JP2002513750A - Solvent / co-solvent free microemulsion and emulsion pre-concentrate drug delivery system - Google Patents

Abstract

(57) Abstract: A self-emulsifying pre-concentrated pharmaceutical composition that is capable of forming an oil-in-water microemulsion or emulsion when diluted with an aqueous solution is disclosed. The pre-concentrate comprises a surfactant consisting essentially of a therapeutically effective amount of a poorly water soluble therapeutic agent; a pharmaceutically effective amount of a low HLB oil component; and at least one surfactant having an HLB of about 10-20. Agent system and substantially no or very little hydrophilic solvent system. Also provided is a microemulsion or emulsion formed by diluting the self-emulsifying pre-concentrate with an aqueous solution.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to a pharmaceutical composition containing a poorly water-soluble (almost insoluble in water) therapeutic agent. In particular, the present invention relates to the administration of self-emulsifying microemulsions and pre-concentrated formulations of microemulsions or microemulsions and emulsions containing poorly water-soluble therapeutic agents, oil components and surfactant systems, especially oral administration to humans. About.
The pre-concentrates, microemulsions and emulsions described above have the advantage that they contain substantially no or very little hydrophilic solvent system.

BACKGROUND OF THE INVENTION Certain oily mixtures of lipophilic drugs such as cyclosporin, when combined with vegetable oils or other lipidic substances, surfactants, solvents and other excipients, can be used in aqueous media. It is known that when mixed, dispersions with a very small average particle size (eg, less than 200 nm) spontaneously form. These dispersions are known as microemulsions, and the oily mixture that generates the microemulsion is commonly referred to as a microemulsion pre-concentrate. When administered orally, this microemulsion pre-concentrate is believed to produce a similar dispersion with very small particle sizes, together with gastric and other physiological fluids.

[0003] A number of microemulsion pre-concentrated formulations are known, including soft gel formulations, to enhance the solubility and oral bioavailability of poorly water soluble pharmaceutical compounds such as cyclosporin A. Generally, these preparations contain the active ingredient,
Included is a hydrophilic solvent system containing an oil component, a surfactant that emulsifies the formulation, and a solvent / co-surfactant to solubilize the active ingredient.

[0004] Representative solvents / surfactants include ethanol, polyethylene glycol, propylene carbonate, dimethyl isosorbide, Transcutol and / or Gly.
cofurol. Disadvantages of the above formulations include stability or precipitation problems due to migration of volatile hydrophilic solvents or cosolvents (eg, ethanol can penetrate gelatin shells at normal storage temperatures), hygroscopic solvents or Includes stability or precipitation issues due to surfactant aids (eg, propylene glycol, Transcutol, Glycofurol) and toxicity issues due to the addition of certain solvents and surfactant aids (eg, dimethyl isosorbide). It is.

For example, US Pat. No. 5,603,951 discloses cyclosporine as an active ingredient, dimethyl isosorbide as a necessary surfactant aid, a surfactant, an oil which can be refined fish oil, from 1: 1 to 5: 1. : 2 to 10: 1 to 5 containing microemulsion concentrate. The inventor of the '951 patent discloses that ethanol, T
To address the above deficiencies with prior solvents / surfactant aids such as ranscutol or Glycofurol, the trade name ARLASOVE®
Was added to this formulation. The '951 pre-concentrate is formed by dissolving cyclosporine in dimethyl isosorbide while heating to about 60 ° C, and then adding the oil component and surfactant. WO97
/ 33610 discloses a microemulsion pre-concentrate system containing propylene carbonate or a mixture of a polyoxyethylene-polyoxypropylene block copolymer and propylene carbonate as a surfactant aid. US Patent No. 5,589
455 discloses a microemulsion pre-concentrate system containing a polyethylene glycol solvent. WO 93/20833 discloses a hydrophilic phase, such as Trans
Disclose microemulsion pre-concentrate systems containing cutol, Glycofurol, 1,2-propylene glycol or ethanol. EP76023
No. 7 discloses a microemulsion pre-concentrate system comprising a phospholipid, preferably lecithin. Phospholipids are known to have stability problems,
Disadvantageous.

In general, the oil components of conventional microemulsions are mono-, di- or triglycerides of fatty acids derived from vegetable oils; medium-chain triglycerides and / or mono- or diglycerides; mixtures of glycerides and polyglycolized glycerides; tocol, tocopherol and And / or tocotrienol; or a hydrophobic alcohol. WO97 /
No. 22358 discloses a microemulsion system containing tocol, tocopherol, tocotrienol and derivatives together with propylene carbonate or polyethylene glycol. EP 570715 discloses a microemulsion pre-concentrate system containing as a lipophilic phase a mixture of polyglycolized glycerides having an HLB of less than 16. WO 94/25068 discloses a microemulsion pre-concentrate system that uses a hydrophobic alcohol instead of a combination of hydrophilic and hydrophobic solvents. While the above system eliminates the need for a hydrophilic solvent system, the disadvantage of hydrophobic alcohols is that they have poor taste.

[0007] Cyclosporine is one example of a class of poorly water soluble drugs. Cyclosporin A (
CyA) is a lipophilic cyclic undecapeptide that can be isolated from the fungus Tolypoclodium inflatum Gams and intercalates interleukin-2 and several other cytokines, most notably calcium-dependent transcription in helper T lymphocytes. Inhibits specifically and reversibly. Due to its immunosuppressive properties, it can cause transplant rejection (e.g., allo- or xenograft rejection such as occurs in patients undergoing heart, lung, cardiopulmonary, liver, kidney, pancreas, skin or corneal transplants) and various autoimmune and inflammatory Is widely used as the first line of therapy for the prevention and treatment of diseases. CyA is used, for example, in the treatment of multidrug resistance syndrome in patients undergoing chemotherapy or after organ transplantation. In patients with severe disease refractory to standard treatment, CyA is associated with acute ocular Behcet's syndrome; endogenous uveitis; psoriasis; atopic dermatitis; arthritis, especially rheumatoid arthritis; active Crohn's disease and It is an effective treatment for nephrotic syndrome. Other conditions include chronic progressive and osteoarthritis, hemolytic anemia, aplastic anemia, autoimmune hematological disorders including erythrocytic anemia and idiopathic thrombocytopenia, systemic lupus erythematosus, Polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (eg, ulcerative colitis) , Endocrine ophthalmic diseases, Graves' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis,
Includes juvenile diabetes, keratoconjunctivitis sicca and verrucosa, interstitial pulmonary fibrosis, psoriatic arthritis, glomerulonephritis, juvenile dermatitis, asthma, tumors, hyperproliferative skin disorders, and fungal infections. This drug has also been used to treat patients with moderate to severe aplastic anemia to which bone marrow transplantation does not apply and patients with primary biliary cirrhosis. CyA may be effective in patients with refractory gangrenous pyoderma, polymyositis / dermatomyositis or severe corticosteroid-dependent asthma. CyA is known to have very specific effects on T cell proliferation, but the exact mechanism is unknown. Many non-immunosuppressive analogs of cyclosporin A have been shown to have resistance-altering activity, some of which are more potent than the parent compound. Nephrotoxicity,
Hepatotoxicity, hypertension, headache, hirsutism, gingival hyperplasia, neurological and gastrointestinal effects, thrombocytopenia and microvascular hemolytic anemia, hyperkalemia, hyperuricemia, and skin and lymphoproliferative malignancy Tumor growth is a common adverse event in cyclosporine recipients.

