JPS6289617A - Drug composition and preparation - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed Description of the Invention] 3. Lamb of the Day J Now a Day (Prior Art) My first application (European Patent No. 11hO073006, 19
(filed August 17, 1982) discloses lipid-soluble drugs, pharmaceutical compositions that allow the drugs to be administered orally, and methods for preparing such compositions.

As I have previously disclosed, the present invention provides for the preparation of drugs and drugs dissolved in lipid droplets of extremely small size (primarily about 3 microns or less in diameter, preferably about 1 micron or less in size). We are proposing a drug delivery system like this. Each small mantle passes undeformed through the stomach and is absorbed by the brush layer of the small intestine directly into the thoracic duct and from there into the blood system.
surrounded by a layer of water. Emulsion capsules in the original application required mixing the powder and emulsion and then encapsulating this mixture in a capsule.

The method of making the previously disclosed delivery system is
Step 1 of dissolving the drug in lipids.

The process involves emulsifying the lipid in water (generally about 30% of the total effusion) and emulsifying the lipid in water in the presence of a surfactant. In this emulsion, extremely fine spherules of lipid are encased within a surrounding water layer. The overlying water layer helps to keep the lipid spherules in a finely separated shape.
It also serves to shield lipids from the digestive fluids of the digestive system, so the lipid spherules pass unchanged from the stomach to the small intestine for transport into the bloodstream. The method also requires encapsulation of the powder.

(Summary of the invention) The pharmaceutical composition of the present invention is a lipid, non-lipid liquid.

and a pharmaceutical ingredient, wherein the ingredient is emulsified, encapsulated as a liquid in a gelatin capsule, and encapsulated in a physical form capable of delivering the pharmaceutical ingredient to the brush layer of the small intestine in its original unaltered state. . a medicinal composition characterized in that the non-lipid component is not attacked by water, lipid enzyme activity, a water substitute;
or a mixture of a water substitute and water, the total water in the emulsion does not exceed 20%, and the physical form of the component is: fb) each spherule contains a drug component dispersed therein; and (11,) the surface tension of each spherule is wrapped in a layer around the non-lipid liquid component in contact with the spheres, the surrounding layer holding the spheres in an isolated shape;
and serves to provide only the non-lipid surface to gastric fluids.

The method for preparing a pharmaceutical composition of the present invention is a method for preparing the above-mentioned pharmaceutical composition, and includes the following three steps: (dispersing the drug product in the al lipid; Forming an emulsion comprising a lipid containing a drug, a non-lipid liquid that is not attacked by lipid enzyme activity, and at least one surfactant; the emulsion contains no more than 20% of the total water content. (c) homogenizing the emulsion to reduce the lipids into individual drug-containing microspheres having a diameter of primarily less than 3 microns; each microsphere being in a layer around a non-lipid liquid; and (dl) encapsulating the emulsion in gelatin capsules.

It has now been determined that emulsions containing drugs identical to those disclosed in my original application can be encapsulated in either soft or hard gelatin capsules without the use of the heretofore requisite powders. . Such emulsions, which may be directly encapsulated, contain non-lipid liquids.

This non-lipid liquid is not attacked by the enzymatic activity of the liquid as a medium. The drug-containing lipid is dispersed in the medium. And this non-lipid liquid.

Forms an enveloping layer that protects the drug from the digestive juices of the stomach.

This emulsion therefore allows the passage of unchanged lipid globules into the brush layer of the small intestine.

A non-lipid liquid as long as the total water content of the emulsion is about 20% or less by weight.

It can be water, a water substitute, or a mixture of a water substitute and water. A preferred water substitute is polyethylene glycol, which does not exceed a limit of 20%.

The emulsions of the present invention contain a lipid component, a drug dispersed in the lipid, a non-lipid liquid, and one or more surfactants. Although the composition can be formed and the drug delivered using a single surfactant, using multiple surfactants.

It is generally more preferred in the present invention that such surfactants are primarily lipophilic, but also have at least hydrophilic properties.

Also, more preferred surfactants are either uncharged (nonionic) surfactants or surfactants with a charge opposite to that of the pharmaceutical agent.

Therefore, if the drug is cationic, anionic surfactants are preferred. Conversely, if the drug is anionic, a cationic surfactant is preferred. Nonionic surfactants may also be used, especially if the Moraron drug does not have any charge. The reduction in net charge in the emulsion components results in a more stable emulsion with a longer shelf life.

One particular method of the invention for preparing an oil emulsion containing a drug that is lipid soluble and does not have any charge comprises:
Mixing the drug with one or more nonionic surfactants, thereby dispersing (i.e., suspending or dissolving) the drug in the surfactant; and then in a lipid preparation to form an emulsion. to suspend the drug in
It involves combining a mixture of drug and surfactant with a lipid. Another possible method involves mixing the lipid-insoluble drug with the lipid and then adding a surfactant to facilitate dispersion of the drug in the lipid.

Alternatively, a water-soluble drug may be dissolved in a small amount of water, and the water-drug solution may then be mixed with one or more nonionic surfactants to suspend the solution in the oil. in the presence of lipids. If the drug is lipid soluble, the drug need only be mixed with the lipid into a solution and then emulsified.

Any one of these forms of drug-containing lipids is mixed with a non-lipid liquid in a lipid-incompatible formulation to form an emulsion.

The lipid is then emulsified in an immiscible, non-lipidic liquid to form the lipid into microspheres of about 3 microns or less in size, preferably about 1 micron or less. In the final emulsion, each lipid spherule contains a drug.

In the final emulsion it is surrounded or encapsulated by a surrounding layer of immiscible, non-lipid liquid.

The non-lipid liquid of the present invention is a drug-containing fat.

