JP2002532389A - Phospholipid composition - Google Patents

Abstract

  (57) [Summary] The present invention relates to the preparation of a powder or solid composition comprising single and double chain amphipathic lipids associated with a polymer that allows the composition to be cured and ground into powders or granules. The composition can serve as a carrier for the biologically active compound and can be administered to an organism. Such compositions may include monoacyl and diacyl membrane lipids associated with the bioactive compound and the polymer, wherein the composition, when stored in a glass container, is stored at 40 ° C. and 75% relative humidity for 3 months. It is a solid that retains fluidity. The lipid can be selected from those having a GRAS state, such as lecithin modified by an enzyme, and the polymer can be selected from natural polysaccharide polymers, starch and its derivatives, cellulose and its derivatives, and gelatin.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION [0001] The present invention generally relates to the preparation of powder or solid compositions containing single and double chain amphipathic lipids. In particular, it relates to a lipid composition comprising polymer-associated monoacyl and diacyl membrane lipids and a biologically active compound for administration to an organism. Specifically, the present invention describes the preparation of novel lipid polymer compositions with improved physical properties and higher lipophilic and hydrophilic compound loading capacity. More specifically, it relates to a granular, small and stable membrane lipid composition having excellent bioavailability and suitable for oral and other applications.

BACKGROUND OF THE INVENTION Problematic Drugs A major problem in delivering bioactive compounds to humans or animals is related to poor absorption, possibly due to: (i) in aqueous media Low solubility; and (ii) low membrane permeability. These harm bioavailability and reduce effectiveness. This problem applies especially to lipophilic compounds and presents a particularly challenging challenge, both from a technical and a commercial standpoint, to the pharmaceutical industry. Commercially, the inability to improve bioavailability can result in significant delays or disruptions to the time to market approval, which can be costly. In fact, many compounds with promising pharmacological effects have been abandoned late in development due to poor bioavailability and instability. It may be possible to improve bioavailability by making highly hydrophilic derivatives without unacceptable changes in pharmacokinetics.

[0003] It is difficult to find a carrier system that improves the bioavailability of lipophilic compounds that are effective and non-toxic when administered orally and can be manufactured in conventional solid dosage forms. Although ethanol and ethoxylated surfactants are widely used in liquid compositions, their use has significant limitations. Another approach is
A method in which the active substance is colloidal or coprecipitated in order to improve the dissolution properties. However, this method will not completely solve the problem, since the low permeability of the membrane will not accept the effort to improve bioavailability.

[0004] The problem of low bioavailability is not limited to hydrophobic compounds.
Some hydrophilic compounds having a large molecular weight have similar problems. Examples of hydrophilic compounds with low absorbency include peptides, such as insulin, peptidomimetic compounds, antibodies, and genetic material, such as oligosense nucleotides. The low bioavailability of these compounds may be due to degradation in the upper gastrointestinal tract and poor membrane permeability rather than poor solubility.

[0005] Carrier systems are designed to improve delivery of active compounds and to maximize performance. The system must be compatible with the biological system and must be able to deliver the active compound in a controlled manner. In particular, the components used must be non-toxic and must conform to specifications giving reproducible performance. While oral administration is the preferred route of drug administration, the compounds may be delivered by other routes, for example, inhalation, parenteral and transdermal. However, these pathways can create problems and are generally only considered when gastrointestinal absorption is inadequate or poorly controlled. An effective oral delivery system would provide the key to unlocking the clinical potential of problematic compounds in drug discovery programs. As used herein, delivery also includes absorption from the oral cavity and other mucous membranes. Improving bioavailability or controlling the release of potent drugs may also reduce toxicity because of the smaller doses that need to be administered. This is an important idea for compounds that are expensive or available only in small quantities. The importance of delivery systems is widely recognized, and improving and controlling the bioavailability of problematic drugs is one of the most active quests in pharmaceutical research.

Lipids as Drug Carriers The advantages of using diacyl lipids, such as phospholipids, as carriers for drugs and other bioactive substances are well known. Phospholipids are the major component of liposomes, microscopic vesicles that carry biologically active compounds. The production of liposomes can be carried out,
-0158441.

More recently, it has been proposed to use anhydrous systems as carriers, based on monoacyl lipids or mixtures of monoacyl and diacyl lipids. WO 98/58629 discloses a carrier system comprising one or more monoacyl lipids or other related micelle-forming amphiphiles, optionally as a mixture with one or more bilayer-forming diacyl lipids. It has been disclosed. The system, when prepared as a standard, is in the form of an anhydrous or near-anhydro solid, waxy solid, or liquid, and comes into contact with the aqueous liquid during or shortly before use. Upon contact with the aqueous liquid, the carrier system is converted to drug-associated lipid particles,
Depending on the ratio of diacyl and monoacyl lipids, they will be in the form of liposomes, micelles, or mixed micelles. At this stage, the lipophilic drug, which has been incorporated into the original carrier system, exists in the form of molecules intercalated between the lipids to form lipid aggregates (liposomes or mixed micelles) or It is carried in the form of a lipid-drug complex. The monoacyl component promotes solubilization of the bioactive compound in the mixture of monoacyl and diacyl lipids, and aids dispersion into small aggregates when contacted with aqueous liquids. When the carrier comprises a partially enzymatically digested diacyl lipid, the compound is primarily molecularly dispersed in the partially digested lipid mixture,
No bile acids or other emulsifiers are required to release the compound from the gastrointestinal tract. But,
As an unexpected advantage, dispersion into lipid aggregates may be further improved, especially at 37 ° C., in the presence of emulsifiers such as bile acids.

[0008] The problem with which the present invention is concerned is that lipids are generally not suitable for processing into a solid form under ambient conditions, except when used in small amounts. This is a lipid,
One reason for this is that phospholipids are not more widely used as carriers, especially in effective amounts.

SUMMARY OF THE INVENTION It is an object of the present invention to provide an improved carrier for hydrophilic and especially hydrophobic compounds having pharmaceutical and industrial applicability.