[0008] Since cyclosporin is very lipophilic and poorly water-soluble, it has been supplied as a solution of olive oil and peanut oil for clinical use. However, the bioavailability of cyclosporine from such oily solutions is very low, causing large inter-patient variability and systemic availability is reported to be 4-25% (Takada, K. et al.
., J. Pharmacobio-Dyn., 11: 80-7 (1988)). It has been reported that the bioavailability of cyclosporin depends on food, bile, and other interacting factors (Clin. Pharmacokinetics, 24: 472-95 (1993)). SANDIMMUNE® for oral administration, a widely used commercial preparation of CyA, is a solution of CyA in a vegetable oil derivative containing other inert excipients. For this formulation, it has been observed that the bioavailability of CyA varies widely between and within patients and with food. NEORAL®, a commercially available microemulsion pre-concentrated formulation, provides high bioavailability of CyA and is said to have low inter- and intra-patient variability. However, conversion to NEORAL® has been pointed out to pose a risk of adverse drug reactions (eg, Dr.
ug Saf., 16: 366-73 (1996); Lancet, 348: 205 (1996)).

[0009] CyA and fish oil have been co-administered to organ transplant patients in various clinical trials. For example, Andreassen et al. (JAAC, 29 (6): 1324-31 (1997)) reported that hypertension was effectively prevented in heart transplant patients given cyclosporin A and 4 g of fish oil. Kidney transplant recipients treated with cyclosporin A and fed fish oil had improved renal function after episode rejection (Transplantation, 54).
: 257 (1992)). U.S. Patent No. 5,118,493 describes administering CyA with an omega-3 fatty acid oil that mediates the nephrotoxic effect of cyclosporine.

[0010] ω3 fatty acid oils are useful for the treatment of autoimmune and inflammatory diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, immunosuppressive treatment, healthy people and heart. Prevention of hypertension in transplant patients, coronary heart disease, hyperlipidemia,
It has properties that can be used for a number of therapeutic effects, including hypertriglyceridemia, improved renal function, and reduced nephrotoxicity. U.S. Patent No. 4,678,808 describes autoimmune diseases, acute and chronic inflammatory diseases, atherosclerosis, stroke, myocardial infarction, deep venous thrombosis, surgery, hyperlipidemia, The use of the above oils for treating disorders caused by arachidonic acid metabolites, including hypertension, increased platelet responsiveness, vascular lesions and occlusions, vasospasm and diabetes is described. According to US Pat. No. 5,225,441, which describes a composition for treating gingivitis and periodontitis, ω3 polyunsaturated fatty acids are used as substrates for the arachidonic acid cascade.
It can compete with the system 6 polyunsaturated fatty acids and alter the biosynthesis of prostaglandins and leukotrienes, potent mediators of inflammatory and immune responses. Other uses of omega-3 fatty acid oils are disclosed in US Pat. No. 5,034,415 (diabetes), US Pat.
No. 4,843,095 (rheumatoid arthritis), JP2253629 (anticancer), US Pat. No. 4,879,312 (enhancement of angiogenesis), JP1290625 (improvement of brain function), EP378,824 (anti-illness) Reduction of fluid, cholesterol and triglyceride levels, inhibition of platelet aggregation, inhibition of colon adenocarcinoma growth), US Pat.
No. 457,130 (cancer cachexia, malignant tumors, abnormal cAMP levels in adipose tissue, inhibition of lipolytic activity) and US Pat. No. 5,436,269 (hepatitis).

It is an object of the present invention to include poorly water-soluble therapeutic agents that can increase the bioavailability of the therapeutic agent, while minimizing inter- and intra-patient or food-induced variability of the bioavailability of the therapeutic agent. It is to provide a stable self-emulsifying microemulsion or emulsion pre-concentrate and / or a microemulsion or emulsion. A further object is to provide self-emulsifying pre-concentrates or corresponding microemulsions and emulsions with a high reproducibility of the therapeutic dose compared to conventional formulations. An additional object is to provide a self-emulsifying pre-concentrate or corresponding microemulsion or emulsion that contains a poorly water soluble therapeutic agent and provides a greater amount of therapeutic agent in a single dosage unit.

An additional object of the present invention is to provide a stable self-emulsifying pre-concentrate, microemulsion, containing a poorly water-soluble therapeutic agent and containing substantially no or very little hydrophilic solvent system. Or providing an emulsion. In this way, the disadvantages of prior art systems containing hydrophilic solvent systems, such as stability problems, precipitation of the therapeutic agent, and / or toxicity problems, are avoided.

[0013] It is a further object of the present invention that the poorly water soluble therapeutic agent is substantially dissolved in the oil component,
It is to provide a stable self-emulsifying pre-concentrate and / or microemulsion or emulsion that eliminates or dramatically reduces the need for a substantial amount of a hydrophilic solvent system.

[0014] An additional object of the present invention is to provide a stable self-emulsifying agent that contains a poorly water soluble therapeutic agent and wherein the oil component and the surfactant system are selected such that the presence of a hydrophilic solvent system is not required. It is to provide a microemulsion or pre-concentrate of the emulsion and / or a microemulsion or emulsion.

[0015] An additional object of the present invention is to provide a stable self-emulsifying pre-concentrate containing a poorly water-soluble therapeutic agent and a low HLB oil component that is free or substantially free of a hydrophilic solvent system. And / or providing microemulsions or emulsions.

A further object of the present invention is to pre-concentrate a stable self-emulsifying microemulsion or emulsion containing a poorly water-soluble therapeutic agent and suitable for formulation into soft / hard capsules for oral administration. To provide a formulation and / or microemulsion or emulsion.

A further object of the invention is to provide a soft / hard capsule formulation of a stable self-emulsifying microemulsion or a pre-concentrate of an emulsion, comprising both oil components and sparingly water-soluble therapeutic agents in relatively large amounts. It is to be.

DISCLOSURE OF THE INVENTION Surprisingly, a pre-concentrate of a stable self-emulsifying microemulsion or emulsion containing a poorly water-soluble drug is combined with an oil component having an HLB of 4 or less, It has been found that it can be formed from a two-component self-emulsifying system containing a surfactant system containing one or more surfactants with HLB. This two-component system eliminates or dramatically reduces the need for a substantial amount of hydrophilic solvent system, and pre-concentrates that are substantially free of hydrophilic solvent systems or contain only minor amounts of hydrophilic solvent systems. Product formulation. It has also been found that the poorly water-soluble drug dissolves in the low HLB oil component, thereby enabling the preparation of a pre-concentrate containing a relatively large amount of the poorly water-soluble drug. The self-emulsifying microemulsions and emulsion pre-concentrates according to the present invention are poorly water-soluble therapeutic agents among the low HLB oil components that can be self-emulsified by surfactant systems when diluting this pre-concentrate in an aqueous medium. Takes a form in which is substantially solubilized.

Thus, the present invention is suitable for administration to mammals, in particular for oral administration to humans,
A self-emulsifying pre-concentrated pharmaceutical composition capable of forming an oil-in-water microemulsion or emulsion when diluted with an aqueous solution, comprising: (a) a therapeutically effective amount of a poorly water-soluble therapeutic agent; And (c) about 10-20, preferably 13-19, most preferably 15-18 H.
A surfactant system consisting essentially of at least one surfactant having LB, wherein the composition provides a composition that contains little or substantially no hydrophilic solvent system. The present invention also provides a microemulsion or emulsion formed by diluting a self-emulsifying pre-concentrate with an aqueous solution.

The disadvantages of the prior art systems indicated above are avoided, since the compositions according to the invention are substantially free or contain only trace amounts of hydrophilic solvent systems.