Any liquid that can be emulsified with the substance and form an outer layer surrounding the spherules, and that can pass through the digestive system without being acted upon by it. Water is currently one of the more preferred non-lipid liquids. Polyethylene glycol is currently the more preferred non-aqueous and non-lipid liquid. I mean,
It is able to form an enveloping layer, since the digestive system recognizes it as water and does not act on it, allowing the polyethylene glycol-covered lipid spherules to pass unchanged into the small intestine. A mixture of polyethylene glycol and water works in the same way. Furthermore, even when mixed with water, polyethylene glycol (due to the fact that its surface tension is usually stronger than water alone)
It appears to adhere to lipid spherules more tenaciously than water alone. More preferably, the total emulsion is about 20
In the present invention, polyethylene glycol and water can be encapsulated in soft capsules as long as the total emulsion contains less than or equal to about 10% water, and hard capsules as long as the total emulsion does not contain more than about 10% water. Mixtures may be used.

As a specific example, it has been found that insulin can be dispersed in lipids with the aid of a mixture of surfactants, thereby successfully delivering insulin orally by either: This can be done by (1) dissolving insulin in a mixture of nonionic surfactants and then using a surfactant and insulin solution to incorporate the insulin into the lipids; Either mix first and then add a surfactant to disperse the insulin in the lipid. In either case, the lipid is emulsified with either the polyethylene glycol itself or with a certain amount of water present. The resulting emulsion therefore contains insulin dispersed in a lipid, the oil having the form of small spheres of size less than about 3 microns, preferably less than about 1 micron. Each spherule is surrounded by a layer of polyethylene glycol or polyethylene glycol plus water. Such an emulsion passes through the digestive system unchanged and insulin can be supplied through the brush layer of the small intestine.

Generally, the finer the emulsion, the better. Emulsions of small spheres on the order of 0.3 microns are most preferred.

The emulsions of the present invention consist primarily of oil or lipid droplets or lipid spherules having a diameter of about 3 microns or less, and preferably micelle sizes ranging from about 0.3 to about 1.0 microns. In this emulsion, the administered drug is dispersed. With the technology proposed here, 3.0
Experiments have shown that emulsions containing droplets or spherules of sub-micron size, preferably predominantly (on the order of 70% to 90%) droplets or spherules of size corresponding to i,o microns or smaller, are obtained. has been confirmed. Each microscopic droplet or spherule is trapped or wrapped in a layer around a non-lipid liquid, preferably water, polyethylene glycol, or a mixture of polyethylene glycol and water, so that it is not attacked by the digestive system. It will be done.

Although the exact delivery system is currently unknown, it appears that non-lipid fluid-encased spherules of this size do not stimulate or trigger the bile action of enzymes in the body. .

Apparently, this digestive system perceives the outer liquid layer as watery and attacks the oil globules enclosed in the outer layer? No.

Therefore, the tiny micelle-sized oil spherules contemplated by the present invention are supplied unchanged from the stomach, directly absorbed in the brush layer of the small intestine, transferred directly to the thoracic duct, and therefore directly transferred to the bloodstream. can enter the system and move into one systematic cycle.

Smaller globule sizes are more preferred. This is because the smaller size allows for better final delivery to the bloodstream with less interference with the digestive system.

The non-lipid liquid layer can be observed microscopically. It is (a
) to preserve the integrity of the individual oil spherules, and also (
b) Once the emulsion is formed, it acts to prevent the agglomeration of the oil globules into single clumps, and (c) to protect the oil globules from the bile action of enzymes in the body. This outer layer, formed and held together by the surface tension of the non-lipid liquid component of the emulsion, withstands the passage of the emulsion through the stomach and is delivered to the brush layer of the intestine.

Although the absorption mechanism in the brush layer is currently not fully understood, it is believed that the outer layer is stripped off either immediately before or during the passage of the spherules through the intercellular space of the eye. There is reason to believe.

The present invention is applicable to the following drugs, whether they are lipid soluble or completely or partially lipid insoluble. Manufactured drugs or drugs (these are.

It is particularly suited for oral delivery of drugs (usually delivered parenterally into the body). Typical examples of such drugs are:

Currently, insulin is delivered by subcutaneous injection. Other types of drugs that fit this description include doxorubicin, calcitonin, and similar drugs. For example, the need for parenteral administration of insulin results from the alteration, or destruction, of the drug by the digestive fluids of the stomach. Of course, the advantages of delivering such drugs by oral ingestion are readily accepted by young people suffering from diabetes, who must receive at least two injections of insulin per day every day of their lives. right.

According to the invention, it is also possible to administer small doses (insulin 1-5
It is now possible to supply (in unit orders).

Insulin therapy may therefore be utilized in adult diabetic patients. According to the oral supply of insulin.

Frequent administration is possible for better and more constant control of blood sugar levels in all diabetic patients.

The pharmaceutical ingredients of the emulsion are either (a) dissolved directly and in the desired dosage in the initial lipid solvent component, or (b) dispersed in the lipid component in the desired dosage. . Examples of lipid soluble drugs that can be used in the present invention include vitamin A palmitate, other retinyl esters, procarbazine.

BCNU (1?X-chloroethylnitrosourea).

CCNU (>X-chloroethylnitrosourea).

Methyl CCNU, ascorbyl palmitate, tysterone cypionate, testosterone enanthate, nandrolone fenpropionate, cholecalciferol, chloral hydrate, vanculonium bromide, acetophenazine maleate, ambenonium chloride, anirelidine hydrochloride, betamethazone phosphorus sodium acid, bromodiphenhydramine hydrochloride, sodium butabarbital, carfenzin maleate, cephalolidine, chloralhetaine, chlorotetracycline hydrochloride, dehydrohydrochloric acid, dexbromopheniramine maleate, dexchloropheniramine maleate, dimethyltubocurarine iodide, diphenadione , dromostanolone propionate, ephedrine hydrochloride, erythromycin estradiol, estradiol benzoate, glycopyrrolate.

Hydroxocobalimine, hydroxyzine hydrochloride, hyocyanine hydrobromide, indomethacin, isobucaine hydrochloride, isoproterenol sulfate, menadione sodium disulfite, mephentermine sulfate.

