salt, wherein the lipophilic phase (B) consists of triglycerides of caprylic acid, capric acid, or a mixture thereof, wherein the lipophilic surfactant (C) consists of a mixture of mono and diglyceride of caprylic and/or capric acid, wherein the hydrophilic solvent (E) is propylene glycol, water, or mixtures thereof.
18. A method according to claim 12 , wherein the formulation is an enteric dosage form, wherein the enteric dosage form is pH dependent, wherein the thromboembolism is phlebitis, deep-veins thrombosis or pulmonary embolism, and wherein the condition related to blood coagulation disorder and/or for preventing and/or treating arterial thrombosis is acute coronary syndromes, myocardial infarction, or stroke.
19. A method according to claim 13 , wherein the formulation is an enteric dosage form, wherein the enteric dosage form is pH dependent, wherein the thromboembolism is phlebitis, deep-veins thrombosis or pulmonary embolism, and wherein the condition related to blood coagulation disorder and/or for preventing and/or treating arterial thrombosis is acute coronary syndromes, myocardial infarction, or stroke.