Preferred therapeutic agents include cyclosporins, especially cyclosporin A, nifedipine or indomethacin, and other class 4 drugs. Preferred low HLB oil components include Labrafil M1944CS; Labrafil M2125C
S; and fish oils or other ω3 fatty acid oils. Preferred ω3 fatty acid oils include, for example, ω3 free fatty acids, ω3 fatty acid triglycerides and ω3 fatty acids such as EPA, DHA, EPA triglycerides, DHA triglycerides, EPA ethyl esters, DHA ethyl esters and mixtures thereof. Includes ethyl esters.

When utilizing fish oil in the composition of the present invention, at least 50%, preferably at least 70%, more preferably at least 80%, in order to obtain a pharmaceutically effective amount of ω3 fatty acid oil in small amounts. It is preferable to use a fish oil containing an ω3 fatty acid oil.

As used herein, the term “low HLB oil component” refers to natural or synthetic pharmaceuticals in which the oil or mixture of oils has a HLB (hydrophilic-lipophilic group balance) of 4 or less. Means a commercially acceptable oil or mixture of oils. Examples of low HLB oil components include, but are not limited to, medium and long chain (eg, longer than C13) fatty acids and mono / di / triglycerides or esters thereof having an HLB of 4 or less; unsaturated fatty acids having an HLB of 4 or less And its mono / di / triglycerides or esters; and H of 4 or less
Natural oils such as canola, soybean, corn, olive, sunflower and their mono / di / triglycerides or esters having LB; or mixtures thereof. Preferred low HLB oil components include esters of medium and long chain fatty acids, especially ethyl esters. Specific examples of low HLB oil components include, but are not limited to, Lab
rafil M1944CS; Labrafil M2125CS; ethyl oleate and oleic acid; omega-6 fatty acids and esters such as mono / di / triglycerides or ethyl esters; and fish oil and other omega-3s as defined below.
Fatty acid oils, and mixtures thereof. Examples of oils that are not low HLB oil components include Miglyol 812 (HLB: about 8-10); Gelucire 44
/ 14 (HLB: about 14); Gelucire 48/09 (HLB: about 9);
And Labrafil WO2609BS (HLB: about 6).

As used herein, the term “ω3 fatty acid oil” refers to natural or synthetic ω3 fatty acids and their pharmaceutically acceptable esters, derivatives, precursors or salts, or salts thereof. Means a mixture of Examples of the ω3 fatty acid oil include, but are not limited to, 5
, 8,11,14,17-Eicosapentaenoic acid (hereinafter "EPA"), 4,7
, 10,13,16,19-Docosahexaenoic acid (hereinafter “DHA”) and α-
Ω3 polyunsaturated long-chain fatty acids such as linolenic acid; esters of glycerol and ω3 fatty acids such as mono / di / triglycerides; ω3 fatty acids such as fatty acid methyl esters and fatty acid ethyl esters and primary alcohols Esters; precursors of EPA and DHA; precursors of ω3 fatty acid oils such as α-linolenic acid; and derivatives such as polyglycolated derivatives or polyoxyethylene derivatives. Preferred ω3 fatty acid oils are EPA or DHA, their triglycerides, their ethyl esters, and mixtures thereof. The ω3 fatty acids or their esters, derivatives, precursors, salts and mixtures thereof may be in pure form or in fish oil (also known as marine oil), preferably high purity fish oil concentrate or perilla oil or seaweed oil (marine oil). micro
algae oil). Suitable fish oils are, for example, pilchard oil, menhaden oil, peruvian
) Fish oils of the type in which substantial amounts are recovered from cold-water fish, such as fish oil, sardine oil, salmon oil, herring oil and mackerel oil. Preferably, the fish oil contains 50
% Or higher, more preferably 70% or higher, most preferably 80% or higher. Examples of suitable omega-3 fatty acid oils include the following oils available from Croda Oleochemicals (England): Incromega TG3525 (EPA: DHA ratio, 35:25; triglycerides), Incromega E5015 (EPA: DHA ratio, 50: 1).
5; ethyl ester) and Pronova Biocare (Sandefjo)
RD, Norway): EPAX6000FA, EPAX
5000TG, EPAX4510TG, EPAX2050TG, K85TG, K
85EE, K80EE and EPAX7010EE (details are listed in Table 1 herein). Preferred mixtures include K85EE and EPAX6000FA
EPAX5000TG and EPAX6000FA; K85EE and EPAX500
Fatty acid ethyl esters and fatty acids, such as mixtures containing 0TG; and K85EE, EPAX6000FA and EPAX5000TG; fatty acid ethyl esters and fatty acid triglycerides; fatty acids and fatty acid triglycerides; and mixtures of fatty acid esters, fatty acid triglycerides and fatty acids.

As used herein, the term “therapeutic agent” refers to a poorly water-soluble drug, or a combination of such poorly water-soluble drugs, that has therapeutic use in mammals, especially humans. The drug or drug combination is insoluble in water or at 20 ° C.
Has a water solubility of less than about 1 part by weight per 1000 parts by weight of water.

The therapeutic agent includes, but is not limited to, an analgesic, an antiallergic, an antifungal, an antiinflammatory, an antiarrhythmic, an antibiotic, an anticoagulant, an antidepressant, an antidiabetic, an antiepileptic, an antiepileptic, Antihypertensive, anti-gout, anti-malarial, anti-migraine, anti-muscarinic, anti-neoplastic, anti-animal, anti-anxiety, thyroid, anti-thyroid, anti-viral, appetite suppressant, bisphosphonate, Cardiac inotropics, cardiovascular drugs, corticosteroids, diuretics,
Dopaminergic drugs, gastrointestinal drugs, hemostats, histamine receptor antagonists, hypnotics, immunosuppressants, renal protective drugs, lipid modulators, muscle relaxants, neuroleptics, neurotropics, opioid agonists and antagonists It can be selected from a variety of known types of drugs, including drugs, parasympathomimetics, protease inhibitors, prostaglandins, sedatives, sex hormones, stimulants, sympathomimetics, vasodilators and xanthine. The therapeutic agent may include a combination of poorly water soluble drugs. Examples of therapeutic agents include nephrotoxic drugs such as cyclosporine and amphotericin B; indomethacin; nifedipine; cardiotoxic drugs such as amphotericin B and FK506; rheumatism, arthritis, psoriasis, inflammatory bowel disease, Crohn's disease, or multiple Drugs or anti-inflammatory drugs having immunosuppressive effects such as drugs for treating demyelinating diseases including sclerosis; melphalan, chlormethine, extramustine phosphate, uramustine, ifosfamide, mannomustine, triphosphamide, streptozocin (streptozotocin), mitobronitol, methotrexate, fluorouracil, cytarabine, tegafur, idoxido
Antitumor agents such as, taxol, paclitaxel, daunomycin, daunorubicin, bleomycin, amphotericin; hyperlipidemic or hypercholesterolemic agents such as fenofibrate; dioplar disease agents; lipid and / or triglyceride level increasing agents And Alzheimer's disease therapeutics. Preferred therapeutic agents include class 4 (low solubility; low permeability) drugs.

When the low HLB oil component is an ω3 fatty acid oil, the composition according to the invention also advantageously has an additive or synergistic therapeutic effect between the therapeutic agent and the ω3 fatty acid oil, or the therapeutic agent has At least one negative side effect may be mediated by omega-3 fatty acid oils. For example, omega-3 fatty acid oils, in addition to other useful co-administration effects, reduce the nephrotoxicity of co-administered cyclosporine, thus permitting treatment with higher levels of cyclosporine, Produces a large clinical response.