Methacycline hydrochloride, methantheline bromide, metapyriline hydrochloride, methosilazine hydrochloride, mesenamine.

Mesiodal sodium, methylbenshisonium chloride,
Methylergonovine maleate, oxymorphone hydrochloride, valamethacin acetate, pargyline hydrochloride, balamomycin sulfate, bentazocine hydrochloride, pentolinium tartrate, belphenazine, phenazoviridine hydrochloride, phenolphthalein, phenylpropanolamine hydrochloride, methyl pordine sulfate.

Potassium sorbate, Priloin hydrochloride, Propiomacin hydrochloride, Profoxicaine hydrochloride, Pseudoephedrine hydrochloride, Pyrylamine maleate, Pyrobutamine phosphate,
Pyrocaine hydrochloride, rotoxamine tartrate, Secside A and B, simethicone.

Stibofene, sulfoxone sodium, testosterone, chetylperazine maleate, triethylperazine maleate, triamcinolone diacetate, trifluoperazine hydrochloride, trimethohensamide hydrochloride, triprolidine hydrochloride, tromethamine.

Warfarin potassium, amodiaquine hydrochloride, candicidin, carfenazine maleate, cylindamycin phosphate, floxuridine, isoproterol sulfate, levalorphan tartrate, menadione sodium disulfite, methylprednisolone sodium succinate, methycelcito maleate, piperazine phosphate, propionic acid Sodium, sulfituxyl ciolamine, tetrahydrozoline hydrochloride, various prostaglandins for human or animal use, 7 alpha 19 nortestosterone and testosterone propionate.

Can be suspended in lipids. Or a drug that can be dispersed.

Some examples of drugs that have at most a limited degree of lipid solubility are listed below. Valpriocic acid, dihalpresox sodium, methylclothiazine and decervidin, pargyline hydrochloride, deserpidine,
Barramesadione, ethotoin, phenacemide, ethochlorpinol, hydroflumethiazide, griseofulvin ultramicrosize, propranolol hydrochloride, primidone, diviridamol, mesoridazine besylate.

Chlorthalidone, allopurinol, ibuprofen, hydroflumethiazide, carmustine, mido-thene, megestrol acetate, etoposide, methyltestosterone bucal, fluoxymesterone, erythrityl tetranitrate, azathioprine, digoxin, busulfan, acyclovir sodium, hydralazine hydrochloride, Aminoglutethimide, hydrochlorothiazide usp, maprotiline hydrochloride.

Desoxycorticosterone acetate, reserpine usp.

Phenylbutacin USP, baclofen, oxyphenbutacin USP, carbamazepine asp, iodoquinol, furosemide, methyltestosterone, cyclanderate, trimipramine maleate, ethionamide, cyclothiazide, digitoxin, acetohexamide, diltiazem HCI, pimozide, estradiol, Methyldopa MSD, probenecid MSD.

Dexamethacin MSD, Metyrosine MSD, Chlorothiazide Sodium MSD, Diflunisal MSD, Ethacrylic Acid MSD, Hydrochlorothiazide MSD, Indomethacin MSD, Amiloride HCI MSD, Carbidoparevodova MSD, Mepenzolate Bromide USP, Probucol, Trichlormethiazide USr', Chlorotri Anisen USP.

Metronidazole, Griseofulvin Microsize, Methsuximide, Prazepam, Phenytoin.

Quinestrol, phensuximide, phenelzine sulfate, mefenamic acid, pyrvinium bamoate.

ethosuximide, doxepin, metolazone, chlorpropamide, piroxicam, nifedipine, polythiazide,
Flucytosine, Sulfamethoxazole, Phenazoviridine Hydrochloride, Pumetanide, Sulfisoxazole, Levodopa, Procarbazine Hydrochloride, Diazepam, Glipicid, Ergoloid Mesylate Thioridazine, Nortributyline, Bromocriptine Mesylate, Temazepam, Pindolol, Ethinyl Estradiol, Ultra Microsized griseofulvin, trichlormethiazide, methyltestosterone, halazempam, fluphenazine hydrochloride,
Diazoxide, spironolactone, oxiatrolone, cisopyramide phosphate, prochlorperazine, trimethylene, cimetidine, chlorpromazine, captopril, nadolol, hydroxyurea, pendroflumethiazide, chloral hydrate, fluphenazine hydrochloride, fluphenazine caprate, testolactone, Simethicone, tamoxifen citrate, atenolol, oxymetholone, norethindrone and ethinyl nistrodiol, phenylbutacin, glutethimide.

Chlorthalidone, indapamide, triazolam.

Fluoxymesterone, minixodil, ibuprofen, tolazamide, methylclothiazide, danazol, chlormezanone, stanolzolol, lorazepam, guanabenz acetate, insulin and calcitonin.

If such drugs are lipid soluble, they can be easily incorporated into the emulsion of the present invention by dissolving them in the lipid component. However, most such drugs are either lipid-insoluble or not sufficiently lipid-soluble to provide sufficient dosage levels by simply dissolving in the lipid component.

Such relatively lipid-insoluble drugs are successfully incorporated into emulsions by first dissolving or suspending the drug in either an oil or a surfactant, or preferably a mixture of surfactants.

One of the surfactants or emulsifiers useful in the present invention is natural gums, such as gum arabic, gum tragacanth, etc.
Or something similar. When using gum tragacanth, more emulsion water is required, on the order of 10 times the amount required when using gum arabic.

Gum arabic usually contains enzymes that are destroyed by heating the rubber to a temperature of about 80° C. prior to use in the present invention. Surfactants can also be used, preferably those which have little tendency to crystallize, but which have some problems with retaining the aqueous layer surrounding the oil spherules.For these reasons, gum arabic is Current amounts are also preferred surfactants, with natural rubber type surfactants being more preferred.

