DE1467861A1 - Use of organopolysiloxane elastomers as drug carriers in solid form with controllable release of active ingredients - Google Patents

Description

Lawyer LF. Drissl . . _nunetteh vu _to 27. 9. 1968

Munich 23, Clomensstr. 26 Dr. Wg. / Ku

In Gen. Volinio ·.:! ·.! for 1467861

Duw Coming Corporation, ρ if 67 861. 6

Midland, Michigan ( _Dc 1028/596)

No. 534 / ÖO *

Use of organopolysiloxane elastomers as Drug carrier in solid form with controllable

Active ingredient releases

Ee iet known, arenic agents and pharmaceutical preparations »with arsenic oil carriers, such as beeswax, beanut butter, To dispose of stearates and the like and to administer them intramuscularly aögliohen such a delayed release of the drug. Such Porters do not satisfy Jedooh because they are often unexpected Side effects beige, such as foreign body reactions and scarring. In addition, orenuloma formation (benign fibrinous tumor) and abaea formation can occur at the injection sites. The drug is released in the individual pulls ao quickly, because often "injections bit in each case small active ingredients are necessary. Auflerde" iet the active ingredients in the d # sr elnaelnen injection bounded by the carrier nose.

Furthermore, the various types of containers were prepared developed that can be inserted into body cavities and the small openings are provided which serve to release the active ingredient. Experience fiddled, however, tS the small openings «rather raeoh duroh the body's own Tissues become clogged so that the drug is released a few hours or days of sun breastfeeding koawt. Sine others

909805/0980

U67861

Measure of the introduction of drugs into the body consisted in the use of tablets with a smooth, solid surface, which is partly covered with an insoluble protective layer, 3o that only the unprotected parts of the surface can be attacked exposed to body fluids. Of course, the absorption of the drug from the unprotected surface can occur during the dissolution of the entire tablet cannot be accurately controlled or predicted.

According to the invention, organopolysiloxane elastomers which contain an average of 1.98 to 2.02 monovalent, optionally halogenated hydrocarbon radicals per Si atom and are prepared by heat curing or curing at room temperature, optionally in the presence of catalysts and / or fillers, in a conventional manner have been used as a drug carrier in solid form, e.g. B. used as closed tubes, capsules or tablets with controllable drug release.

The German Auslegeschrift 1 063 309 already discloses the use of non-hardening, elastic, cold-deformable organopolysiloxanes as protracting solvents and embedding compounds for fragrances and active ingredients, and German Auslegeschrift 1 068 863 describes the

- 2a 909805/0980

Prior art mentions that to preserve tablets, which contain, for example, oxidation-sensitive vitamins, these by embedding in suitable substances, whereby inter alia. silicone resins are also listed, must be protected.

For the medicament carriers according to the invention, however, Organopolysiloxane elastomers used by thermosetting or have been produced by curing at room temperature in a manner known per se.

The decisive feature of the medicament carriers according to the invention is that they are polymeric due to their special properties Structure, despite their hardened state, are able to slowly slow incorporated drugs to a precisely controllable extent free to give. This feature can be described as surprising in view of the German Auslegeschrift 1 063 309, since herein the organopolysiloxanes which can be used for the stated purpose are expressly identified as "non-curing". Even with a simple protective effect for oxidation-sensitive vitamins, those with silicone resins, their different structural structure is sufficient compared to organopolysiloxane elastomers is known to be achieved as an embedding compound, this feature has nothing to do with it.

The pharmaceutical carriers according to the invention can be in the form of

- 2b 909805/0980

U67861

holders or capsules containing the drug, or as mi ^ solids mixed with the drug are introduced into the living organism. So z. B. capsules or other carriers

909805/0980

^Χ U67861

In the tissue of an organ or a certain part of the body are implanted and thus enable a controlled Active ingredient releases in a practically constant dosage over a long period of time. Under "drug" are to understand all therapeutic agents that are suitable for treating undesirable conditions in or on the living body or to fix in the body fluids or to achieve desired properties, e.g. hormones, vitamins, antibiotics, Anticoagulants, caneeriζide means »apermicidal gowns or vasoactive agents.