As used herein, the term “pharmaceutically effective amount of a low HLB oil component” solubilizes or substantially solubilizes a therapeutically effective amount of a poorly water soluble therapeutic agent. Means an effective amount. As used herein, low HLB of poorly water soluble therapeutic agents
The term "substantially solubilize" in relation to solubility in the oil component refers to the fact that a poorly water-soluble therapeutic agent can dissolve in the oil of a low HLB oil component or has a low
It has a solubility of more than 1 part by weight with respect to 100 parts by weight of the B oil component. Generally, unit doses for low HLB oil components range from about 5% to 70% (w / w) of the microemulsion or emulsion pre-concentrate. Low HL
When the oil component B is an ω3 fatty acid oil, the amount of the ω3 fatty acid oil in the unit dose of the self-emulsifying microemulsion or emulsion pre-concentrate and / or the microemulsion or emulsion is determined by the daily dose of the ω3 fatty acid oil. Is about 1.0 g to about 6.0 g / day in humans, preferably about 2.0 g to about 5.0 g / day, most preferably about 2.5 g to about 4.0 g / day. In another approach, typical dosages of omega-3 fatty acid oils range from about 14-86 mg / kg / day, and typical dosages of fish oil contain equivalent amounts of omega-3 fatty acid oils.

As used herein, the term “surfactant” refers to a nonionic or ionic having an HLB of about 10-20, more preferably 13-19, and most preferably 15-18. Means a surfactant. Suitable surfactants include, but are not limited to,
Polyoxyethylene glycolated natural or hydrogenated vegetable oil; polyoxyethylene sorbitan fatty acid ester; polyoxyethylene fatty acid ester; polyoxyethylene alkyl ether; polyethylene glycol mono / difatty acid ester; ester of natural vegetable oil triglyceride and polyalkylene polyol Exchange reaction products; and fatty alcohol ethoxylates. Examples of suitable surfactants include Cremophor-RH40, Cremophor-RH60, Cr
emophor-EL, Tween-20, Tween-40, Tween-6
0, Tween-65, Tween-80, Tween-85, Labraso
1, Nikkol HCO-50, Nikkol HCO-40, Nikkol
HCO-60, Brij 30, Gelucire 44/14, Gycer
ox 767, Imwater 742, Imwater 308, Labra
fac Lipophile, Labrafac CM10, Tagat TO
, Myrj 52, Myvacet 9-45, and Vitamin E-TP
GS is included.

As used herein, the term “hydrophilic solvent system” refers to poorly water-soluble therapeutic agents and / or surface-active auxiliaries having an HLB greater than about 20 (other than the low HLB oil component). It means a system containing a solvent or co-solvent. Examples of hydrophilic solvent-based components include ethanol, alkylene glycols such as propylene glycol, polyethylene glycol, polyoxypropylene block copolymer, Transcuto.
1, Glycofurol, dimethyl isosorbide and mixtures thereof. As used herein, "trace" used in connection with a hydrophilic solvent system
The term refers to less than about 10% by weight of the components present in the pre-concentrate, preferably less than about 5%.
By less than% by weight, most preferably less than the amount of therapeutic agent present in the formulation.

A self-emulsifying microemulsion and an emulsion pre-concentrate according to the invention,
And microemulsions and emulsion formulations can optionally include minor amounts of a hydrophilic solvent system to increase the shelf life or stability of the pre-concentrate. Other additives such as antioxidants and preservatives may also be present. For example, tocopherol, tocopherol excipients, ascorbyl palmitate, butylated hydroxyanisole, or other antioxidants and preservatives listed in the USP XXII Formulation Table.

The self-emulsifying pre-concentrates and microemulsions and emulsions of the invention can be applied for oral administration. Preferred oral dosage forms of the pre-concentrate include hard capsules and soft gel capsules. Preferred oral dosage forms of microemulsions and emulsions are preformed microemulsions and emulsions. The formulation according to the invention also comprises i. v. Or i. p. It can be administered by other routes of administration, including topical or parenteral administration, such as administration.

The present invention provides an oil component having an HLB of 4 or less, and an HLB of about 10-20 each.
A stable self-emulsifying microemulsion or emulsion comprising a poorly water-soluble drug, formed from a two-component self-emulsifying system containing a surfactant system containing one or more surfactants having I do. This two-component system eliminates or dramatically reduces the need for a substantial amount of hydrophilic solvent system, and pre-concentrates that are substantially free of hydrophilic solvent systems or contain only minor amounts of hydrophilic solvent systems. Product formulation. If not limited by any particular theory, a very lipophilic oil component and about 10
~ 20, preferably 13-19, more preferably 15-18 HLB (about 5-1
Combination with a surfactant system containing a surfactant having an HLB of 0 (in the absence of an oil or surfactant) is believed to provide a stable pre-concentrate system.
These particular components allow for the preparation of pre-concentrates that are substantially free of, or contain very little, hydrophilic solvent system. Due to the solubilizing properties of the low HLB oil component combined with a surfactant having an HLB of about 10-20, HLB is 2
It is believed that it is possible to formulate a pre-concentrate that is substantially free of a hydrophilic solvent-based component such as a surfactant or surfactant aid or solvent such as a solvent. The enhanced bioavailability of the therapeutic agent from the pre-concentrate of the present invention may be due to the absence of these hydrophilic solvent-based components that partition into the aqueous phase as the microemulsion or emulsion forms and precipitate the therapeutic agent.

[0034]

【Example】

Example 1: Preparation of a microemulsion / emulsion pre-concentrate To prepare a pre-concentrate formulation, a solution containing a poorly water-soluble therapeutic agent and an oil component is added at a suitable ratio while adding the therapeutic agent little by little and stirring. Was prepared. The surfactant system was prepared by separately mixing a proportion of the selected surfactant. The oil component / therapeutic agent solution is then combined with the surfactant-based solution, and for about 5 minutes, 30-40
The pre-concentrate was formed in such a way as to heat to 0 ° C. or to stir without heating until homogeneous. In another approach, a formulation according to the invention was formed by simply combining a quantity of a therapeutic agent, a quantity of an oil component, and a quantity of a surfactant system and stirring until a homogeneous solution was formed. Other approaches include adding a therapeutic agent to a mixture of an oil component and a surfactant system and stirring until a homogeneous solution is formed, or preparing a mixture of surfactants and adding the oil component to the drug agent. Can be added. To test the behavior of the pre-concentrate when contacted with an aqueous system, using water or an aqueous solution such as a simulated gastric fluid that mimics the gastric conditions, 1: 1, 1:10, 1:20, 1:50 and 1: 100
The pre-concentrate was diluted as a v / v dilution.

As shown in the examples below, a wide variety of surfactant systems are combined with various oil components in various ratios to determine the ratio that will provide a suitable microemulsion and emulsion pre-concentrated formulation. The resulting solution was diluted with water. The clarity of the resulting solutions was classified as follows: C1 means a clear solution, where the particle size indicates that the average microemulsion droplet size of the C1 series is less than 30 nm; C2 is a translucent solution And the droplet size is about 50-70 nm; C
3 means a slightly opaque solution, droplet size is around 100 nm; C4 means a milky solution, droplet size is much larger than 100 nm. Generally speaking, self-emulsifying microemulsion systems correspond to C1 and C2 solutions, and self-emulsifying emulsion systems correspond to C3 and C4 solutions. Creating a ternary phase diagram that maps the various clarity regions for a particular oil component / surfactant system will provide a visual indication of the preferred ratio required to form a microemulsion pre-concentrate or emulsion pre-concentrate formulation. Understandable.