Examples of such other surfactants or emulsifiers, natural and synthetic, which may be used are: dibentonite, sodium stearate, -valent soaps (castile soap, soft soap), triethanolamine stearate. , triethanolamine oleate, Tween R (
polysorbate), acacia, agar, alginic acid, sodium carboxymethylcellulose, carrageenan, powdered cellulose.

Gelatin, gNa cetyl sulfate/cholesterol, lactylate (carboxylic acid) sulfate monoglyceride, spans (sorbate), sodium lauryl sulfate, calcium stearate, polyethylene glycol monostearate 400. Polyoxyl stearate 40 (Myrj”
52), glycerol monostearate, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, povidone, propylene glycol monostearate,
Stearyl alcohol and xanthan gum.

More preferred surfactants for use in the present invention are:

It is nonionic, suitable for medicinal use, and is an approved surfactant. An example of such a nonionic surfactant is Tousheen 80. Tween 20 and Span 8
There is 0. If the manufactured drug has some electric charge,
Preferred surfactants are those with an opposite charge.

Tween 80. Tween 20 and Span 80.

All were commercially available nonionic surfactants. The surfactants are complex esters and ester-ethers.

Spans are partial esters of common fatty acids (such as lauric acid, palmitic acid, stearic acid and oleic acid) and hexitol anhydrides (hexitane and hexide) derived from sorbyl. Tweens are derived from spun products by adding polyoxyethylene chains to unesterified hydroxyl groups. Span 80. Tween 80 and Tween 20 are all liquids, which are soluble in oils such as corn oil.

Dispersible in water. These have both hydrophilic and lipophilic properties. This is because its free hydroxyl and oxyethylene groups are hydrophilic, and its long chain fatty acid component is lipophilic. Both Spans and Tweens are suitable and approved as pharmaceutical ingredients.

Of course, a single surfactant can be used to incorporate the pharmaceutical drug or agent into the oil.

However, I have found that mixtures of two or more surfactants are useful for stabilizing the final emulsion. The reason for this phenomenon is
Although not completely understood at this time, it appears that the use of two or three surfactants in combination not only helps disperse the drug in the oil, but also aids in the formation of the final emulsion. Of course, surfactants have these functions.

(1) to help incorporate the drug into the oil; and (2) to obtain a very fine emulsion with extended shelf life. It fulfills both functions.

Once the drug-toxin dispersion is formed, other emulsion ingredients are added. These emulsion components include (1)
It can form emulsions with lipids, (2) it can form an outer layer on lipid spherules, and (3) it can pass through the digestive system without being altered. It may contain any non-lipid liquid. This non-lipid component protects the lipid components and the drug they contain from the digestive system. This is because the digestive system simply recognizes non-lipid oils as water.

Although any suitable non-lipid liquid can be used, I currently use as a non-lipid liquid.

It is more preferable to use water, polyethylene glycol, or a mixture of water and polyethylene glycol. In particular, I have found polyethylene glycol to be particularly useful.

It is approved as a pharmaceutical ingredient, has a favorable viscosity and surface tension for incorporation into the final emulsion, and is able to pass through the digestive system without alteration. Polyethylene glycol 400 (PEG4
00), n is 8.2 to 9.1 and the molecular weight is about 380 to
Approximately 420 H(OCHzCllz)nOH.

It is a viscous, somewhat clear liquid, 210'
It has a viscosity of 7.2 centistokes at F.

Of course, other polyethylene glycols with molecular weights ranging from about 200 to about 9,000 are also available and may be used if appropriate.

Preferably, the non-lipid liquid is selected from the group consisting of polyethylene glycol or a mixture of polyethylene glycol and water. Preferably, the glycol-water mixture is comprised of 50% or less water. When this emulsion is incorporated into a soft gelatin capsule, 20% or less of the total emulsion will consist of water, and when the emulsion is incorporated into a hard gelatin capsule, approximately 10% or less of the total emulsion will consist of water. .

prior to emulsification to aid in the formation of this emulsion and specifically to increase the surface tension of the layer of non-lipid liquid surrounding each lipid spherule.

Fumed silica may be added to the mixture.

Fumed silica is a colloidal form of silica, which is made by burning silicon tetrachloride in a hydrogen-oxygen furnace. It is a very fine white powder with a very large exposed surface area. Using this smoked silica.

It appears to thin out or reduce the thickness of the non-lipid layer surrounding each lipid microsphere. Smoked silica also improves the stability of the final emulsion.

Formation of this emulsion may be accomplished by any desired method known to those skilled in the art. Preferred emulsions are formed simply using a portable stirrer operated at the fastest speed. However, there is a limit to the fineness of such emulsions. Finer emulsions are typically 8,
It is obtained by using commercially available emulsifying and homogenizing equipment, such as galarin emulsion machines or homogenizers, which can be operated at high pressures on the order of 9,0 OOp, s, i. The ingredients of this emulsion.

It can be passed through a Galarin homogenizer several times to obtain an emulsion with increased fineness and stability.

Ultrasonic vibration devices may also be used to form an emulsion of the required sphere size and to micronize the drug to ensure its incorporation into the lipid components of the emulsion. Generally, such devices.

A culm is used, which is inserted into a liquid and vibrated sonically at very high frequencies. If the drug is not completely lipid soluble, it can be mixed with a lipid or mixed with one or more surfactants, either in solid or liquid form. This mixture is.

The lipid or surfactant is vibrated ultrasonically to reduce the drug into very small or micronized solid particles or liquid droplets. The remainder of the emulsion ingredients are then added and the mixture is ultrasonically vibrated again with the drug contained within each microsphere to reduce the lipid to its final microsphere size.

A non-lipid fluid is formed that envelops and covers each lipid spherule. By using such ultrasound equipment, lipid spherules in the range of about 0.1 to about 0.5 microns are easily obtained, and even smaller spherules are possible.

The procedure for adding ingredients to form this emulsion may vary depending primarily on the drug formulation.