[0010] It is a further object of the present invention to provide a safe, effective and cost-effective carrier composition having excellent bioavailability, being applicable in manufacturing.

A further object of the present invention is to modify the lipid component, which is a soft or waxy material at room temperature, to make it hard (ie brittle or pulverizable) and fill it into hard gelatin capsules and the like. Or be convertible to a free flowing powder that can be compressed into a solid dosage form, such as a tablet.

[0012] It is a further object of the present invention to provide an extended range of lipid substances that can be converted into a hard, millable composition.

The present invention provides the composition in a non-liquid form that is easy to prepare and may be a solid compact or may be particulate. Most preferably, the compositions are based on monoacyl and diacyl membrane lipids, by themselves or in mixtures with other single-chain amphiphilic lipids or in combination with membrane lipids. At least one hydrophilic substance, most preferably a polymer, is typically included in the composition.

[0014] At least one bioactive compound can be present in the lipid polymer association. The active compound may be added to the lipid or polymer solution or suspension before removal of the solvent, or may be formulated with the lipid-polymer association after drying. in this case,
The active compound can be associated with the lipid polymer by hydration. Alternatively, the composition may be, for example, a mixture of two or more lipid polymer associations of different active compounds. Incompatible substances or compounds that work better in combination can also be separated in a separate lipid polymer association. Such separation of the active compounds in the same dosage form would not be possible in aqueous solutions.

[0015] Lipid polymer associations have the potential to swell in water or other aqueous media to form a viscous intermediate composition that may or may not be a bilayer.
Hydration can occur in situ, for example, from powders or granules inside hard capsules, or from tablets on the gastrointestinal tract and other fibrous membrane surfaces. Depending on the ratio of monoacyl and diacyl lipids, polymers and other components present in the composition, the hydrated structure may be further dispersed in water or other aqueous medium to form micelles, vesicles, or small lipid aggregates. It may resemble a mixture of The preference for the type of small lipid aggregate formed is
It depends on the nature of the biologically active compound and other requirements. In addition, release of the biologically active compound may occur from either the hydrated bulk structure or the small lipid aggregates.

As far as the Applicants are aware, generally the phospholipids, especially the hydrolyzed phospholipids in GRAS (generally regarded as safe) state to form solid lipid polymer associations Has been previously disclosed in the form of an enzymatically degraded lecithin, optionally with a bioactive compound, and having improved oral bioavailability.

As used herein: lipid means an amphipathic molecule based on or containing one or two hydrocarbon chains and includes mixtures as well as single compounds.

Active compound means a biologically active substance that has a physiological or pharmacological action in an organism.

By lipid association is meant a composite structure formed between a lipid and one or more hydrophilic polymers, and optionally one or more active compounds. The active compound may be in molecular association or suspension in the lipid-polymer association. Alternatively, it may be simply mixed with a lipid-polymer association. The lipid-polymer association may be microparticles having an average diameter between about 0.05 mm and 5 mm, or may be a solid compact.

[0020] By small lipid aggregate is meant a multimolecular structure that can be formed when the lipid polymer association is contacted with a suitable aqueous medium. These structures may be vesicular, non-vesicular, micelles, reverse micelles, mixed micelles, or mixtures thereof.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention relates to a single-chain amphipathic lipid forming at least one micelle and / or a double-chain amphipathic lipid forming at least one bilayer, typically Comprises at least one polymeric substance, optionally in association with an active compound, in the form of compacts and / or particulates.

Particulate Composition The particulate composition of the present invention is in the form of particles or granules. Although there is no limitation on the particle size, it is preferable that the average particle size of the solid lipid polymer association is between about 50 μm to 5000 μm.

The powder composition can be obtained by milling or pulverizing using a usual apparatus. Alternatively, the lipid polymer association may be obtained as a free flowing powder after spray drying to remove the solvent and other suitable techniques. The powder composition is suitable for filling into hard capsules or for use as is. The fine flowable powder is near the lower end of the size range mentioned above, and typically has an average particle size between 50 μm and 2000 μm, preferably between 100 μm and 1000 μm, depending on the fill weight of the capsule.

[0024] The granular lipid polymer association is between 1 mm and 5 mm in diameter. Granules are obtained by grinding the dried lipid polymer cake or by compressing the powdered material into slag and breaking it into granules. The granules can be used as is in various dosage forms or can be further compressed into tablets.

Tablets Powders and granules can be compressed into tablets, lozenges, troches, buccal or mucosal tablets, vaginal suppositories and the like. If necessary, direct compression aids, such as lactose,
Microcrystalline cellulose, dicalcium phosphate, or the like may be used. Alternatively, small amounts of the active compound may be mixed directly with the lipid polymer association for compression into tablets. By using a suitable polymer and forming a suitable aggregate, the present invention compresses the waxy lipid material into tablets with good compression properties and properties, such as weight uniformity, hardness, etc. Enable. Disintegration properties and solubility vary greatly depending on the type of lipid and polymer used to form the aggregate. Thus, the tablets may disintegrate quickly, or more preferably, may not substantially change in aqueous liquids, thereby allowing for controlled release of the active compound in the gastrointestinal tract and other sites . Lipid polymer tablets hydrated, for example, by contact with saliva, have good retention on mucosal surfaces and are particularly suitable for mucosal, eg, sublingual and buccal delivery. Such tablets may be retained on mucosal surfaces for an extended period of time, i.e., 12 hours or more, depending on the lipid, polymer type, and lipid / polymer ratio. Other suitable excipients that can be used are preservatives, flavoring agents, foaming agents, glidants, lubricants, binders, disintegrants, flow aids, colorants,
And antioxidants. Lipid polymer associations can be used, for example, for pharmaceutical, dietary, food, cosmetic, beauty, veterinary, aquaculture, horticultural and other industrial applications, or for improving solubility and / or improving solubility of poorly water-soluble compounds. It can be used when it is necessary to promote or control the absorption of both fat-soluble substances.