An oral dosage form containing a pre-concentrate can be manufactured. For example, the therapeutic agent-containing pre-concentrate can be transferred to a soft capsule maker and encapsulated by conventional methods of making soft capsules.

Example 2 Labrafil M1944CS / Labrasol / Tween
Labrafil M1944CS, an 80 / CyA oil component, and Labrasol and Twe
For surfactant systems comprising en 80, samples having all three components in varying percentages were prepared according to Example 1. This (placebo) system produced a C1 microemulsion region containing up to about 20% oil component. Table 1 shows the transparency when this (placebo) system was diluted 20-fold with water, and Table 2 shows that the same system obtained by adding 25, 50 and 100 mg of the therapeutic agent cyclosporin A (CyA) per 1 ml of the solution was diluted 20-fold. This shows the degree of transparency.

[0038]

[Table 1]

Example 3-Labrafil M1944CS / Labrasol / Cremo
phor RH40 / CyA Oil component Labrafil M1944CS, and Labrasol and Cre
For surfactant systems containing mophor RH40, samples having all three components in varying percentages were prepared according to Example 1. This (placebo) system results in a C1 or C1 / C2 microemulsion region containing up to about 52% of the oil component, and as shown in the ternary phase diagram of FIG. Occurred. Since this system offers the advantage of a good clear system with a high oil content, it should sufficiently solubilize the lipophilic drug. Table 3 shows the clarity when this (placebo) system was diluted 20-fold with water. Table 4 shows the corresponding system in which 25, 50, 100, 150 and 200 mg of the therapeutic agent CyA was added per 1 ml of the solution. Shows the transparency when diluted. As shown in the three-component phase diagram of FIG.
At a loading of 100 mg / ml CyA, a C1 or C2 system was obtained up to 52% oil.

[0040]

[Table 2]

Example 4 Labrafil M1944CS / Tween 80 / Cremo
phor RH40 / CyA Oil components Labrafil M1944CS, and Tween 80 and Cre
For surfactant systems comprising mophor RH40, samples having all three components in varying percentages were prepared according to Example 1. This (placebo) system produced C1 or C1 / C2 microemulsion regions containing up to about 55% of the oil component, and these pre-concentrates produced extensive microemulsion regions. Since this system offers the advantage of a good clear system with a high oil content, it should sufficiently solubilize the lipophilic drug. Table 5 shows the clarity when this (placebo) system was diluted 20-fold with water, and Table 6 shows that the therapeutic agent CyA was 25 per ml of solution.
, 50 and 100 mg were added to show the transparency when the corresponding system was diluted 20-fold. Cy
At a load of 100 mg / ml A, C1 or C2 systems were obtained up to 27% oil.

[0042]

[Table 3]

Example 5-Labrafil M1944CS / Tween 80 / Cremo
phor40 / Labrasol / CyA oil component Labrafil M1944CS and Cremophor R
Samples were prepared according to Example 1 for a surfactant system comprising H40, Tween 80 and Labrasol. Cremophor RH40 and Tween
The ratio of 80 was kept constant at either 2: 1 or 4: 1 and Labrasol, La
The amount of brafil and Cremophor RH40 / Tween 80 was varied. When the ratio of Cremophor RH40 to Tween 80 is 2: 1, the placebo system is a C1 or C1 / C2 containing up to about 45% oil component.
Microemulsion regions were generated, and these pre-concentrates generated extensive microemulsion regions. At a load of 100 mg / ml CyA, a C1 / C2 system was obtained at the test points at an oil content of 20% to 50%. Cremophor RH40 and T
When the ratio of ween 80 is 4: 1, this placebo system has an oil content of about 45
% To produce C1 or C1 / C2 microemulsion regions. CyA5
Similar clear systems were obtained at loadings of 0 mg / ml and 100 mg / ml. Since this system offers the advantage of a good clear system with a high oil content, it should sufficiently solubilize the lipophilic drug. The following formulations were prepared and encapsulated in soft gel capsules.

[0044]

[Table 4]

Example 6-Labrafil M1944CS / Tween 80 / Cremo
phor RH40 / Labrasol / therapeutic agents indomethacin and nifedipine Oil components Labrafil M1944CS and Cremophor RH
40, a sample was prepared according to Example 1 for a surfactant system comprising Tween 80 and Labrasol. Cremophor RH40 and Tween
The ratio of 80 was kept constant at either 1: 1, 1: 2, 2: 1 or 4: 1 and Labr was
asol, Labrafil and Cremophor RH40 / Tween
The amount of 80 was varied. Tables 7 and 8 show the transparency of this placebo system when diluted 20 times, 50 times and 100 times in deionized water at 37 ° C. At 20-fold dilution, extensive microemulsion regions were observed in all cases up to 45% oil component, resulting in either C1 or C1 / C2 microemulsions. Increasing the oil content further to 50% resulted in a C3 or C2 / C3 system at Cremophor to Tween 80 ratios of 1: 2 and 1: 1. Cremop with 50% oil content
Increasing the ratio of hor to Tween to 2: 1 resulted in a C2 line. Dilution factor (f
The effect of increasing actor) from 20-fold to 50-fold, 100-fold was evaluated, but such larger dilutions would be closer to the gastric conditions after oral administration of the microemulsion pre-concentrate. In all cases, increasing the dilution factor observed that the microemulsion remained the same clarity as the 20-fold dilution or returned to a more transparent system.

[0046]

[Table 5]

The above Labrafil M1944CS, Labrasol and Cremo
Indomethacin 25mg to phor RH40 / Tween 80 (4: 1) system
/ Ml and 50 mg / ml resulted in the clarity shown in Table 9 (20-fold dilution). A slightly more transparent system was obtained with 50 and 100 dilutions.

The addition of nifedipine to the microemulsion pre-concentrate was tested at 25, 50 and 100 mg / ml. Cremophor RH40 and Tween 8
When the ratio of 0 was 1: 2, 1: 1, 2: 1 and 4: 1, 25 mg of nifedipine was completely dissolved in all pre-concentrates. 50mg for compositions up to 35% oil content
Was solubilized. Nifedipine 25 mg / g total composition and oil content 35
When diluting the nifedipine-loaded pre-concentrate of the nifedipine 50 mg / g formulation to%, a broad microemulsion region of C1 or C1 / C2 clarity was observed. A 50-fold dilution and a 100-fold dilution were also examined, but in all cases, neither a change in the transparency nor the evolution to the more transparent C1 system was observed. Table 10 shows that the above 1: 1, 1: 2, 2: 1
And the transparency of nifedipine 25 mg / g in the Cremophor RH40 / Tween system of 4: 1. Malvern using flow-through cell
When measuring the size of various samples on the Mastersizer S, the visually determined C3 value corresponds to an average particle size of less than about 500 nm, and the C2 value is about 300
It corresponds to an average particle size of less than nm.

[0049]

[Table 6]

Example 7-Solubility of Cyclosporin in Fish Oil at Ambient Temperature The solubility of cyclosporin A (CyA) at ambient temperature was determined using polyunsaturated omega-3 free fatty acid oil EPAX6000FA, omega-3 fatty acid glyceride oil EPAX5000T.
G, EPAX4510TG, EPAX2050TG and K85TG, ω3 fatty acid ethyl ester K85EE, and free fatty acid and ethyl ester EPAX600
0FA / K85EE mixture (Pronova Biocare, Sandef.
jord, Norway). K85TG is a mixed glyceride obtained by transesterifying K85EE with glycerol, and includes K85 monoglyceride (5 to 15%), K85 diglyceride (20 to 30%), K85 triglyceride (50 to 70%), and residual K85EE (5%). %). All of these oils have an HLB of 4 or less. Table 11 shows details of the solubilities of the ω3 fatty acid oil and CyA.