If the drug is lipid soluble, the first step is simply dissolving the drug in the lipid and using a surfactant to form an emulsion. If the drug is not lipid-insoluble and highly ionic, it is added to the lipid and dispersed therein by a surfactant.

The surfactant can be added with the drug or added before adding the drug. In some cases, such as with insulin, the drug is first moistened with lipid, preferably before adding the surfactant. If the drug is highly ionic, it may be added to the surfactant or mixture of surfactants before adding the resulting mixture to the lipid.

For example, this is more preferred when making an atenolol emulsion.

Therefore, the final emulsion obtained is.

It contains numerous lipid spherules smaller than about 3 microns, preferably primarily 1 micron or less in size. Each spherule contains a drug or a compound therein, either in solution or in finely divided suspension, or in the case of partially lipid-soluble drugs, both in solution and suspension. Contains dispersed drug. Each lipid microsphere is surrounded by a layer of non-lipid fluid. This layer can pass through the digestive system unchanged. Of course, this non-lipid layer may contain very small amounts of surfactant components and the smoky silica components of the pre-emulsion mixture. and if the manufactured drug or agent is dissolved in a non-lipid liquid.

Similarly, it may contain pharmaceutical ingredients. Preferably, the envelope layer is polyethylene glycol or a mixture of polyethylene glycol and about 30% water or less.

The final emulsion can be packed into hard or soft gelatin capsules. If the amount of water in the emulsion is not critical, the emulsion may preferably be administered as a liquid.

In certain cases, i.e. when the pharmaceutical ingredient is atenolol or when the soft capsule is gelatin with glycerin as a plasticizer.

Some of the glycerin plasticizer migrated into the capsule contents or entered the emulsion before drying. As soon as the capsule is dried, the glycerin is removed from the capsule shell and some of the emulsion is removed with it. However, in such cases, especially for highly ionic or polar drugs,

The problem may be avoided by excluding glycerin from the capsule ingredients. Other plasticizers can be used, such as sorbitol or polyethylene glycol, which are more preferred.

If this emulsion is encapsulated in soft shell capsules as explained above.

Emulsions may contain up to 20% water.

(Margin below) (Example) The present invention will be described below with reference to examples.

What is contained in the prepared composition:
Heavy I''''-) Corn oil
100 polyethylene glycol 400 76
Tween 2016 Tween 8014 Span 8023 Smoked Silica 4 Water
lO atenolol
25 The mixing procedure was as follows: 1. Surfactant was mixed.

2. Atenolol was dissolved in the surfactant mixture.

3. Corn oil was then added and mixed.

4. Fumed silica, polyethylene glycol 400 and water were added and mixed.

5, then the final mixture was 8,000p
,s,i.

It was passed through a Galarin homogenizer several times.

When this emulsion is examined under a microscope, 50% of the oil spherules are approximately 0.5 μm in size or smaller, and virtually all oil spherules are approximately 1 μm in size.
It was smaller than Atenolol was dispersed in oil spherules, which were surrounded by an envelope layer of polyethylene glycol and water along with surfactant.

This emulsion remained stable for several days, exhibited a shelf life of 6 months, and passed one food and drug administration stability test.

Some of the emulsion was wrapped in soft gelatin capsules. Each capsule contained 25 μ of atenolol.

Mainly prepared composition contains: charcoal-min.
heavy duty) corn oil
109 Polyethylene Glycol 400 65.
4 Tween 2027 Tween 8022 Snowin F3Q 16
．． 4 Smoked silica 4.3 Hydrocortisone 0.150 Mixing procedure is 2
It was done as follows: 1. Hydrocortisone was dissolved in corn oil.

2. Surfactant was added.

3. Polyethylene glycol 400 was added.

4. Added smoked silica.

5. When stirred with a hand mixer, an emulsion was immediately formed, and when stirring was continued, the fineness of the emulsion improved.

The emulsion remained stable for two days and showed no separation when examined under a microscope. The total amount of emulsion was sufficient to make approximately 100.0 capsules each weighing 25 mg. However, only 10 capsules were filled and stored.

■What is contained in the main prepared composition: Soko-Ku
, 1iiL) Corn oil
96 Polyethylene Glycol 400 57.
6 Tween 2024 Tween 80 19.2 Span 80 14.4 Smoked Silica 3.8 Water
24 Hydrocortisone
The 0.150 mixing procedure (excluding water addition) and results were as shown in Example 2.

Emperor's opening↓ A composition was prepared as in Example 1. but.

0.147 g of insulin (27° 1 unit/1
■Insulin) was replaced with hydrocortisone.

Insulin was dissolved in a mixture of surfactants. Although the relative amounts of some components were changed.

A similar mixing and emulsification procedure was followed.

Sixty soft gelatin capsules containing approximately 250 inches of emulsion were prepared. Each capsule content: bottom-light l quantity uni) corn oil
96.000 Polyethylene Glycol 400 57.600 Tween 20
24.000 Tween 3Q
19.2 (1 (1 span 80
14.400 oxidized silica
3.840 insulin (27.1 units/1 mg insulin) 0.1
47 (4 insulin units) water
24.000 The emulsion finally obtained was storage stable and had oil spheres of approximately 1 μm.

Sanitoyo Goko Nine compositions were prepared using the procedure of Example 2.

However, the relative amounts of the ingredients were varied to yield the following composition, which included insulin instead of hydrocortisone.

60 capsules were prepared. Each capsule content: bottom-and
Insulin (27.1 unit/1 ■ insulin) 0.147
(4 insulin units) Corn oil
109.000 Tween 20
23.200 Tween 80
21.800 span 80
16.350 polyethylene glycol 400
65.400 oxidized silica 4.
300 This emulsion, when examined under a microscope, shows approximately 1
The presence of μm-sized oil spheres was shown. This emulsion was storage stable.

Three diabetic dogs were tested for 5 days each. Each person has been injected with insulin and maintained since their diagnosis of type 1 diabetes. This dog is.

Currently, he is being maintained with NPH insulin (long-acting, injectable insulin) injected twice a day at 9am and 4pm.

