Phospholipid formulations

Details Phospholipid formulations Phospholipid formulations

1999-03-29

2001-04-10

Park, Hankyel T. (Department: 1648)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

C424S001110, C514S008100

Reexamination Certificate

active

06214375

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to improved delivery of medicinally active compounds into the body. In particular it relates to production of stable liposomes for delivery of cosmetics, drugs, enzymes, growth factors, hormones, interferons, interleukins, moisturizers, peptides, proteins, and steroids. A variety of administration techniques, e.g. oral, injection, topical, may be used, depending on the medicinally active ingredient.
BACKGROUND OF THE INVENTION
Drugs, to be effective must be present at the site of action in an effective concentration for a desired period of time. Oral and parenteral administration of drugs relies on the blood circulation to carry the drugs to the target organs. Consequently, the drug is distributed throughout the body and deposited in all organs, which often lead to unwanted side effects. Attempts have been made to favourably influence drug distribution by combining the drug with a “carrier”. Among the variety of carriers, liposomes, due to their composition and compatibility with the living organism, seem to have a good potential for selective drug delivery.
It is believed that a substance will have a different destiny when delivered using a liposome rather than by commercially used carriers (sometimes known as excipients), which, due to their composition are foreign to the living organism. Liposomes are made of similar components of cell membranes, and are compatible with the skin superficial layer structure. According to one source, the horny skin layer can be compared to a wall, where keratinized cells represent the bricks, and intracellular lipids the cement which keeps them together. Lipids, lying in lamellae, show a bilayer structure similar to that of biological membranes. They have a lipidic layer enclosed in a water layer. The function of the lipid layer is double: on the one hand it represents the most important part of the barrier of the cutaneous permeability, on the other hand it maintains the hydration of the skin, indispensable for the integrity of the skin. It is believed that liposomes, made of phospholipidic fractions which absorb water, act both as a water carrier and as a reintegrator of permeability, since they interact with the lamellar lipids of the horny skin layer. Moreover, the liposome vesicle has the function of “carrier”, that is, it releases the encapsulated active substances both through diffusion from its walls and through spill when it opens.
Materials like vaccines, hormones, enzymes, interferons, interleukins, are rapidly inactivated when injected into body and when they enter systemic circulation. Accumulation of these active substances in the body, to generate a superior response or therapeutic effect, is not satisfactory and systemic side effects can occur frequently. Incorporating such materials into liposomes can increase their efficacy several folds and provides superior therapeutic effect.
Interest in the use of liposomes in dermato-cosmetology has increased in the recent years, mainly for two reasons: the particular affinity of liposomes with the skin, and the fact that they are applied directly on the part where they are destined. The advantages of this kind of transportation into the skin include release of the active ingredients at different levels in the skin, longer contact with the cutaneous layers, and reduced systemic absorption. Release of the active ingredient mainly occurs in the multilamellar liposomes, which allows a slower release of the active ingredient in the chosen site, with a so-called depot effect, which is very useful in order to streamline the effects on the skin.
The clinical use of liposomes has been delayed because of difficulties in mass production, sterilization, stability and safety. The present invention is aimed at production of stable liposomes for delivery of medicinally active ingredients.
Molecular weights indicated herein are weight average molecular weights (Mw)and can be determined by known light scattering methods or gel filtration chromatography methods. Light scattering methods are preferred.
DISCLOSURE OF THE INVENTION
Accordingly the present invention provides a formulation comprising i) at least one medicinally active ingredient, ii) at least three compounds selected from the group consisting of egg phosphatidylcholine (PC) dilauryl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine(DPPC), dioleoyl phosphatidylcholine (DOPC), dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylglycerol(DPPG), dimyristoyl phosphatidic acid (DMPA), dipalmitoyl phosphatidic acid (DPPA), dipalmitoyl phosphatidylethanolamine (DPPE), distearoyl phosphatidylcholine (DSPC), brain phosphatidylserine (PS), brain sphingomyelin (SM), cholesterol (C), cardiolipin (CL), trioctanoin (TC), triolein (TO), soy phosphatidylcholine, poly(adenylic acid), phosphatidylethanolamine (PE), phosphatidyl glycerol (PG), phosphatidyl inositol (PI), sphingosine, cerebroside (glycolipid), and iii) at least one biodegradable polymer selected from the group consisting of copolymers of sucrose and epichlorohydrin having molecular weights of from 70 000 to 400 000, branched hydrophilic polymers of sucrose having molecular weights of from 70 000 to 400 000, polyethylene glycols having molecular weights of from 1000 to 100 000, polyvinyl alcohols having molecular weights of from 70 000 to 110 000, methoxypolyethylene glycol, ethoxypolyethylene glycol, polyethylene oxide, polyoxyethylene, polyoxypropylene, cellulose acetate, sodium alginate, N,N-diethylaminoacetate, block copolymers of polyoxyethylene and polyoxypropylene, polyvinyl pyrrolidone, polyoxyethylene X-lauryl ether wherein X is from 9 to 20, and polyoxyethylene sorbitan esters.
The letter combinations in parentheses are abbreviations used elsewhere in this specification.
It is to be understood that the term “egg phosphatidylcholine” comprises combinations of substantially saturated phosphatidylcholines, e.g. combinations of 99% saturated Phospholipon H (trade mark) and 90% saturated Phospholipon G (trade mark) in ratios of 70:30 to 95:5 Phospholipon H:Phospholipon G.
In another embodiment the formulation has at least two biodegradable polymers.
In yet another embodiment the combinations of compounds are selected from the group consisting of: i) brain phosphatidylserine, cholesterol, triolein and phosphatidylethanolamine, ii) egg phosphatidylcholine, distearoyl phosphatidylcholine, cholesterol and triolein, iii) cholesterol, cardiolipin, poly(adenylic acid) and triolein, iv) egg phosphatidylcholine, distearoyl phosphatidylcholine, cholesterol and trioctanoin, v) egg phosphatidylcholine, cholesterol, trioctanoin and phosphatidyl glycerol, vi) egg phosphatidylcholine, cholesterol, cardiolipin and triolein, vii) dioleoyl phosphatidylcholine, cholesterol, cardiolipin and triolein, viii) egg phosphatidylcholine, cholesterol, brain phosphatidylserine and triolein, ix) dioleoyl phosphatidylcholine, brain phosphatidylserine, cholesterol and triolein, x) egg phosphatidylcholine, dipalmitoyl phosphatidylglycerol, cholesterol and trioctanoin, xi) dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine and triolein, xii) egg phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine and trioctanoin, xiii) phosphatidylcholine, cholesterol, brain phosphatidylserine and triolein, xiv) phosphatidylethanolamine, cholesterol cardiolipin and triolein, xv) phosphatidylcholine, cholesterol, trioctanoin and dipalmitoyl phosphatidylethanolamine, xvi) dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine and triolein, xvii) phosphatidylcholine, phosphatidylethanolamine, cholesterol, brain phosphatidylserine and triolein, xviii) phosphatidylcholine, phosphatidylthanolamine, cholesterol, cardiolipin and triolein, xix) phosphatidylcholine, dioleoyl phosphatidylcholine, cholesterol, cardiolipin and triolein, xx) phosphatidylcholine, dioleoyl phosphatidylcholine, cholesterol, brain phosphatidy

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