The pharmaceutical carriers according to the invention preferably consist of organopolyeiloxaöelastomers which are inactive against the drug, are non-toxic to the body and are known to be compatible with the living organism. The organopolyailoxanes can either be heat curable or at Be room temperature curing elastomers, which can be produced in the form of suitable containers, e.g. as hollow tubes, capsules, pills or in the form of a prosthetic device in which, due to their polymeric structure, a suitable Remedies can be incorporated. However, the pharmaceutical carriers according to the invention can also be used in conjunction with the drug injected directly into the body tissue

The drug carriers according to the invention enable one slow passage or diffusion of the drug contained in it

909805/0980

H67861 *

to the outer surface of the polymerizate, to then of the Body fluid to be absorbed. The drug is preferably used in dry, powdered form, since the solids are generally more stable, and thus advantageously stored within the body until they are removed from the polymer Carrier is released.

The support according to the invention thus enable a relative slow diffusion of a powder, a semi-solid or a liquid through the surface of the polymer. The mechanism causing diffusion or emigration can best be explained by the concentration gradient that the substance trapped in the carrier caused by emigration In the surrounding medium overcomes · The action usually comes then total standstill when enough substance has reached the outer boundary of the surrounding medium. In the present case However, the molecules emerging from the surface of the polymer are absorbed by the body fluids and absorbed by the tissue so that migration continues until all the substance is consumed

The substances which can penetrate the surface of the polymer are generally those which are noticeably soluble in the polymer. In addition, the ease with which these substances permeate the interstices of the individual polymeric molecules depends substantially Ton * ν composition ά from the carrier ·

. 909805/0980

- * - U67861

When using so-called thermosetting organopolyoiloxane elastomers Are the Si-bonded organ-like rectangles preferably monovalent hydrocarbon radicals, such as alkyl, aryl, Alkenyl, alkaryl and aralkyl radicals, and among these are the methyl, phenyl and vinyl creations are particularly preferred. The organic radicals can, however, also be monovalent, halogenated Hydrocarbon radicals aein, such as chlorophenyl and 1.1 »1-triiluoropropyl radicals.

By varying the organic groups in the organopolyailoxanes can decrease the drug solubility in the polymer can be changed so that the emigration speed can be precisely determined.

Of course, when selecting the organic substituents, care must be taken that the presence of the polymer in the organism does not result in any undesirable effects such as foreign body reactions.Pure methyl polyailoxanes and dixaethyl polyailoxanes with a small amount of methyl vinyl siloxane units (e.g. up to about 0.5 mol ?) Have been the best investigated toxicologically up to now and have proven to be completely inert, so that their use for the purpose according to the invention is particularly preferred or no meaning

909805/0980

The thermosetting organopolysiloxanes usually contain Fillers to improve the tensile strength and other physical properties of the elastomers · The So-called reinforcing SiOg fillers are particularly useful for this suitable · organopolysiloxanes containing such fillers have been used extensively with regard to their compatibility with implantations in a wide variety of body tissues investigated and found to be inert · From this founder SiOg-containing fillers are preferred, e.g. with preservation the structure dehydrated silica hydrogels, pyrogenic in c Silicon dioxide and other types of silicon dioxide obtained in the gas phase with a relatively high pore volume and large surface area; these fillers can optionally be applied to their surface Organosiloxy groups contain bound.

The is typical of the thermosetting organopolysiloxanes Addition of a peroxide-based hardening catalyst · Benzoyl peroxide or di-chlorobenzoyl peroxide are used for the manufacture of implants preferred as hardening catalysts, as these decompose during hardening and therefore not in the end product »Or are included.

The manufacture of the thermosetting organopolysiloxanes is and can be found in, for example, U.S. Patents 2,541,137, 2,890,188, 2,723,966, 2,863,846, and 3,002,951 • rfο Ig en.

909805/0980

~ * ~ H67861

Organopolyailoxanes which cure to give elastomers at room temperature are also known. In general, can for this purpose the same starting materials as for the thermosetting Elastomers are used, although the polymers often have a larger proportion of in the terminal units Contain hydroxyl-containing siloxanes. Optionally, these organopolyeiloxanes can be made with pull materials listed types are processed and the crosslinking by introducing components such as orthosilicates, polyailikates and organopolysiloxanes with Si-bonded H atoms achieved · Curing takes place at room temperature in the presence a httritngskatalyeatcro, which is usually around before use is added. Typical hardening catalysts are metal salts of carboxylic acids and for the use of these organopolyoiloxars for implantations according to the invention Stanno-2-ethylhexoate ice hardening catalyst is particularly preferred.

Hanohmal it is desirable to be involved in or at the according to drug carriers sponge-like organopolysiloxane ' elastomeric or »to be attached and thus an anchoring for creating implants. These sponge-like or hemmed polymers are generally made of one organopolysiloxanes having a relatively high amount of Si-bonded OK groups and Si-bonded Η atoms Organopolysiloxanes, fillers and metal salt catalysts

/ noön

U67861 ■

of the types listed. The catalysts work in dleeera Pail not only a networking under training dea olastoxneren stateo, but catalyze also an Hp development and this evolved gas acts as a sponge-forming agent in the system.