The doses on which the dogs have been maintained to date are as follows: Dog I (Ruffian) is female, born in January 1979 and diagnosed with diabetes in February 1979. Her usual insulin control is on a daily basis: 17 units of NPH insulin is injected at 9 o'clock, and 5 units of NPH insulin is injected at 16:00.

Dog ■ (Morgan) is a female, born in September 1981, and diagnosed in November 1981. Her normal controls include 12 units of NPH and 5 units of regular insulin injected at 9:00 and 18 units of NP11 insulin at 4:00 p.m.

Dog ■ (f:zu) is a male and was born in October 1978.

He was diagnosed with diabetes in February 1979. He took 20 units of NP11 insulin at 9 o'clock and took 24 units of N.
PH insulin is given by injection at 16:00 in both cases.

Dog ■ (Ruffian) developed some fever during the test.

This condition caused an increase in temperature, making diabetes control more difficult. moreover.

Due to generalized edema, G.1. It seems that the control of adsorption from the tube has decreased.

The dogs received their usual schedule of injections at 9:00 and 18:00 and were fed at 9:00 on November 4, 1985, respectively. On November 5th, 6th, 11th, and 15th, the dogs were given oral insulin capsules at the indicated doses and 9 saline injections to avoid changes in the dogs' psychological control. given at the time. The insulin capsules were placed inside one or more meatballs and given at two regular feeding times. At 16:00,
They received regular insulin injections. The dogs maintained normal activity on each day. From November 6th to 11th and November 11th to 15th, the dogs continued to receive two regular injections.

Each person's blood sugar level was measured hourly and recorded as shown below. This measurement was made using GlucoCheck, which is accurate and effective when blood sugar levels are 450 or below.

The results of this dog test are reported in Tables 12 and 3.

(Margin below) The results of these tests are shown in FIGS. 1-3.

Discussion: The test results showed that both the formulations of Example 4 and Example 5 were effective in delivering orally administered insulin to the blood of dogs.

It is clear that the effect of the formulation of Example 5 in reducing blood sugar levels is higher than that of the formulation of Example 4.

Dog ■ (Boz) was a severely diabetic animal who quickly lost insulin control.

However, in the November 15, 1985 test, it absorbed some percentage of the insulin (probably 30-40%).

The results for dog■ (Ruffian) and dog■ (Morgan) are
This clearly indicates absorption of insulin from the orally given capsule.

An emulsion was prepared in essentially the same formulation as the emulsion of Example 5. However, doxorubicin (Adriamycin) was replaced with the insulin of Example 5,
Sesame seed oil was replaced with corn oil. Stir doxorubicin into sesame seed oil.

Suspended as a solid, polyethylene glycol 400 was then added, and silica smoked as a surfactant was added. This emulsion.

The size of the oily spheres prepared using a hand mixer and tested showed that they were primarily on the order of 3 μm or less. This emulsion.

It was stable in storage.

If this capsule contains 2 ■ doxorubicin, the emulsion dosage unit contains: tLi Dan I: 1 doxorubicin 2.000 sesame seed oil
109.000 Tween 20
23.200 Tween 80 21
．． 800 span 80 16.35
0 Polyethylene glycol 400 65.400 Smoked silica 4/3 m shadow 83.23 g of gum arabic and 166.68 g of sterile water were mixed using a magneta ink mixer.

33.25 g of sesame seed oil and 24.30 g of propranolol hydrochloride were mixed in an ultrasonic mixer to suspend propranolol in the sesame seed oil. The propranolol-sesame seed oil suspension was then added to the gum arabic-water mixture and mixed using a laboratory propeller blender or micronizer.

This mixture was then first processed in a Gaulin 15M homogenizer at 500 pounds per square inch.

When tested under a microscope, most emulsions are
It contained oil spheres with a size smaller than μm. This emulsion was then placed in a Galarin homogenizer at 8,0
Passed twice with 00 p, s, i.

Testing under a microscope showed that 90% of this emulsion contained sesame seed oil with a diameter smaller than 1 μm. However, the viscosity of this emulsion was too high for filling soft gelatin capsules.

An additional 229.90 g of sterile water was added to reduce the viscosity. 500g of emulsion was separated,
220 g sesame seed oil and 240 g polyethylene glycol 400 were added. The emulsion mixture containing the added sesame seed oil and polyethylene glycol was passed through the homogenizer once again.

The resulting emulsion had a viscosity low enough to flow the soft gelatin filling.

1, 900 capsules are filled, this capsule is 48
dried for an hour. Each capsule contained 10 μ of propranolol. Due to the high proportion of water, the formed capsules had indentations. but.

The 1.300 capsule had few dents and was suitable for use. When testing the emulsion in the capsule,
It was found that 90% of the spheres contained oil particles and were smaller than 1 μm.

It was given as 10 mg commercially available propranolol hydrochloride capsules to three healthy adult patients. Serum levels for each patient were determined by methods approved by the Disease Control Center of the Toxicology Center in Van Lenda, Michigan. The serum values were measured using IIPLc, a high performance liquid chromatography device, after 1, 2.3°, 4 and 6 hours, respectively.

Four days later, the same three patients were given a total of 10 μl of capsules containing propranolol hydrochloride prepared in Example 8, and each patient's serum levels were determined as described above.

As shown in FIG. 7, the following first-order results were obtained.

1 hour 2.167 2.0 -2 hours
5.5 9.389 64.33 hours
6.067 8.50 52.94 hours 3
．． 833 5.722 52.36 hours 2
．． 867 3.112 12.7 In order to avoid the presence of excess water and to avoid interference of the composition with gum arabic 9 a more preferred formulation may be used as follows: Tuusheen 80 100 g sterile water
100g polyethylene glycol 100g sesame seed oil 40
0g Propranolol Hydrochloride A 28g 260■ capsule contains 10■ of propranolol.

Susei LfLL The general procedure was the same as in Example 8.