The solubility of CyA was found to vary with different oils. EPA for K85EE
When mixed with X6000FA, the ability to dissolve CyA was greatly increased as compared with the ω3 fatty acid oil alone. Furthermore, this C in a mixture of K85EE and EPAX6000
The yA solution remained in the form of a clear solution at low and high temperatures, such as 2-8 ° C or about 40 ° C. No precipitation or crystallization occurred upon cooling to about -20 ° C for more than 24 hours. Thus, the initial results above indicate that the CyA microemulsion pre-concentrate made with this fish oil blend may have very good thermal stability over a wide temperature range.

[0052]

[Table 7]

Example 8-K85EE / Cremophor RH40 / Labrasol K85EE of ω3 fatty acid oil, and Labrasol and Cremophor
For surfactant systems containing RH40, samples having all three components in varying percentages were prepared according to Example 1. Table 12 shows the transparency when this (placebo) system was diluted 20-fold with water, and Table 13 shows that when the corresponding system in which 25, 50, 100 and 150 mg of CyA was added per 1 ml of the solution was diluted 20-fold. Indicates transparency. From the analysis of the placebo system, it is believed that the maximum amount of oil possible for the microemulsion pre-concentrated formulation formulated by this system is about 40-45% K85EE.

[0054]

[Table 8]

Example 9-K85EE / Tween 80 / Labrasol For K85EE of ω3 fatty acid oil and a surfactant system containing Labrasol and Tween 80, samples having all three components in various percentages were prepared according to Example 1. did. Table 14 shows that this (placebo) system was
The transparency at 0-fold dilution is shown. Table 15 shows that CyA was 25
And the transparency when the corresponding system to which 50 mg was added was diluted 20-fold.

[0056]

[Table 9]

A comparison of the K85EE / Cremophor RH40 / Labrasol system of Example 8 with the K85EE / Tween 80 / Labrasol system of Example 9 shows that although the placebo system is similar, the addition of cyclosporine to the system results in K85EE.
The / Cremophor RH40 / Labrasol system is shown to provide a larger microemulsion area when plotted on a pseudo-ternary phase diagram.

Example 10-K85EE / Cremophor RH40 / Tween 80 /
K85EE, a Labrasol ω3 fatty acid oil, and a surfactant system (Cremophor RH) containing Labrasol, Tween 80 and Cremophor RH40.
K85EE, Labr).
Samples with different percentages of asol and Tween 80 / Cremophor RH40 were prepared according to Example 1. Table 16 shows the clarity when this (placebo) system and the corresponding system containing 5% ethanol were diluted 20-fold with water. Table 17 shows two corresponding systems in which 100 mg of CyA was added per 1 ml of the solution.
Shows the transparency when diluted 0-fold.

[0059]

[Table 10]

Tables 16 and 17 show that, compared to the same system without ethanol, the addition of 5% ethanol resulted in similar microemulsion region sizes for both the placebo system (20% to 50% oil) and the corresponding 100 mg / ml CyA system. To bring.

[0061]

[Table 11]

Example 11-EPAX5000TG / Cremophor RH40 / Labr
asol ω3 fatty acid oil EPAX5000TG, Labrasol and Cremo
For surfactant systems containing phor RH40, samples having all three components in varying percentages were prepared according to Example 1. Table 18 shows this (
Placebo) Clarity when system was diluted 20-fold with water, and C per ml of solution
Shows the transparency when the corresponding system with 25, 50, 100 and 150 mg of yA added was diluted 20-fold.

[0063]

[Table 12]

Example 12-EPAX6000FA / Cremophor RH40 / Labr
asol ω3 fatty acid oil EPAX6000FA, Labrasol and Cremo
For surfactant systems containing phor RH40, samples having all three components in varying percentages were prepared according to Example 1. Table 19 shows this (
Placebo) Clarity when system was diluted 20-fold with water, and C per ml of solution
Shows the transparency when the corresponding system with 25, 50, 100 and 150 mg of yA added was diluted 20-fold. From the analysis of the placebo system, the maximum amount of oil possible for the microemulsion pre-concentrated formulation formulated by this system is about 27% EPAX6000FA
It is considered to be.

[0065]

[Table 13]

Example 13-K85TG / Cremophor RH40 / Tween 80 /
K85TG of Labrasol ω3 fatty acid oil, and Labrasol, Cremophor
Surfactant system containing RH40 and Tween 80 (Cremophor RH)
The ratio of 40 to Tween 80 is kept at 2: 1).
Samples with various percentages of ol and Cremophor RH40 / Tween 80 mixture were prepared according to Example 1. Table 20 shows the transparency when this (placebo) system was diluted 20-fold with water. This placebo system
FIG. 3 shows a pseudo-ternary phase diagram showing the microemulsion region (transparency of C1, C1 / C2 and C2) when diluted twice.

[0067]

[Table 14]

Table 21 shows the transparency when the corresponding system in which 25, 50, 100 and 150 mg of CyA was added per 1 ml of the solution was diluted 20-fold. The pseudo ternary phase diagram in FIG. 4 shows the microemulsion region when the system having 100 mg / ml of CyA per 1 ml of the solution was diluted 20-fold.

[0069]

[Table 15]

Example 14-K85TG / Cremophor RH40 / Labrasol K85TG of ω3 fatty acid oil, and Labrasol and Cremophor
For surfactant systems containing RH40, samples having all three components in varying percentages were prepared according to Example 1. Table 22 shows the clarity of this (placebo) system when diluted 20-fold with water, and 25% CyA per ml of solution.
, 50, 100, and 150 mg are shown, showing the transparency when the corresponding system was diluted 20-fold. From the analysis of the placebo system, it is believed that the maximum amount of oil possible for the microemulsion pre-concentrated formulation formulated with this system is about 27% K85TG.

The K85EE / Cremophor / Labrasol provided in this example
The microemulsion region of the ternary phase diagram obtained by plotting the system data is Cy
Similar to that of the corresponding EPAX5000TG system (Example 11) and EPAX6000FA system (Example 12) over the range of A0-150 mg / ml. The corresponding K85EE system (Example 8) appears to form a microemulsion region larger than the K85TG system.

[0072]

[Table 16]

Example 15-Mixed Fish Oil / Cremophor RH40 / Tween 80 / L
A system containing a mixture of abrasol K85EE and EPAX6000FA, and Labras
For surfactant systems including ol, Tween 80 and Cremophor RH40, samples having various percentages of these were made according to Example 1 as described in Table 23. Table 23 shows the clarity when this (placebo) system was diluted 20-fold with water, and the clarity when the corresponding system in which 50 or 100 mg of CyA was added per 1 ml of the solution was diluted 20-fold. The transparency of the microemulsion obtained by adding CyA was slightly improved.

[0074]

[Table 17]

Example 16-Formulations The following formulations according to the present invention were prepared as follows. A certain amount of cyclosporine,
A certain amount of the oil component containing the ω3 fatty acid oil and a certain amount of the surfactant system were stirred until a homogeneous solution was formed. The resulting cyclosporin-containing composition was transferred to a soft capsule making machine and then encapsulated by conventional methods for making soft capsules. The above product is designed for daily administration, for example, 3 to 8 capsules daily, and a therapeutically effective amount of therapeutic agent cyclosporin A (300 to 800 m for formulations 2 and 3) per day.
g, 75-200 mg of cyclosporin A) for formulation 4 and a pharmaceutically effective amount of ω3
Both fatty acid oils (1.03-2.74 g EPA + DHA for Formulations 2 and 4, or 1.39-3.70 g EPA + DHA for Formulation 3) are provided. Formulation 5 contains a mixture of ω3 fatty acid oils, as well as a trace amount of a hydrophilic solvent system. Of course, the daily dose will depend on the therapeutic agent, such as the formulation 2, 3, 4 and 5 capsules and / or ω3
It may include a combination of capsules having various amounts of the systemic fatty acid oil.