Furthermore, so-called one-component corns, which cure at room temperature without any further additives are used · The ones used for this purpose Organopolysiloxanes contain e.g. at the terminal S! Atoms two aoyloxy, preferably acotoxy, groups each bonded and optionally fillers of the types mentioned. Be admittance the aeyloxy groups hydrolyze under from atmospheric moisture Formation of new trifunctional Slloxan units that in the polymer as a crosslinker with the formation of elaotomeric Bond products work

The production of the listed, at room tempo door closed Elastomer-curing organopolyailoxane is known and may, for example, according to U.S. Pat. No. 2,927,907 » 3,035,016 and British patents 793,669-and 804 199 «follow ·

The listed organopolyailoxanes can be in capsules or Tablets joder bellobigen greetings and wall thickness obsolete and with the drug or active agent in the desired

BAD ORIGINAL 90P.8Ü5 / 098 0

- * - U67861

Amount to be filled. Since the degree of diffusion of the drug molecules is a determinable and characteristic quantity, the dose of the drug that is released from the contiguous surface of the container in a certain time can be precisely determined. Those in a particular The amount of active ingredient released is therefore both of the time Dlffusiongesochwlndigre the drug through the organopolysiloxane as well as on the absorption capacity of the body tissue surrounding the container. By limitation the surface of the carrier, which is used to release the active ingredients, can determine the amount of drug that passes through the surface, be closely controlled.

Although the pharmaceutical carriers according to the invention in the The most varied forms can be used, their use is in the form of tubes with a certain volume, be - - ' stlmmter length and calibrated speed of the drug; released particularly advantageous

Hollow tubular sleeves or capsules having uniform Oberfläohe filled with a preferred amount of the active 'agent were to release ₉ may be a standardized active substance are prepared in advance for medical and surgical use.

909805/0980

If the amount of active ingredient released in a certain time is to be reduced, a part of the elastomer surface can be coated with a non-permeable / plastic layer or the tube can be inside with a metallic or plastic lining, which has a certain number of openings of a certain size, through which in turn the active ingredient ' release · can be regulated. Standard tubes of a certain length guarantee the release of a prescribed one Amount of active ingredient in a period of 24 hours. The implants can also trigger desired physiological effects in certain periods of time. 70, 80 or 90 heartbeats per minute.

For the intended purpose it is advantageous to use hollow, Tubular containers formed from the organopolysiloxane, with a wall thickness that allows the tubular structure to be maintained so that it can be inserted into the Body tissues are not squeezed or bent; can "The wound thickness of the container is for the wall speed of the drug in the unit of time is decisive, but not for the amount of drug released, as this primarily a puncture of the solubility of the drug in the organo- ί polysiloxane is, so that in the end the same amounts of drugs are released by thick or thin capsules "

9.0 9805/0980

U67861

The organopolyeiloxane carrier according to the invention can also In the form of prosthetic devices for the body are made, from which the drug is released according to its own can. Thus beiapielaweiae can be vaacular or intravaacular Prostheses are impregnated with anticoagulants such as heparin or ethylenediaminetetraacetic acid, ao that duroh slow releases would provide adequate protection against the drug Thrombosis is achieved. The drug can be used during dea Procession of the prosthesis together with the organopolyailoxane processed or distributed in the finished product. For example, the finished prosthesis can be converted into a saturated solution of e.g. heparin or ethylenediaminetetraacetic acid in one suitable solvents such as alcohol, acetone, xylene or water.

Another embodiment of the pharmaceutical carrier according to the invention consists in the use of relatively liquid, cold-curing organopolysiloxanes that contain the drug in dissolved form.

The liquid mixture can be composed directly into the tissue be injected with a catalyst that polymerizes the liquid organopolyailoxane in situ to form a solid implant, which is then able to absorb the active ingredients relatively slow to release "

Example 1:

100 g of a liquid, in the terminal units Dimethy! Polysiloxane containing hydroxyl groups

90 9 805/0980

Η67861

Age of about 10,000 cSt./25 ° C _f 3 g of ethyl polysilicate, 250 mg of penicillin and about 0.5 wt. ^ (Based on the weight of the liquid organosiloxane) Stonno-2 ~ ethyl oxoate are mixed and injected. After the injected mixture has polymerized, the penicillin is slowly released into the tissue. In the case of injectable, cold-curing organopolysiloxanes, Killetoffθ is not necessary, since the elasticity of the polymer is not critical. If necessary, however, fillers can also be used as long as they do not affect the consistency of the injection liquid too much.