Lipids A lipid or other amphiphile that can be hardened by mixing with a polymer according to the present invention may have one hydrocarbon chain and may have two hydrocarbon chains. Or, if preferred, a mixture of single- and double-stranded materials. Preferred lipids are membrane diacyl lipids and monoacyl derivatives thereof, but the definition also includes mono- and di-esters and ethers of sugars and polyols, fatty acid esters and other fatty acid derivatives. They can also hydrate and swell upon contact with water, forming a layered or bilayer stack. In general, in excess water, monoacyl lipids at concentrations higher than the critical micelle concentration (CMC) form micelles, while diacyl lipids form bilayer vesicles or reverse micelles above the phase transition temperature (Tc). Tends to align. Preferred lipids are amphiphilic membrane lipids such as phospholipids, glycolipids, ceramides, gangliosides and cerebrosides.

Preferred compositions are compacts or powders containing at least one monoacyl membrane lipid component. However, monoacyl and diacyl membrane lipids can be used per se. Most preferred compositions comprise a mixture of at least one monoacyl and at least one diacyl phospholipid. One or more charged monoacyl or diacyl lipids can also be included to improve the association, hardness, and hydration properties of the lipid-polymer association. The composition can also contain significant amounts of other single-chain amphiphilic lipids in addition to the phospholipids. It is preferred that the active compound be molecularly associated with the lipid polymer, but the active compound may be a solid suspension. Generally, it is preferred that the lipophilic compound be a solid molecule solution, while the hydrophilic compound can be a suspension. In order to make a highly hydrophobic compound into a complete molecular solution, a large amount of a single-stranded component or a single-stranded component of the compound itself may be required.

The single-chain material preferably comprises a monoacyl derivative of a neutral or charged phospholipid, but can also be a monoacyl derivative of a glycolipid and a sphingolipid. Lipids include monoacyl phospholipids derived from polyethylene glycol (PEG), such as pegylated monoacylphosphatidylethanolamine,
It may be of natural plant origin, or animal or microbial material, synthetic or partially synthetic. Examples of charged monoacyl phospholipids are phosphatidic acid (PA), phosphatidylinositol (PI), phosphatidylserine (P
S), and monoacyl derivatives of phosphatidylglycerol (PG).
Examples of neutral monoacyl phospholipids are phosphatidylcholine (PC), phosphatidylethanolamine (PE), and monoacyl derivatives of sphingomyelin. Other amphiphilic single-chain lipids such as fatty acids, alcohols, propylene glycol, glycerol, or sugar monoesters and their derivatives can be used alone or preferably in combination. The hydrocarbon chain can be either unsaturated or saturated, can have 10 to 24 carbon atoms,
Eighteen are preferred.

The double-chain lipid is preferably a phospholipid, but the monoacyl derivative may be a mixture with the other amphiphilic diacyl lipids described above. Charged membrane lipids can be used by themselves or may be included in the mixture. The acyl chain can be either unsaturated or saturated, can have 10 to 24 carbon atoms,
14-18 are preferred. Other membrane lipids such as glycolipids, ceramides, gangliosides, and cerebrosides can be used instead of phospholipids or with partial substitution.

The lipid composition may itself contain at least one or more single- or double-chain components, but the weight ratio of single-chain to double-chain lipid in the mixture is from 1:99 to 99
: 1, preferably between 1:25 and 25: 1, preferably 1: 1.
Most preferably it is between 0 and 10: 1. Lecithin containing a large amount of a natural monoacyl lipid component within the above range can also be used. That is, more than about 3% by weight can be used, and preferably about 5% by weight. Deoiled lecithin is an example of such a lipid mixture. This can be obtained from either eggs or soy. Mixtures of lecithin and fatty acid mono- and diesters and ethers of sugars, alcohols, polyglycerols and their derivatives can also be used.

In the case of phospholipids, instead of mixing pure fractions of the two lipids to achieve the target ratio, partially enzymatically hydrolyzed lecithin with the required ratio of monoacyl and diacyl lipid components Mixtures are particularly preferred. These phospholipid mixtures are known as enzymatically degraded lecithins, are freely recognized in foods without restriction, and therefore pose no problems for oral use. Whenever possible, hydrolyzed lecithins containing 5-95 mol%, preferably 60-80 mol%, of monoacylphospholipids obtained by enzymatic hydrolysis with phospholipase A2 are preferred. Lecithin must be substantially pure and substantially free of non-polar lipids. Preferably, the lecithin is free of GMO or free of detectable levels of genetically modified components.

Lipid: Active Compound Ratio The amount of lipid used to form the aggregate depends on several considerations. These include the amount of active compound present and its physicochemical properties. The type and charge of the lipid or lipid mixture are also factors to consider. If it is desired for the present invention to include the active compound in a substantially molecular association, more lipid will be required to form the aggregate. For very potent compounds or highly hydrophobic and problematic drugs, a 99: 1 or higher lipid: active compound ratio may be used. In most cases, depending on the type and charge of the lipid, a lipid: active compound ratio between 40: 1 to 1:40 will be sufficient. Usually, (i) to solubilize substantially fat-soluble compounds, or (ii)
Subsequently, a lipid: active compound ratio of between 20: 1 to 1:20 will be almost sufficient to improve the bioavailability of both lipophilic and hydrophilic compounds.

In general, the higher the proportion of the monoacyl component, the less lipid is required to solubilize the lipophilic compound and the lower the total amount of lipid in the composition. This is also the case when the active compound is hydrophilic and the lipid polymer composition is used primarily to control hydration and to improve bioavailability at the site of absorption. If the active compound is dispersed as discrete particles in the lipid polymer composition, the particles must have an average diameter of less than 1 μm, preferably less than 250 nm.

Polymer The composition typically comprises one or more polymers dispersible or soluble in warm water or an organic solvent. To disperse or dissolve the polymer, water-miscible polar solvents such as C2-C6 alcohols, esters or ketones are preferred, but water-immiscible solvents can also be used. The amount of polymer used may be between 5% to 90% by weight or more, preferably 10% to 75% by weight, depending on the required hardness and hydration properties of the lipid polymer association.