83.24 g gum arabic, 166.49 g sterile water, 333.02 g sesame seed oil and 64.75 g
An emulsion containing g of chlorthalidone was prepared.

Transfer this emulsion to a Galarin homogenizer with 8.0
I faced difficulties when passing with 00p, s, i. The homogenizer valve was blocked by a large mass of chlorthalidone particles. 846.49g of additional water is added to this emulsion.

Immediately passed through a homogenizer at 8,000 p.s.

When analyzing the particle size, 90% of the sesame seed oil globules are.

The diameter was smaller than 1 μm.

Next, 200 g of Tween 80 and 220 g of polyethylene glycol were added to the emulsion and again
,0OOp,s,i, through a homogenizer. The final emulsion was packed into soft gelatin capsules. The capsules were dried for 48 hours and then stored. No effects or dents due to main drying were observed in the capsule.

Preferably, non-fat soluble drugs are dispersed and strongly degraded in oil before forming an emulsion. This can be done by passing the pharmaceutical-lipid mixture through a micronizer such as a "Dynomil". A more preferred composition of chlorthalidone is as follows: Tween 80 100 g sterile water
100g polyethylene glycol 100g sesame seed oil 400g
Chlorthalidone 70 g This emulsion yields 2800 soft gelatin capsules, each capsule containing 25 μ of chlorthalidone.

333.73 g of sesame seed oil and 146.00 g of triamethylene were mixed using an ultrasonic mixer. This triamethylene was added to Example 8 and Example 9 in sesame seed oil.
It dissolved better than the formula. 84.42 g of gum arabic and 83.80 g of sterile water were each mixed separately using a magneta ink mixer, the oil-triamethylene dispersion was added, and mixed using a laboratory propeller mixer. Ta. As a result, the obtained emulsion is
Passed through a Galarin homogenizer at 8+000p, sj. In the first distribution, 90% of the 9 spheres had a diameter of 1
An emulsion with a size of less than μm was obtained. To reduce the water content, 200g of Tween 80 and 220g
of polyethylene glycol 400 was added to this emulsion and again placed in the homogenizer at 8.000 p, s, i
, was passed. 3.480 capsules were prepared by soft gelatin encapsulation.

The capsules were dried for 72 hours. Each capsule is
It contained 25 μm of triamethylene. A more preferred formulation for making 2800 force cells (this is 300
(containing 50 mg triamethylene) is prepared as follows: Tween 80 100 g sterile water 100 g polyethylene glycol 400 100 g sesame seed oil
400 g triamethylene 1
40g backbone U Prepare the emulsion by adding the following ingredients to the procedure of Example 8.
Mold: Gum arabic 83.24 g Sterile water 166.49 g Sesame seed oil
333.02 g Hydrofloratiazide 64.75 g As soon as the ingredients were mixed, the emulsion separated. This is because the negative charge of gum arabic caused dissociation of the emulsion when mixed with the negatively charged hydrofloratiazide.

A suitable formulation is as follows: Tween 80, 100 g sterile water 100 g polyethylene glycol 400 10Q g sesame seed oil
400 g hydrofloratiazide
In addition to the 64.75 g formulation changes, the iPi drug combination was micronized with oil to disperse the drug in the oil. This is tween in the dyno mill.

The water and polyethylene glycol 400 ingredients were added before being homogenized to form the final emulsion.

Sōtate charcoal fertilizer Sugar and Spice are two healthy, normal animals.

She is a non-diabetic female and is the size of a peagle. the dogs.

The subjects were fasted from 10:00 a.m. on the day before the experiment started.

Oral insulin in the formulation of Example 6 above.

Insulin was administered at a dose of 6 units per kg of each person's body weight at hour 0 (8:00 a.m.) on the day of the experiment. Take blood samples from each person.

Blood sugar levels were measured at the intervals shown in FIG.

At 60 minutes they reached the maximum hypoglycemic effect and during the next 60 minutes there were two elevated peaks in blood sugar levels. These peaks are.

Literature (Cardiovascular Review Report, 7
Volume, l1h7. July 1986, p, 649-65
6), it was explained that it represents the opposite hormonal control effect and the effect of substrates other than glucose.

Over the next 150 minutes they maintained minimal hypoglycemic effects. At 270 minutes, they returned to the 40 range and remained there for over 60 minutes of the first order.

Animals were fed at 450 minutes. Their blood sugar levels increased according to their diet. The graph in Figure 4 shows the average blood sugar for both dogs over a 500 minute period.

After the meal, a more normal rise in spice occurred. Sugar did not reach a sufficient response to diet. The details of each person's blood are shown in the graph of FIG. However, the active values of the first 300 minutes were lost in the longer time frame.

After 3 weeks, established blood sugar levels without insulin were obtained for rainy weather, as shown in Figure 6.

A test three weeks later surprised observers: 9 blood sugar levels in both dogs were at the normal time for dogs to eat.
:00 It remained at 50 all day except for the peaks at a and m. The peak was 80, which wasn't very high on the first day. The dog returned to an average level of 57 for the remainder of the first day of testing. One week later, the animal was tested again in the morning and returned to normal blood sugar levels.

When we try to understand the consequences of this long term.

It can be assumed that the insulin in the lipid globules is supplied intact to the lymphatic system, and that the phagocytic cells of the endothelial system seize these foreign globules and slowly dissociate them over an hour.

Also, under such circumstances 1 interference with normal insulin metabolism will occur. This theory appears to be in good agreement with the results of this test, especially the behavior after 3 weeks of insulin administration.

SUMMARY OF THE INVENTION Containing a lipid, a non-lipid liquid, and a pharmaceutical ingredient, the ingredients are emulsified and delivered as a liquid to a gelatin capsule and to the brush layer of the small intestine in its original, unaltered state. Discloses medicinal compounds that exhibit properties as a result of being encapsulated in a physical form that can be used. Non-lipid ingredients.

water substitutes that are not attacked by hydrolipid enzyme activity, and mixtures of water substitutes and water. Also, the total water in the emulsion is not more than 20%. The physical forms of the ingredients are as follows.

