Phospholipid depot
The present invention is directed to phospholipid compositions and methods of preparation of phospholipid depots that are injectable through a fine needle. The phospholipid depots prepared by the methods described herein comprise nanometer-sized phospholipid particles and exhibit a higher degree of structural order compared to compositions prepared by other methods.
1. An nanoemulsion based injectable one-phase gel composition, comprising:
about 30% to about 60% by weight of phospholipid based on the total weight of the gel, wherein the phospholipid is a member selected from the group consisting of a lecithin, phosphatidylcholine or a mixture thereof;
0.1% to 65% by weight based on the total weight of the gel;
10% to 50% by weight of an oil based on the total weight of the gel, wherein the phospholipid comprising particles are stacked together and have an average particle size of about 30 nm to about 100 nm in diameter;
and wherein the composition has an increased degree of order as shown by an increase in the Scherrer crystalline domain size over a composition containing the same quantities of the same components but prepared by a process without forming a nanodispersion and the discrete phospholipid particles; is extrudable or injectable through a 25 G, ½ inch long needle from a 1 cc syringe at an extrusion rate of 2 cc/min by an applied force of no more than 12 pounds.
2. The gel composition of claim 1 , further comprising a pharmacologically active agent having concentration of no more than 20% by weight of the final gel composition.
3. The gel composition of claim 2 , wherein the pharmacologically active agent is a heat-sensitive pharmacologically active agent.
4. The gel composition of claim 2 , wherein the pharmacologically active agent is a protein or peptide.
5. The gel composition of claim 2 , wherein the pharmacologically active agent is a member selected from the group consisting of an insulin, an insulin analog, a crystalline insulin with zinc and/or protamine, an NPH insulin, and a combination thereof.
6. The gel composition of claim 5 , wherein the phospholipid comprises 30% to 40% by weight based on the total weight of the gel.
7. The gel composition of claim 1 , wherein the phospholipid is a lecithin.
8. The gel composition of claim 1 , wherein the oil is selected from the group consisting of a synthetic oil, a vegetable oil, a medium chain oil, ethyl oleate, fatty acid, vitamin E, vitamin E succinate, cholesterol, or a mixture thereof.
9. The gel composition of claim 1 , further comprising one or more sugars selected from the group consisting of sucrose, dextrose, lactose, glucose, trehalose, maltose, mannitol, sorbitol, glycerol, amylose, starch, amylopectin, or a mixture thereof.
10. The gel composition of claim 1 , further comprising one or more non-aqueous solvents selected from the group consisting of ethanol, propylene glycol, glycerol, sorbitol, polyethylene glycol, ethyl oleate, or a mixture thereof.
11. The gel composition of claim 1 , further comprising a functional pharmaceutical excipient selected from the group consisting of an acidifying agent, an alkalizing agent, a pH buffering agent, a metal ion chelator, an antioxidant, a preservative, a tonicity/osmotic pressure modifier, a condensing agent, a solubilizing agent, or a mixture thereof.
12. The gel composition of claim 1 , where the gel composition has a small-angle X-ray scattering diffractogram of FIG. 10 and a lattice d spacing of 67 Å and 33 Å.
13. The gel composition of claim 1 , wherein the gel has an increase in the Scherrer crystalline domain size over a composition containing the same quantities of the same components but prepared by a process without forming a nanodispersion and the discrete phospholipid particles having a diameter of 30-100nm; and (2) a small-angle X-ray scattering diffractogram of FIG. 10 and a lattice d spacing of 67 Å and 33 Å.
14. An injectable one-phase gel composition, comprising about 30% to about 60% by weight of phospholipid, wherein the phospholipid is a member selected from the group consisting of a lecithin, phosphatidylcholine or a mixture thereof based on the total weight of the gel;
10% to 50% by weight of an oil based on the total weight of the gel; and
0.1% to 65% by weight water based on the total weight of the gel, wherein said composition is prepared by a process comprising:
i mixing one or more phospholipid(s) and water to form a primary dispersion;
ii homogenizing the primary dispersion to form a nanodispersion with an average particle size of about 30 nm to about 100 nm in diameter;
iii passing the nanodispersion through a filter; and
iv removing the excessive water to obtain a one-phase gel composition comprising (a) discrete phospholipid particles that are stacked together and have an average particle size of about 30 nm to about 100 nm in diameter; (b) an increased degree of order as shown by an increase in the Scherrer crystalline domain size over a composition containing the same quantities of the same components but prepared by a process without forming a nanodispersion and the discrete phospholipid particles of (a); and (c) is extrudable or injectable through a 25 G ½ inch long needle from a 1 cc syringe at an extrusion rate of 2 cc/min by an applied force of no more than 12 pounds.