The polymer will typically make up less than 50% by weight of the composition. However, this is not a strict requirement. The polymer is usually added as a solution in an organic solvent or hydrophilic medium, and a solid lipid associate is formed after removal of the solvent. If the polymer is water-soluble, the solvent may be water. The definition of a hydrophilic medium may be extended to sugars. In fact, sugars can be viewed as "solid" hydrophilic media.
This is thought to be the reason that the combination of the polymer and the saccharide is particularly effective in curing lipids. Mannitol, lactitol and xylitol, and combinations thereof, are suitable examples for use with polymers in solid lipid compositions. A higher amount of polymer produces a composition that is easier to convert to powders and granules and that is easier to compress into tablets and the like. Compositions, especially in the form of solid compression moldings, tend to take a long time to hydrate and swell, and therefore mucosa,
For example, it is more suitable for long-term retention on the oral mucosa.

The water-insoluble polymer can first be dissolved or hydrated in an organic solvent, such as ethanol, with the lipids and active compound to form a homogeneous solution or dispersion.
If a water-soluble polymer is used, the polymer is separately dissolved / hydrated in water before being added to the organic lipid solution. Removal of the hydrophilic medium results in an anhydrous or nearly anhydrous solid lipid polymer association structure that is micronized or hard enough to be compacted, for example, converted into granules suitable for tablets. Alternatively, the composition can be spherical or pelletized during removal of the hydrophilic medium. Removal of the hydrophilic medium can be performed by any suitable method, including vacuum drying, spray drying, freeze drying, or a combination of methods. The polymer facilitates the processing of lipids with low melting points, for example, less than about 30 ° C., and natural unsaturated phospholipids with low phase transition temperatures characterized by being likely to be soft at room temperature for processing into solid and particulate forms. Can be The polymer also allows the use of large amounts of phospholipids. The use of time-dependent polymers with different swelling properties can provide a way to modify the hydration of the solid lipid association in an aqueous environment and control and prolong the release of the active compound in the gastrointestinal tract. In a low pH aqueous environment, such as the stomach, protection of lipids and active compounds against hydrolysis and disintegration is possible if the polymers used are insoluble in acidic media. When the pH rises, the lipid polymer association hydrates and swells, releasing the active compound. In this way, the drug can be delivered to the lower regions of the gastrointestinal tract.

Preferred polymers for curing lipids are natural rubber and derivatives. It may also be a synthetic polymer, such as methacrylic polymers and copolymers, carboxyvinyl polymers and copolymers. Gelatin or partially hydrolyzed gelatin can also be used. Most preferred polymers are cellulose, such as carboxymethylcellulose, ethylcellulose, and combinations of cellulose with alginates or methacrylic polymers. Sodium alginate can also be used per se. Starches and modified starches, such as corn starch, phosphorylated starch, pregelatinized starch, hydroxypropylated starch, and sodium octenyl succinate starch, as well as starches having a high amylose content, are particularly suitable. Monoacyl phospholipids complex with amylose to form lipid associations that are harder and have better resistance and better physicochemical stability. This is considered preferable for producing a lipid polymer aggregate having improved bioavailability.

[0038] Charged polymers significantly increase the hardness of lipids. Some of the best lipid-cured polymers include negatively charged carboxyl groups (sodium alginate and Eudrag).
Some have a negatively charged sulfate group (such as carrageenan). Charged molecules are generally more soluble in aqueous media than in organic solutions, so that more polymers can cure lipids than are soluble in ethanol than those that are soluble in ethanol. In general, suitable ethanol-soluble lipid-cured polymers are also soluble in aqueous media at a suitable pH.
To increase hardness, preferably the polymer should be dissolved or at least partially dispersed in the solvent before drying with the lipid. Heat may be used.

Table 1 summarizes the charges found on some common pharmaceutical polymers.

[Table 1]

Polymers modify the physical properties of soft or waxy lipid substances. The polymer is
It also affects the formation of intermediate structures by hydration in water or other aqueous media and the conversion of these structures into small lipid aggregates. Bioactive compounds have been found to have very high association properties in anhydrous solid forms, hydrated structures, and, where appropriate, in aqueous dispersions of the resulting small lipid aggregates. It is believed that the polymer further improves the association between the lipid and the active compound, allowing for almost complete association between the lipid and the biologically active compound. Polymers improve chemical and physical stability and protect lipids from degradation by oxidation and hydrolysis. A polymer is a solid that is resistant to relatively large amounts of residual, adsorbed, or intentionally added water and does not significantly degrade or change its physical properties, such as flowability, friability, and softness. A lipid composition is provided. The powdered lipid polymer association stored in the glass container is
The fluidity is maintained after storage at 40 ° C. and 75% RH for 3 months.

Most of the natural polysaccharide polymers, starch and their derivatives, cellulose polymers, and gelatin are pharmaceutically acceptable for oral, mucosal, and topical administration. Due to their widespread use in foods, they are not considered to be harmful to health. Table 2 summarizes the physical properties and lipid curability of some pharmaceutical polymers. It should be clearly understood that this table is not an exhaustive list and that hydrophilic polymers not included in this table may be suitable. The polymers can be used in combination, and any suitable method of mixing and solvent removal can be used to produce a solid lipid polymer composition on a commercial scale.

[Table 2]

It has been found that the appearance of the composition is not significantly affected by the concentration of the polymer. To substantially harden soft lipids using the processing and drying methods of the present invention,
At least one polymer required at least about 10% by weight of the total weight of the solid composition. For example, high displacement mixing may require less water to obtain a homogeneous composition prior to water removal. Hot air and vacuum assisted drying methods are also effective in reducing processing time and reducing residual moisture to obtain a stable and harder solid lipid composition. However, large amounts of residual moisture, up to about 30% by weight, are believed to be tolerated without adversely affecting hardness and other physical properties. Thus, it does not seem necessary to completely remove water from the composition. Any method for drying and solvent removal can be used, including, but not limited to, fluid bed drying, spray drying, freeze drying, supercritical fluid extraction, or a combination thereof.