Example 2ι

By extrusion molding of a mixture of 75 parts of a dimethylpolysiloxane containing about 0.14 mol ^ methylvinylsiloxane units, 24 parts of pyrogenic silicon dioxide obtained in the gas phase and 1 part of 2,4-dichlorobenzoyl peroxide, the mixture being heated to 350 ° C. for 30 seconds ( ^{730 0} P) and then post-cured ^{by heating to 204 0} C (400 °?) For 2 hours, tubes 1 cm long with an inner diameter of 305.72 mm (0.14 inch) and a wall thickness of 0.794 mm were made (0.03 inch), the ends of which were sealed with a cold-curing mixture of liquid dimethylpolysiloxane end-blocked with methyl diac et oxysily! Units and fumed silica obtained in the gas phase. The cold curing took place within

909805/0980

IS

f U67861

24 hours. Before the ceilings were closed, they were approx 20,000yug triiodothyronine filled.

The tube lines can instead also be filled with e.g. vitamin B ^ " Powder to be filled.

Excipients a length of 14 mm _t is prepared in the same manner and with 10,000 ug triiodothyronine were filled / »give in 24 hrs · about 10 / ug of drug free. This provoked about 120 heartbeats per minute in the dog · If a drug carrier 24 mm in length was used ₍ which was manufactured in the same way and filled with the same amount of drug _t was released within 24 hours · About 30 aig of the drug and a heart rate of about 200 beats per minute achieved

With the aid of the medicament carrier according to the invention it is possible, for example, in surgery, to implant more highly effective medicaments in dry form and in relatively large quantities. A capsule containing 30,000 Mβ digitoxin can be safely introduced into the body without excessive or irregular release of the drug. The capsule is first sterilized and all digitoxin molecules that have already penetrated the surface are carefully removed, then the capsule is surgically implanted in the heart ^{muscle.In one case, about 4} OyUg digltoxin were released per day and provoked nervous heart palpitations

909805/0 98 0

■ *

in almost physiological degrees. If the drug is only released in very small amounts, no systematic effect can be observed. It is certain that the drug is effective in such a low concentration that the Total active ingredients are released directly inside the heart · Above in addition, the drug does not have to be sterilized, as the walls * tion by the polymer in the molecular range; takes place » while the considerably larger bacteria are definitely retained.

According to a further embodiment of the invention Excipients according to which they are used in conjunction with sponge-like organopolysiloxane elastomers, For example, a sleeve made of the foamed elastomer is slipped onto the surface of a capsule.This foam cover is used but Anchoring of the capsule in the HShIe created in the tissue. The soleplate expands in the cavity and prevents the capsule from detaching. It also serves to absorb liquids, fibrin or bin! tissue in 3 areas around the implantation site and mediates the transport the drug from the capsule surface to the organ of success

As already mentioned, the Arenel * according to the invention can medium wearer also in the form of prosthetic devices * · »·»> »» manufactured, for example as an aortic tube, and impregnated to prevent thrombus formation

909805/0980

'ft
- νί-

U67861

When using the drug according to the invention Heart muscles can be triggered nervously © heartbeats,

the oardiographisoh are detectable · With surgical

Introduction of an implant in a dog with totalein Herzblook displayed 55 heartbeats per minute «Hach Introduction of the implant (organopolysiloacankapael with a Length of 17 µm »filled with 20,000 yug triiodothyronine and,

as described in Example 2, closed) by incision 150 heartbeats per minute were in the left ventricle produced, which electrocardiographically still after 8 hours

Implant insertion have been demonstrated.

In some cases, the implant can be used to introduce a Orunddosie of the drug can be used and an additional Dosing can be done by oral or parenteral delivery. In this way, the quantities of medication required for the patient can be precisely regulated

Heating increases the rate of diffusion, see above that capsules that are heated prior to use allow greater initial diffusion of the drug. The capsules can Also include several drugs that are released at different rates, so that the body comes first with the rasoh diffusing drug and only at a later point in time with the slowly diffusing Drogo can when the first drug is ready to serve its purpose.

90 9805/098 0

U67861

The application of the new drug carriers is illustrated above by dogs. Ba is however. it goes without saying that the mode of action in the human body is the same.