[0076]

[Table 18]

[Table 19]

Example 17-Ethyl oleate / Tween 80 / Cremophor RH
40 / Labrasol A pre-concentrated formulation containing ethyl oleate suitable for a formulation having a therapeutically effective amount of a poorly water-soluble therapeutic agent according to the present invention was prepared as detailed in Table 24 (w / w%). Cremophor RH40 and Tween 80 (2: 1) were first weighed and mixed at about 37 ° C. until homogeneous. After this, Labrasol was added as needed and the three surfactants were combined until a clear homogeneous mixture was formed. The appropriate oil component was added to the surfactant mixture and mixed. Finally, any ethanol present was included.

Microemulsions were formed by diluting 20-fold with deionized water to evaluate microemulsion formation. As shown in Table 24, the average particle size was measured by photon correlation spectroscopy (C3 and C4 formulations were diluted up to 400 times as needed)
.

[0079]

[Table 20] For a formulation containing 5% ethanol, 5% and 10% in 30% ethyl oleate.
% Of both Labrasol concentrations produced clear pre-concentrates and microemulsions with a droplet size of less than 30 nm. Ethyl oleate content from 30% to 40%
%, The pre-concentrate was still clear, but the droplet size of the microemulsion increased by 10-15 nm to reach about 40 nm. At 45% ethyl oleate, a C2 microemulsion with a droplet size of 62.3 nm was observed. As the composition of ethyl oleate was further increased to 50%, the clarity of the microemulsion decreased to a C2 / C3 system. At this concentration of ethyl oleate, the composition of Labrasol was found to affect droplet size, increasing to 74.5 nm and 113.3 nm for Labrasol concentrations of 5% and 10%, respectively. 55% ethyl oleate and 5% Labrasol
Produced a cloudy pre-concentrate with a C4 microemulsion with a droplet size of 135.8 nm.

In a formulation without ethanol, a pre-concentrate containing 30% ethyl oleate and 5% and 10% Labrasol produces a clear pre-concentrate and microemulsion with a droplet size approximately equal to 26 nm. Was observed. The ethyl oleate content was increased to 35%, 37% and 40% while Labras
When the ol concentration was 15%, 5% and 5% respectively, the pre-concentrate was still clear and the droplet size of the microemulsion was less than 38 nm. With 40% ethyl oleate, increasing the Labrasol content to 10% gives 37.9 n
A droplet size of m was produced. 45% ethyl oleate, 10% Labraso
1 together formed a microemulsion with a droplet size of 50.6 nm and clarity C2. Formulation of 50% ethyl oleate with 5% and 10% Labrasol both reduced the microemulsion clarity to C2 / C3 and increased the droplet size to 72.0 nm and 70.3 nm, respectively. 55
At% ethyl oleate and 5% Labrasol, the pre-concentrate appeared cloudy after formulation but became clear on standing. Dilution of this pre-concentrate resulted in a C3 microemulsion with a droplet size of 95.5 nm.

Therefore, when the concentration of ethyl oleate is less than 40%, the Labrasol concentration (
Up to 10%) has little effect on the droplet size of the microemulsion. However, when the concentration of ethyl oleate exceeds 40%, Labrasol
Concentrations (5% and 10%) have a significant effect on microemulsion droplet size. Using ethyl oleate up to 40% with 5% and 10% Labrasol produces a clear pre-concentrate, followed by a microemulsion with a droplet size of less than 40 nm. Regardless of the concentration of Labrasol, increasing the concentration of ethyl oleate above 40% resulted in a microemulsion with a droplet size of greater than 40 nm. At higher oil contents of 50% and 55%, it was found that the absence of ethanol in the formulation reduced the microemulsion droplet size.

Example 18-Oleic acid / Tween 80 / Cremophor RH40 /
Labrasol Similar to Example 17 above, a pre-concentrated formulation containing oleic acid suitable for a formulation having a therapeutically effective amount of a poorly water-soluble therapeutic agent according to the present invention was prepared as shown in Table 25 (w / w%). Was evaluated.

[0083]

[Table 21] The resulting pre-concentrate was a clear, single-phase formulation at the time of preparation and showed no signs of phase separation or streaking even after standing for 24 hours. When the 15% and 30% oleic acid pre-concentrates were diluted (20-fold), the clarity was C4 and the average particle size was 194.0 nm and 211.3 nm, respectively. 37% with 5% Labrasol, 5% ethanol and appropriate amount of Cremophor: Tween (2: 1)
A pre-concentrate was prepared using oleic acid at a concentration of 50%. All formulations showed a single phase, clear, pale yellow pre-concentrate. The emulsions subsequently produced are (
In all cases, the transparency is C4, and even when diluted 800 times, Zetas
The size could not be measured by iser (unsizable). Finally, 37% and 50% oleic acid pre-concentrates without ethanol were formulated. Again, both formulations showed a single phase, striped, light yellow pre-concentrate. The 37% formulation produced a C4 emulsion at a 20-fold dilution and could not be measured by PCS at 800-fold dilution. The 50% formulation also produced a C4 emulsion at 20-fold dilution, and its size could not be measured at 800-fold dilution.

The present invention is not limited by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are also considered to be within the scope of the appended claims.

[Brief description of the drawings]

1 shows a ternary phase diagram when the pre-concentrate was diluted 20-fold with water in the placebo system described in Example 3. FIG. The figure shows the relative concentration of Labrasol (0-100%), the relative concentration of oil component Labrafil M1944CS (0-100%), and the relative concentration of Cremophor RH40 (0-100) in the placebo system.
%). The relative concentration of Labrasol increases from 0% at the lower right corner to the lower left corner at 100%, the relative concentration of Cremophor RH40 increases from 0% at the baseline of the figure to 100% at the top, and the relative concentration of Labrafil M1944CS at 0% at the top of the figure. From 100% to 100% in the lower right corner. The shade area is the area of the composition having a C1, C1 / C2 or C2 transparency as a microemulsion area where the pre-concentrate is diluted 20 times with water.

FIG. 2 shows the pre-concentrate in water with the CyA 100 mg system described in Example 3
The three-component phase diagram when diluted by a factor of 0 is shown. The figure shows the relative concentration of Labrasol (0-100%) in a composition containing 100 mg of CyA, Labrafil M1944.
The relative concentrations of CS (0-100%) and Cremophor RH40 are plotted (0-100%). The relative concentration of Labrasol increased from 0% at the lower right corner of the figure to 100% at the lower left corner, the relative concentration of Cremophor RH40 increased from 0% at the baseline to 100% at the top of the figure, and Labrafil M194.
The relative concentration of 4CS increases from 0% at the top of the figure to 100% at the lower right corner. The shade area is a microemulsion area obtained by diluting the pre-concentrate by 20 times with water.
Regions of the composition having C1 / C2 or C2 transparency.