Bioactive Compound The composition can further comprise a bioactive compound having lipophilic and / or hydrophilic properties. The bioactive compound is preferably in solution in the composition, but may be in suspension.

Examples of bioactive lipophilic compounds include hydrophobic neutral cyclic peptides such as cyclosporin A. Taxol, tacrolimus, or macrolides, such as rapamycin, and derivatives thereof are also suitable examples. Examples of hydrophilic bioactive compounds include insulin, calcitonin, and heparin. Another group of unrelated compounds that may be beneficial to use are antioxidants, such as ubiquinones, tocopherols, carotenoids, and bioflavonoids. Other therapeutic compounds may be included in the present invention. The type and concentration of the active compound in the composition will depend on the application and is not a limitation of the present invention.

The present invention is illustrated in the following examples, which are particularly directed to the effects of changing lipids and polymers on the formation and properties of solid lipid associations, and as such, as powders or granules. Illustrates the use of different lipids and polymers, with or without bioactive compounds, to obtain solid microparticle lipid associations that can be used to fill hard capsules or the like, or compression molded into tablets, for example. I do. In addition, the lipid polymer aggregates hydrate in situ in water or other hydrophilic media, such as intestinal fluids, to form drug-loaded small lipid aggregates with high capture and good bioavailability. Have the ability.

Preparation of Solid Polymer Lipids Example 1 A solid associate comprising cyA, phospholipid and methacrylic acid copolymer was prepared using a two-step process. The first stage involved dissolving 5 parts of lipid, 1 part of drug and 2 parts of polymer in a minimum amount of ethanol. The PC: MAPC weight ratio of the lipid mixture used in this formulation was approximately 33:66. The components were sonicated at 50 ° C. until a visually clear ethanol solution was obtained. The second stage is 5
This was a step of producing a solid lipid polymer aggregate by removing ethanol by vacuum drying at 0 ° C. for about 6 hours. The sample was weighed to constant weight to ensure complete removal of the solvent from the aggregate. In this example, cyA was completely molecularly dispersed. The obtained aggregate is a brittle pale yellow solid, which is crushed to a diameter of about 1 to 2 mm.
Of lipid / polymer granules. This powder was mixed with 25% by weight of microcrystalline cellulose and the resulting composition was compression molded into tablets that did not disintegrate in simulated gastric juice.

Example 2 A solid aggregate containing cyclosporin, phospholipid and povidone was produced using the method described in Example 1. Required amount of cyA (1 part by weight), lipid (5 parts by weight)
And povidone (6 parts by weight) were weighed into a drying vessel. PC of this lipid: MA
The PC weight ratio was approximately 33:66. 50 ° C solid components in a minimum amount of ethanol
And sonicated to dissolve. The visually clear yellow solution was vacuum dried to remove ethanol. The resulting aggregate was a hard, glassy solid that could be ground and was suitable for filling into hard gelatin capsules. CyA was a molecular solution in lipids.

Example 3 By dissolving 1 part by weight of nifedipine and 5 parts by weight of lipid (PC: MAPC weight ratio 33:66) in a minimum amount of dichloromethane containing 2 parts by weight of methacrylic copolymer (Eudragit L100) at room temperature A nifedipine / phospholipid polymer association was produced. The resulting solution was dried under vacuum until no dichloromethane was detected. The resulting yellow solid aggregate was stored in the dark until hydrated with deionized water. A dispersion was prepared by adding 0.2 g of the solid lipid complex to 10 ml of deionized water. The complex hydrated to form a viscous dispersion, and nifedipine was substantially in solution and partially in suspension.

Example 4 An aggregate comprising griseofulvin, a lipid (PC: MAPC weight ratio 33:66) and a methacrylic acid copolymer was prepared by suspending griseofulvin in an ethanol solution of the polymer and lipid. The weight ratio of griseofulvin: lipid: polymer was 10: 5: 2.5. Lipid: The drug suspension was vacuum dried at 50 ° C. for 6 hours to remove ethanol. The resulting aggregate is an off-white, free-flowing powder, which can be compressed into tablets or filled into hard gelatin capsules.

Example 5 A lipid associate comprising lipid (PC: MAPC weight ratio 33:66): cyA: methacrylic acid copolymer in a ratio of 5: 1: 0.67 was prepared by the method described in Example 1. A hard waxy solid which can be broken up into granules is obtained. The powdered lipid aggregate maintained a suspension state in water below pH 6, and dissolved when pH exceeded 6. cyA remained a molecular solution.

The method used to form the lipid aggregates described in Examples 1-5 comprises a simple vacuum drying at elevated temperature, followed by a grinding step of breaking the brittle lipid complex into granules. Used. For scale-up, any suitable method may be suitable. These include spray drying, freeze drying, supercritical extraction, spray coagulation.

Preparation Methods Used in the Examples The solid lipid compositions prepared with the active substance and the water-soluble polymer were prepared using the following general method. Unless otherwise stated, 5 g of dry lipid polymer composition was prepared in each example. Much larger amounts of the composition can be prepared using suitable equipment. Lipids and active compound (if included) were dissolved in ethanol. The polymer is hydrated in water, but may be heated to about 50 ° C. to obtain a viscous solution. The polymer solution was weighed into a glass container and the lipid / ethanol / active compound dispersion was added. The mixture was stirred well until a homogeneous gel was formed. The gel was vacuum dried at 50 ° C./0.1 mBar for about 24 hours to remove all ethanol and water.

Lipid Types Examples 6-7 The solid lipid polymer compositions shown below were prepared according to the method described above in two different types with significant differences in phosphatidylcholine (PC) and monoacylphosphatidylcholine (MAPC) content and sodium alginate. Was prepared using the following phospholipids. It has been found that the appearance of the solid is influenced in part by the type of lipid used in the formulation. For example, VP145 has about 50% PC and 5% MA by weight.
PC, with the balance comprising glycolipids and other polar lipids, a darker color compared to an equivalent formulation prepared using a lipid containing about 60% by weight MAPC and 40% PC (VP200), A slightly hard solid formed. VP14 used in the following examples
It should be understood that egg phospholipids containing 60% or more PC may be used in place of 5 and VP200. In fact, 100% PC obtained from eggs, soy or other natural or synthetic sources can also be used by itself. The hardness of the obtained lipid polymer association can be adjusted by appropriately changing the amount and type of the polymer used.