The inventions, advocated, "at introduction Drugs that are not destroyed can be used directly on the success organ or on the body tunnel »on which the bright effect desired to be implanted. For example, a Capsule filled with dry nitrogen loat in an or P implanted in the immediate vicinity of a cancerous gowobe will. You can use drugs in the composition you want be brought directly to the body part to be treated without additives that are necessary for a parenteral or oral medication are required and which mask the active thorapeutiachon agents or on their way through the body can accompany. In addition, this avoids interruptions and irregularities, dio with a paronteral or oral medication are more effective thorapeuti-) See agents with greater physiological activity can now be used successfully where earlier forms of application failed. The drugs no longer have to deal with the usual ones Drug carriers are mixed and thus undesired are omitted Influences of these carriers on the drug. In the known processes, the active substances were often chemical bound with a harmless carrier molecule and the active substance of the drug is only released in vivo On the other hand, it is possible for drug carriers to use the

909805/0980

Drug in active form and in any desired concentration directly au applizieron, with the effect occurring immediately and the unhealthy factors of the usual carriers are eliminated

Another advantage of the carrier according to the invention is breathed in that the release of the drug does not depend on the gradual decomposition or dissolution of the carrier. Of the sealed container or the capsule remains unchanged, while with the known carriers the active drug molecules first had to be detached from these or freed from them, as in the pail of beeswax or peanut butter, and only then theirs could develop therapeutic effects. The drugs included in the organopolyailoxane vehicle remain dry, even if the implant remains in the body for several months »This is particularly important for connections that are in wet Are porm unstable.

VIe already mentioned, the invention Arzneimit- · {telträger particularly suitable for processing with Antlkoagulantien such as heparin but you can just as easily for storage and preservation Fris brazen blood dienen.Die unwanted Koagulatlonsersoheinungen that can occur when the blood from Its normal environment la organism is removed can be completely prevented if the areneic agent carrier according to the invention in the form of organopolyeiloxane containers that contain an anti-coagulant

909805/0980

impregnated. The low amount of anticoagulant that is actually released from the container is sufficient to prevent coagulation and enables the blood to be stored in its original form, so that the blood is no longer stored in ACD solution or additionally with anticoagulants in large honeys must be moved, as was customary in practice so far. Xn the inventive containers the blood may have been kept in its original Fora up to 21 say, preferably at a temperature of about 4 ⁰ C, and then used, or directly in blood transfusions used for other purposes that require praktieoh impurity-free fresh blood ·

The excipients according to the invention can be used for any pharmaceutically active ingredient. Such preparations include antibacterial agents, for example sulfathiazole, antibiotics, for example penicillin, fungicidal gowns, for example nystatin; Antimalarial drugs, for example atebrine, and drugs against protozoa, e.g. hydroxystilbeiaidieothionate, antineoplastic gowns, ζ.B ₄ nitrogen loos, as mentioned above, "cardiovascular""drugs, such as digitalis, quinidine and nitroglycerin) Contraceptives, for example, spermiclde drugs, such as hexylreaorcin. Likewise kifaran the erflndungsgemäßen excipients for hormones and the corresponding synthetic derivatives and Antogonieten such as thyroid hormones and insulin, comparable

909805/0980

H67861

or for immunological agents, such as tetanus antitoxin, diuretics, e.g. acetazolamide, skeletal muscle relaxants and their antagonists, e.g. mepheneein, central nervous stinulantls, e.g. ephedrine, and zontral nervous depressants, such as barbitreesoine, prophylactic amines and their various ohemic modifications, anrylic amines, such as Antidotes such as Dimeroaprol, enzymes such as Hyaluronidaae, and agents for promoting blood formation such as liver extract · Radioactive isotopes such as xalt iodine 131 labeled protein and special proteins such as ^ -globulin can also be used. i will be.

Other examples of drugs that work well with the ' drug carriers according to the invention can be administered can are adrenal »and adrenal cortical hormones, such as Aldosterone, deoxycorticosterone, hydroortisone and cortisone;

■ · ι

In addition to Bohllddrttsenhomnono and pituitary hormone, estradiol, Progesterone and testosterone. ;

909805/0980

Claims (1)

U67861 F, a t. e η t a η s. ρ r u c h: Use of organopolysiloxane elastomers containing an average of 1.98-2 * 02 monovalent, optionally halogenated hydrocarbon radicals per Si «atom and by heat curing or by curing at room temperature, optionally in the presence of catalysts and / or fillers in a manner known per se Catfish have been produced * as drug carriers in solid Form, for example as a closed height, capsule or Tablets with controllable release of active ingredients. New documents (Art 7, Section 1, Paragraph 2, No. I, Clause 3 of the amendment of 4.9. IW 909805/0980