(The al lipid component is primarily in the form of individual spherules sized about 3 microns or less in diameter.

(b) Each microsphere contains a drug formulation component dispersed therein.

(c) Each spherule is encased within an overlying layer of the mentioned non-lipid liquid component that is in contact with the spherule by a surface tension force, and the overlying layer is It acts to maintain the sphere and present only a non-lipid surface to the gastric fluids.

It also discloses how to make the same thing.

Figure 1 is a computer-generated graph showing the blood sugar level of a dog over a period of time after oral administration of insulin in accordance with the present invention.

FIG. 2 is a similar graph to FIG. 1, showing the same data for a second dog.

FIG. 3 is a diagram similar to FIGS. 1 and 2.

Similar data related to a third dog.

FIG. 4 is a graph similar to FIG. 1 showing the combined blood glucose levels of two different dogs at certain times after oral administration of insulin in accordance with the present invention.

Figure 5 is a graph similar to Figure 4, showing the blood sugar levels of individual dogs starting 5 hours after insulin administration.

FIG. 6 is a graph similar to FIG. 4, but three weeks after oral administration of insulin.

FIG. 7 is a computer-generated graph showing the results of two oral administrations of propranolol in accordance with the present invention.

Figure 2 shows serum levels of oral propranolol hydrochloride in human body donations over time.

Engraving of the drawing (no change in content) 1 Figure +b 7 (7'/-, +t O22'f b) C'
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,'1 minute a >Yuh゛-guide Sl\1chair small 6 Fig. 3 d l,Fl Yataka・Ryo・Time・K Inoha), Riichi/All 0:/Kη゛- and Suha8 Isri Handiq Procedural Amendment (Method) November 4, 1985 Commissioner of the Patent Office Wl.

1. Indication of the case Patent Application No. 190386 of 1988 2. Name of the invention Pharmaceutical composition and method for preparing the same 3. Person making the amendment Relationship to the case Patent applicant's address 541 Burgundy Square, Lansing, Michigan 48823, United States of America. Apartment 202 Name William Gauff Tucker Nationality United States of America 4 Address of agent 5 Nishitenma, Kita-ku, Osaka, Osaka 530 Date of amendment order (shipment date) October 28, 1985 6 Drawings subject to amendment (plan) 7 , We will present you with a new one that is clearly drawn in a rich black color (no changes to the content).

Claims (1)

[Scope of Claims] 1. Containing a lipid, a non-lipid liquid, and a pharmaceutical ingredient, the ingredients are emulsified and encapsulated as a liquid in a gelatin capsule, and the brush of the small intestine in an unaltered initial state. A medicinal composition characterized in that it is encapsulated in a physical form capable of delivering said drug to a layer, said non-lipid component being free from attack by water, lipid enzymatic activity. or a water substitute and water, the total water in the emulsion does not exceed 20%, and the physical form of the components is: (a) the lipid component is in the form of primarily individual spherules of less than about 3 microns in diameter; (b) each spherule includes a pharmaceutical ingredient dispersed therein; and (c) each spherule is , wrapped in a layer around the non-lipid fluid component that is in contact with the spherules due to surface tension, the surrounding layer holds the spherules in an isolated configuration and keeps the non-lipid fluid components in contact with the gastric fluids. It acts to provide only a lipidic surface. 2. The composition of claim 1, wherein the composition is encapsulated in a hard gelatin capsule, and the total water content in the emulsion does not exceed about 10%. 3. The composition according to claim 1 or 2, wherein the water substitute is polyethylene glycol. 4. The composition of claim 1 or 2, wherein the non-lipid liquid is polyethylene glycol and has from 0 to about 50% water. 5. The composition according to claim 1, wherein the composition contains at least one type of surfactant. 6. The composition according to any one of claims 1 to 5, wherein the lipid spherules have a diameter of 1 micron or less. 7. The composition according to any one of claims 1 to 6, wherein the pharmaceutical ingredient is insulin. 8. The composition according to any one of claims 1 to 6, wherein the pharmaceutical ingredient is atenolol. 9. The composition according to any one of claims 1 to 6, wherein the drug component is doxorubicin. 10. A method for preparing a pharmaceutical composition, comprising a lipid, a non-lipid liquid, and a pharmaceutical ingredient, the ingredients being emulsified and encapsulated as a liquid in a gelatin capsule and in an unaltered initial state. A medicinal compound characterized by being encapsulated in a physical form capable of delivering the drug to the brush layer of the small intestine; a water substitute, or a mixture of a water substitute and water, wherein the total water content in the emulsion does not exceed 20%, and the physical form of the ingredients is: (a) the lipid component is primarily in the form of individual spherules less than about 3 microns in diameter; (b) each spherule includes a drug component dispersed therein; and (c) each spherule is encased in a layer around the non-lipid liquid component that is in contact with the spherule by surface tension, and the surrounding layer holds the spherule in an isolated configuration. and serves to provide only said non-lipid surface to gastric fluids. (a) dispersing the drug product in a lipid; (b) a lipid with the drug product dispersed therein, a non-lipid liquid that is not attacked by lipid enzyme activity, and at least one surfactant; (c) forming an emulsion containing no more than 20% of the total water; (c) reducing the lipids into small spheres containing individual drug products having a diameter of primarily less than 3 microns; (d) homogenizing the emulsion; each spherule is surrounded by a layer of non-lipid liquid; and (d) encapsulating the emulsion in a gelatin capsule. 11. The method of claim 10, comprising first moistening the drug product with oil before forming the emulsion. 12. Claim 10, which includes mixing the drug with at least one surfactant of the same surfactants used to form the emulsion before forming the emulsion; or The method according to paragraph 11. 13. A method according to any one of claims 10 to 12, comprising adding oxidized silica to the emulsion components.