[Table 3]

The powder of Example 6 was ground with a mortar and pestle to produce a free flowing powder. 3 g of the obtained powder was stored in a 5 ml glass vial at 40 ° C. and 75 RH. After 6 months of accelerated storage, the powder remained flowable. Instead of VP145 and VP200, egg phospholipids containing about 60% PC can also be used.

Polymer Types Examples 8-16 To establish polymer types suitable for curing lipids, Examples 8-16
At 16, several different polymers were used with VP145. Examples 6 and 7
The solids were prepared using various concentrations of the polymer, either in aqueous medium, in ethanol, or as a dry powder according to Before adding the lipid to the polymer, it was dispersed in an equal volume of ethanol. The experiments performed are summarized in the table below.

[Table 4]

The charge density of the polymer affected the hardness of the lipid polymer association. For example, a gum arabic polymer may comprise approximately a 3: 3: 1: 1 ratio of L-arabinose, D-arabinose.
Consists of monomers of galactose, L-rhamnose, and D-glucuronic acid.
Because only the glucuronic acid monomer was charged, the charge density of the polymer was low and had only average lipid curability. On the other hand, sodium alginate is composed of D-mannuronic acid and L-guluronic acid monomers, and both are charged. The charge density of this polymer was high and had very good lipid curability. Furthermore, it is not impossible, and may be preferred, to use a combination of two or more polymers.

After drying at 50 ° C./0.1 mBar, most of the ethanol and / or water was removed from the composition to yield a room temperature solid, millable lipid polymer composition.
The solid composition of Example 16 was milled using a Culati Mill with a 1 mm screen to produce a free flowing powder. The lipid polymer was directly compressed in a tablet press to form a compact weighing about 400 mg. In another test, the powdered lipid polymer composition was mixed with three different direct compression aids, lactose, microcrystalline cellulose, and calcium diphosphate, and compressed into tablets.
The ratio of lipid polymer association to compression molding aid varied from 5% to 75% by weight. The tablets obtained were satisfactory.

The foregoing example is a placebo to illustrate the invention and does not include a biologically active compound. However, it is expected with certainty that both lipophilic and hydrophilic compounds can be used in the examples. Typically, the lipophilic compound is dissolved or dispersed in a lipid ethanol solution before combining with the aqueous polymer solution. The hydrophilic compound can be in aqueous solution with the polymer. Lipid polymer associations with the solid solution or dispersion of the active compound are obtained by removal of the solvent.

Example 17 A lipid polymer association composition containing 20 parts of VP145 lipid, 15 parts of carboxymethyl cellulose and 5 parts of mannitol was prepared. The lipid was dispersed in a small amount of ethanol by weight before adding to the aqueous solution of polymer and sugar. The slurry was vacuum dried as in the previous example. A hard cake is obtained and this is Culatti
The mixture was pulverized with a pulverizer using a 1 mm screen. The recovered powder was fluid and mostly less than 1 mm in average weight diameter. One part of nystatin powder was homogeneously mixed with 49 parts of powdered lipid polymer association. The obtained composition may be used as it is or as a tablet.

Polymer Grades Examples 18-20 Solid lipid polymers were prepared using VP145 lipids and nystatin as a bioactive compound in a 20: 1 weight ratio. The lipids and active ingredients are dispersed in equal parts by weight of ethanol and then the polymer (Manugel LBB or Kel)
tonell LVCR). In principle, lipid-nystatin-
There was no upper limit on how much water could be added to the polymer composition before drying, but adding a large amount of water required another treatment, such as spray drying.
In practice, minimal amounts of water were required to produce a hydrated lipid polymer composition suitable for drying from the slurry. The dried composition can be filled into hard gelatin capsules or the like, or can be made into tablets.

[Table 5]

Hardness Examples 21-24 The amount of polymer in the following formulations was varied to see how it affects the final hardness of the solid. Solids were prepared using a 4% or 6% Keltone LVCR polymer solution and 5: 1 VP200 lipid and cyA as active ingredient.
Incorporated in the proportion of Prior to adding the lipids and active ingredients to the aqueous polymer solution, they were dispersed in equal parts by weight of ethanol. The solid compositions from Examples 23 and 24 are particularly suitable for powdering and filling into hard gelatin capsules. 500mg each
The capsule contained 50 mg cyA. Alternatively, the granules could be compression molded into tablets.

[Table 6]

Flowability Example 26

[Table 7]

20 g of a lipid complex containing VP200 (50%) and NaCMC (50%) was prepared in the usual way. The dried lipid polymer aggregates were sized using a Culatti micro-hammer mill to a diameter of 1 mm, 1.5 mm, 2 mm and 4 mm.
Milled through one screen. After milling, all four powders were homogeneously loaded into the HGC, regardless of screen diameter. The obtained free-flowing powder is
The particles were sized using a ts sieve. The particle size distribution of the four powders is shown in FIG. 1
. The powder ground through a 5 mm screen was filled into nine size 0 hard gelatin capsules using a Feton filler. The powder mass in the capsule was very homogeneous. The average capsule weight was 0.312 g with a narrow standard deviation of 0.008 g.

Lipid Stability Assays for the degradation of lipids both during production and after storage of lipid polymer solids (assay
A) short-term stability test was conducted. The stability of the components PC and MAPC of lecithin was followed by HPLC analysis. During the manufacturing process, the PC was initially MAPC. I
The lipids were subjected to high temperature hydrolysis conditions that could easily be hydrolyzed for several hours.
However, the lipids were found to be stable both during the production and storage of the lipid polymer solid.