FIG. 3 shows a pseudo-ternary phase diagram when the pre-concentrate is diluted 20-fold with water in the placebo system described in Example 13. The figure shows Labrasol in a placebo system.
Relative concentration (0 to 100%), relative concentration of ω3 fatty acid oil K85TG (0 to 10%).
0%) and the relative concentration (0-100%) of Cremophor RH40: Tween 80 (2: 1). The relative concentration of Labrasol increased from 0% at the lower right corner to 100% at the lower left corner of the figure, and Cremophor RH40: Twe
The relative concentration of en 80 (2: 1 ratio) increases from 0% baseline to 100% vertex in the figure, and the relative concentration of K85TG increases from 0% vertex to 100% in the lower right corner of the figure. The shade area is the area of the composition having a C1, C1 / C2 or C2 transparency as a microemulsion area where the pre-concentrate is diluted 20 times with water.

FIG. 4 shows a pseudo-ternary phase diagram when the pre-concentrate was diluted 20-fold with water using the CyA 100 mg system described in Example 13. The figure shows the relative concentration of Labrasol (0-100%) in the composition containing 100 mg of CyA, and the ω3-based fatty acid oil K85TG.
RH40: Tween, relative concentration (0-100%) of Cremophor RH40
The relative concentration (0-100%) of 80 (2: 1 ratio) is plotted. Labras
The relative concentration of ol increased from 0% at the lower right corner to 100% at the lower left corner of the figure,
or RH40: Tween 80 (2: 1) relative concentration is baseline 0 in the figure.
% To 100% at the top, and the relative concentration of K85TG increases from 0% at the top of the figure to 100% at the lower right corner. The shade area is the area of the composition having a C1, C1 / C2 or C2 transparency as a microemulsion area where the pre-concentrate is diluted 20 times with water.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR , BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS , JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZWF term (reference) 4C076 AA17 AA66 AA95 BB01 BB11 CC01 CC03 CC04 CC07 CC11 CC12 CC16 CC17 CC20 CC21 CC27 CC29 CC30 CC31 CC35 DD41 DD45 DD46 EE51 EE54 FF16

Claims (28)

[Claims] 1. A self-emulsifying pre-concentrated pharmaceutical composition capable of forming an oil-in-water microemulsion or emulsion when diluted with an aqueous solution, comprising: a) a therapeutically effective amount of a poorly water-soluble therapeutic agent; b. C) a pharmaceutically effective amount of a low HLB oil component; and c) a surfactant system consisting essentially of at least one surfactant having an HLB of about 10-20. Such a composition, wherein the composition comprises trace amounts or substantially no solvent system. 2. The composition according to claim 1, wherein said composition is a microemulsion pre-concentrate. 3. The composition according to claim 1, wherein said composition is an emulsion pre-concentrate. 4. The composition according to claim 1, wherein said composition is suitable for oral administration. 5. The composition according to claim 1, wherein said low HLB oil component is present in an amount ranging from 5 to 70% by weight. 6. The composition according to claim 1, wherein said therapeutic agent is selected from cyclosporine, nifedipine and indomethacin. 7. The low HLB oil component is Labrafil M1944CS;
Labrafil M2125CS; oleic acid; ethyl oleate; EPA;
7. A salt of EPA; DHA; a salt of DHA; a triglyceride of EPA; a triglyceride of DHA; an ethyl ester of EPA; an ethyl ester of DHA; and a mixture thereof, comprising a low HLB oil component. The composition according to claim 1. 8. The composition according to claim 1, wherein the low HLB oil component comprises fish oil or a mixture of fish oils. 9. The composition according to claim 1, wherein the low HLB oil component comprises medium or long chain fatty acid triglycerides. 10. The composition according to claim 1, wherein the low HLB oil component comprises a medium or long chain fatty acid ethyl ester. 11. The method according to claim 1, wherein the remedy is an analgesic, an antiallergic, an antifungal, an antiinflammatory, an antiarrhythmic, an antibiotic, an anticoagulant, an antidepressant, an antidiabetic, an antiepileptic,
Antihypertensive, Antigout, Antimalarial, Antimigraine, Antimuscarinic, Antineoplastic, Antigenic animal, Anxiolytic, Thyroid, Antithyroid, Antiviral, Appetite suppressant, Bisphosphonate , Cardiac inotropic drugs, cardiovascular drugs, corticosteroids, diuretics, dopaminergic drugs, gastrointestinal drugs, hemostatic drugs, histamine receptor antagonists, hypnotic drugs, immunosuppressants, renal protective drugs, lipid modulators, Muscle relaxants, neuroleptics, neurotrophic drugs,
Claims: selected from opioid agonists and antagonists, parasympathomimetics, protease inhibitors, prostaglandins, sedatives, sex hormones, stimulants, sympathomimetics, vasodilators and xanthine or mixtures thereof. The composition according to any one of claims 1 to 11. 12. The composition according to claim 1, wherein said composition is suitable for topical administration. 13. The composition according to claim 1, wherein said composition is suitable for parenteral administration. 14. A microemulsion or emulsion pharmaceutical composition comprising the self-emulsifying pre-concentrate according to claim 1 diluted with an aqueous solution. 15. The composition according to claim 14, wherein said composition is a microemulsion. 16. The composition according to claim 14, wherein said composition is an emulsion. 17. The composition according to any one of claims 14 to 16, wherein said composition is suitable for oral administration. 18. The composition according to claim 14, wherein said therapeutic agent is selected from cyclosporine, nifedipine and indomethacin. 19. The low HLB oil component is Labrafil M1944CS.
Labrafil M2125CS; oleic acid; ethyl oleate;
19. A salt of EPA; DHA; a salt of DHA; a triglyceride of EPA; a triglyceride of DHA; an ethyl ester of EPA; an ethyl ester of DHA; and mixtures thereof, comprising a low HLB oil component. A composition according to any one of the preceding claims. 20. The composition according to claim 14, wherein the low HLB oil component comprises fish oil or a mixture of fish oils. 21. The method according to claim 20, wherein the therapeutic agent is an analgesic, an antiallergic, an antifungal, an antiinflammatory, an antiarrhythmic, an antibiotic, an anticoagulant, an antidepressant, an antidiabetic, an antiepileptic,
Antihypertensive, Antigout, Antimalarial, Antimigraine, Antimuscarinic, Antineoplastic, Antigenic animal, Anxiolytic, Thyroid, Antithyroid, Antiviral, Appetite suppressant, Bisphosphonate , Cardiac inotropic drugs, cardiovascular drugs, corticosteroids, diuretics, dopaminergic drugs, gastrointestinal drugs, hemostats, histamine receptor antagonists, hypnotics, immunosuppressants, renal protective drugs, lipid regulators, Muscle relaxants, neuroleptics, neurotrophic drugs,
Claims: selected from opioid agonists and antagonists, parasympathomimetics, protease inhibitors, prostaglandins, sedatives, sex hormones, stimulants, sympathomimetics, vasodilators and xanthine or mixtures thereof. Any one of 14 to 20
The composition according to Item. 22. The composition according to any one of claims 14 to 19 and 21, wherein the low HLB oil component comprises medium or long chain fatty acid triglycerides. 23. The composition according to any one of claims 14 to 19 and 21, wherein the low HLB oil component comprises a medium or long chain fatty acid ethyl ester. 24. The composition according to any one of claims 14 to 23, wherein said composition is suitable for topical administration. 25. The composition of claims 14 to 23, wherein said composition is suitable for parenteral administration.
A composition according to any one of the preceding claims. 26. The composition according to any one of claims 14 to 25, wherein the amount of aqueous solution to pre-concentrate is 1: 1 or more. 27. The self-emulsifying pre-concentrated pharmaceutical composition of claim 1, substantially as described and exemplified herein. 28. The microemulsion or emulsion pharmaceutical composition of claim 14, substantially as described and exemplified herein.