Active Ingredient Association in Solid Lipid Polymer Compositions Examples 27-30 The following examples were prepared according to the method used in the previous examples. The association of the active substance with the lipid was investigated using analytical filtration. Active substance assays were performed by HPLC. The results show that almost 100% association of the active substance in the lipid polymer association is possible even after storage at high temperature for up to 3 months.

A 40 g sample of the composition described in Example 27 was prepared and ground with a mortar and pestle. Twenty 2 g samples of this composition were stored in 4 ml glass vials.
After 6 months of storage, the samples were physically and chemically stable. After storage at 40 ° C./75% RH for 6 months under the conditions tested, the powder had a water content of about 15% by weight and remained fluid.

[Table 8]

Activity of Lipid Polymer Solids The activity of the drug in the lipid polymer solids was evaluated using a nystatin formulation. Nystatin was chosen because its activity can be assessed using a simple in vitro microbiological assay. The antifungal properties of the nystatin lipid solids were evaluated using a cup-plate diffusion assay. The solid is diluted in an aqueous medium to form a lipid dispersion, which is a commercially available nystatin suspension, Nystan® (
E. FIG. R. Squibb and Sons Ltd. ) Compared to the same concentration.
Tryptone-soy agar plates inoculated with Candida albicans NCPF 3179 to a final concentration of 10 ⁶ viable cells / ml were used. The solution was incubated in 5.5 mm wells for 2 hours at room temperature and then for 18 hours at 37 ° C. The growth inhibition zone of Candida albicans was measured and compared in FIG.

Examples 31-33 In Examples 31-33, three different starches were mixed with VP200 lipids, illustrating the use of these polymers for lipid hardening. Solids were prepared using various concentrations of the polymer in an aqueous medium. In Example 31, the lipid was dispersed in ethanol-free water before adding to the polymer. In Examples 32 and 33, the polymer was dispersed in warm water before the addition of VP200 dissolved in ethanol. Examples 31-33 are basic compositions of solid lipid polymers. The bioactive compound may be added to the lipid and polymer solution before drying, or may be mixed with the dried lipid polymer powder to form a homogeneous mixture. The composition may be powdered for filling into hard gelatin capsules, or formed into granules for tableting.

[Table 9]

Examples 34-36 Examples 34-36 illustrate the use of polymers for lipid curing, commonly used in food applications. Several different grades of gelatin were mixed with deoiled lecithin containing a mixture of neutral phospholipids, charged phospholipids and glycolipids. Solids were prepared using various concentrations of the polymer in an aqueous medium. Before adding the lipid to the polymer, it was dispersed in ethanol-free water to obtain various dispersions. In all cases, the removal of water resulted in a crunchy composition, which could be further ground to a free flowing powder or granules. Powdered lipid polymer compositions can be used in various applications in place of conventional deoiled lecithin, or can be used to carry the active compound either in molecular association or dispersion with a liquid polymer. did it.

[Table 10]

Examples 37-39 The following examples demonstrate that membrane lipids are hard and crushable in combination with other polar lipids to extend their general use, especially in oral dosage forms. The utility of the present invention is further illustrated. In Examples 37-39, lipids are first gently heated on a hot plate, an aqueous polymer solution is added, and stirred to form a homogeneous suspension. Water was removed from the rally at 50 ° C. in a vacuum dryer until the weight of the composition was constant. In each case, a hard, millable solid polymer lipid composition resulted. As in the previous example, the active compound may be added to the slurry before water removal,
Alternatively, it may be mixed with the solid polymer lipid powder after removing water.

[Table 11]

Examples 40-45 The following examples typically make the various polar lipids and combinations thereof hard, grindable, and useful in the present invention in loading both lipophilic and hydrophilic compounds. Exemplify the nature. Examples 40-41 are solid lipid polymer compositions containing a lipophilic compound, which can be powdered and filled into hard gelatin capsules or compressed into tablets with the aid of suitable excipients. Examples 42 to 43 are solid lipid polymer compositions containing a hydrophilic compound. In Example 40, the active compound, lipid and polymer were dissolved in dichloromethane, resulting in a clear yellow solution. The dichloromethane was removed from the solution under vacuum to produce a solid polymer composition comprising flurbiprofen. In Example 41, beclomethasone propionate was added to soybean P
C was dissolved in an ethanol solution. The ethanol solution was added to an aqueous dispersion of the carboxyvinyl polymer and sodium carboxymethylcellulose. After drying,
A crisp yellow composition of BDP was obtained. This composition could be further processed into a free flowing powder or granules. Examples 42-44 were prepared by dispersing the active compound and lipid in an aqueous polymer solution. After drying, a solid, crushable solid polymer lipid composition was formed in each case. In Example 44, acetic acid was added to the polymer solution to produce a solution of chitosan. In Example 45, cyA, EPC and methacrylic acid copolymer were dissolved in ethanol. The solvent was removed to obtain a solid lipid polymer composition of CyA.

[Table 12]

The compositions of the examples can be filled into hard gelatin capsules and the like, or can be compressed into tablets and the like.

Presentation The waxy nature of lipids has historically been a barrier to using effective amounts of lipids in solid dosage forms, and the ability of lecithin to improve drug delivery has so far been poor. This is considered to be one of the reasons for not being used. The use of polymers has now been shown to increase lipid hardness and alter processability, dramatically increasing the likelihood of utilizing such formulations. The formulations of the present invention can be incorporated into several delivery systems, including solutions, suspensions, tablets, capsules, gels, suppositories, and vaginal suppositories, as well as free powders or granules. Perhaps the greater potential is to compress the powder into tablets for oral delivery or to fill hard gelatin capsules.

[Brief description of the drawings]

FIG. 1 is a diagram showing a particle size distribution of four kinds of powders.

FIG. 2 shows a comparison of Candida albicans growth inhibition zones.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/122 A61K 31/122 31/337 31/337 31/352 31/352 31/355 31/355 31 / 436 31/436 31/727 31/727 38/00 47/18 38/23 47/26 38/28 47/32 47/18 47/36 47/26 47/38 47/32 47/42 47/36 A61P 3/02 102 47/38 107 47/42 109 A61P 3/02 102 5/18 107 5/50 109 7/02 5/18 9/04 5/50 35/00 7/02 37/06 9/04 A61K 37/02 35/00 37/26 37/06 37/30 (81) Designated countries 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, TZ, 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, CR, CU, CZ, DE, DK, DM, 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, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA , ZW (72) Inventor Ray, Matthew Louis Stephen 4132 Mutten, Switzerland・ Creeper Ackerstraße ・ 30 ・ Piobox ・ (No address) ・ Fares Drug Delivery Inside F-term (reference) 4C076 AA01 AA19 AA30 AA31 AA37 AA41 AA49 AA54 AA61 BB01 BB22 BB29 BB30 CC07 CC30 CC30 DD63E DD63N DD68E DD68N EE11P EE13P EE15P EE33P EE36P EE37P EE38P EE42P EE48P FF34 FF35 FF67 GG03 GG05 GG12 GG14 GG26 4C08 BA AA02 AA03 BA44 CA62 DA11 DB31 MA37 MA32 MA03 MA05 MA21 MA03 MA05 MA31 MA35 MA37 MA41 MA43 MA52 MA57 MA60 NA06 NA11 ZA54 ZB08 ZB26 4C206 AA01 AA02 BA04 CB27 KA01 MA03 MA05 MA51 MA55 MA57 MA61 MA63 MA72 MA77 MA80 NA06 NA11 ZC21 ZC29

Claims (38)

[Claims] 1. A carrier composition for a biologically active compound, comprising at least one associated single-chain amphipathic lipid and / or at least one double-stranded amphipathic lipid and a polymeric substance. A composition for curing one or more lipids as described above. 2. The composition according to claim 1, wherein at least the lipid component of the composition is a substance having a GRAS (generally regarded as safe) state. 3. The composition according to claim 1, comprising a monoacyl membrane lipid. 4. The composition according to any one of the preceding claims, comprising a diacyl membrane lipid. 5. The composition according to claim 1, which comprises lecithin digested with enzymes. 6. The composition according to claim 5, comprising 60-80 mol% of the monoacyl lipid. 7. The composition according to any one of the preceding claims, wherein the polymer comprises natural rubber or a derivative thereof. 8. The composition according to claim 1, wherein the polymer comprises a synthetic polymer. 9. The composition according to claim 1, wherein the polymer has a cationic group or an anionic group. 10. The composition according to claim 9, wherein the polymer has a carboxyl or sulfate group. 11. A polymer wherein the polymer is a salt of carboxymethylcellulose, alginic acid or a salt thereof, starch modified with anionic groups, agar, carrageenan, acacia, tragacanth, xanthan gum, pectin, carboxypolymethylene, methyl vinyl ether / maleic acid copolymer. The composition according to any one of the preceding claims, wherein the composition is selected from: ammonium methacrylate copolymer, chitosan, methacrylic acid copolymer, hydrolyzed gelatin. 12. The composition according to claim 1, wherein at least 10% by weight of the polymer is present, based on the weight of the base composition. 13. The composition according to any one of the preceding claims, further comprising a sugar. 14. The composition according to any one of the preceding claims, further comprising a polyol, sucrose ester or polyglyceryl ester of a higher fatty acid, or another polyol ester of a higher fatty acid. 15. The composition according to any one of the preceding claims, further comprising a biologically active compound. 16. The weight ratio of lipid to active compound is from 40: 1 to 1:40.
The composition according to claim 15, which is: 17. The composition according to claim 15, wherein the active compound is present in the lipid in a molecular dispersion. 18. The composition according to claim 15, wherein the active compound is present as discrete particles in the composition. 19. The composition according to claim 18, wherein the size of the particles is 1 μm or less. 20. The composition according to any one of the preceding claims, wherein the biologically active compound is cyclosporin A, taxol, tacrolimus or rampamycin. 21. The composition according to claim 1, wherein the biologically active compound is insulin, calcitonin or heparin. 22. The composition according to claim 1, wherein the bioactive compound is ubiquinone, tocopherol, carotenoid or bioflabenoid. 23. The composition according to claim 1, which is a powder having a size of 50 to 2000 μm. 24. The composition according to claim 1, which is a powder having a size of 50 to 1000 μm. 25. The composition according to claim 1, which is a granule having a size of 1 to 5 mm. 26. A method for preparing a composition according to any of the preceding claims, comprising dissolving or dispersing the components in a solvent and removing the solvent. 27. The method of claim 26, wherein the lipid and the bioactive compound (if present) are dissolved in ethanol, the polymer is dissolved in water, the aqueous and ethanolic solutions are mixed, and the mixture is dried. 28. The method according to claim 26 or 27, further comprising the step of grinding the composition after the solvent has been removed. 29. The method of claim 28, comprising the further step of forming said milled composition into tablets. 30. The method according to claim 28, further comprising the step of filling the grinding composition into capsules. 31. A lipid composition for administration to living organisms, comprising a bioactive compound and monoacyl and diacyl membrane lipids associated with a polymer, when stored in a glass container at 40 ° C. and 75% relative humidity. A composition that is a solid that retains fluidity after storage for 3 months. 32. The composition according to claim 31, wherein the lipid is selected from those having a GRAS state and the polymer is selected from natural polysaccharide polymers, starch and its derivatives, cellulose and its derivatives, and gelatin. 33. The composition according to claim 1, wherein the lipid comprises a natural lipid. 34. The composition according to claim 1, wherein the lipid is a natural lipid modified by an enzyme. 35. The composition according to claim 33, wherein the lipid is derived from egg or soybean. 36. The composition according to claim 1, wherein the lipid comprises a partially synthetic lipid. 37. The composition according to claim 1, wherein the lipid comprises a synthetic lipid. 38. The composition according to any one of claims 33 to 37, wherein the polymer is selected from a natural polysaccharide polymer, starch and its derivatives, cellulose and its derivatives, and gelatin.