DK143318B - OSMOTIC DISPENSES - Google Patents

Description

(19) DENMARK

| J | Π2) PROCEDURE WRITING (11) 143318 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 155/72 (51) Int.CI.3 A 61 H 31/00 (22) Submission date 12 Jan. 1972 ® 01 J 4/00 (24) Race day 12 Jan 1972 (41) Aim. available July 14. 1972 (44) Submitted Aug 10 1981 (86) International Application No. - (86) International Filing Day - (85) Continuation Day - (62) S ta Application No. -

(30) Priority Jan 15 1971, 106155, US Mar 25 1971, 127252, US

(71) Applicant ALZA CORPORATION, Palo Alto, US.

(72) Inventor of Takeru Higuchi, US: Masahiro Nakano, US: Anwar Hus = sain, US.

(74) International Patent Bureau.

(54) Osmotic dispenser.

The invention relates to an osmotic dispenser of the kind set forth in the preamble of claim 1, which is simple in construction and can release active agent concentrations at an osmotically controlled rate over a long period of time.

The term "active agent" as used herein refers to any drug (as defined below), any agent which in any way affects any biological whole, any substance having a nutritive or stimulating effect, or growth inhibitory, destructive or any regulatory effect on plant growth, whether controlled or not, any substance which Y} must be assimilated by any organism, e.g. a human, animal or organ of the lower order, for its nutrition or for regulating its growth, any substance exhibiting any of the aforementioned effects, to be applied directly to any of the habitat, environment or environment of the above-mentioned organisms, and any substance having any other effect on any other environment, in particular any aqueous environment.

Suitable active agents for use in the present dispenser therefore include, without limitation, such agents which may generally: (1) prevent, alleviate, serve to treat or cure abnormal and pathological conditions in the living body such as by destroying a parasitic organism or limiting the effect of the disease or abnormality by chemically altering the physiology of the patient / host organism or the parasite; (2) maintaining, augmenting, reducing, limiting or destroying the function of a physiological body or plant, e.g. vitamin preparations, sexual sterilizers, fertility inhibitors, fertility promoters or growth promoters, (3) serve to diagnose a physiological condition or condition, (4) regulate or protect an environment or living body by attracting, invalidating, inhibiting, killing, modifying , repel or withhold an animal or microorganism, such as food and non-food, bait and attractants, biocides, pesticides, algicides, parasiticides, rodenticides, insecticides or fungicides, (5) preserve, disinfect or sterilize, and (6) regulate or influence an environment in the broad sense, such as by introducing a catalyst or dosing a reactant into a reacting chemical system, or by influencing any chemical process therein, such as a fermentation, including propagation and / or attenuation of one. microorganism.

The terms "environment", "environment" and "habitat" as used above and herein denotes any potential site of application of the present osmotic dispenser, or at least any potential site of its water-permeable membrane portion, which site contains or can provide sufficient water for absorption in the device to develop the necessary osmotic pressure on which its driving force depends, and in the above definition of "active agent" is understood to mean an agent which will exert its effect in the presence of such environment, environment or habitat , or an agent that will exert its effect in a remote and / or other environment that does not need to be aqueous.

Any of the drugs used to treat the body, both local and systemic, can be used as the active agent in the adapted chamber in any embodiment of the osmotic dispenser of the invention. "Medicament" is used herein in its broadest sense to include any agent or substance which produces a pharmacological or biological effect.

Suitable drugs for use in the therapy of the present dispenser include, without limitation, the following: (1) protein drugs such as insulin, (2) desensitizing agents such as ambrosia pollen antigens, hay fever pollen antigens, antigen and milk antigen, (3) vaccines such as anti-smallpox, yellow fever, canine fever, swine fever, poultry pox, antidote, scarlet fever, diphtheria toxoid, tetanus toxoid, pigeon pox (pigeon pox), whooping cough, flu, canine madness, measles, poliomyelitis or Newcastle disease, (4) anti-infective agents such as antibiotics, including penicillin, tetracycline, chlorotetracycline, bacitracin, nystatin, streptomycin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, chloramphenicol and erythamycin , sulfadiazine, sulfamerazine and sulfisoxazole, anti-viral agents, including idoxuridine, and other anti-infective agents, including nitrofurazone and sodium propionate, (5) anti-allergenic agents such as antazoline, methapyril, chlorphenyramine, pyrilamine and prophenopyridamine, (6) anti-inflammatory agents such as hydrocortisone, cortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, (7) decongestants such as phenylephrine, naphazoline and tetrahydrazoline, (8) miotic agents and anticholinesterases such as pllocarpine, eaerin salicylate, carbach, fluorocinolone, triamcinolone, medryson, prednisolone, prednisolone 21 phosphate and prednisolone acetate; -isopropyl fluorophosphate, phospholine iodide and demecarium bromide, (9) mydriatic agents such as atropine sulfate, cyclopentolate, homatropin, scopolamine, tropasyreamide, eucatropin and hydroxyamphetamine, (10) sympathomimetics such as epinephrine, (11) sedatives pentobarbital sodium, phenobarbital, secobarbital sodium, codeine, (dC-bromoisovaleryl) urea, and carbromal, (12) psychologically stimulating agents such as 3- (2-aminopropyl) indole acetate and 3- (2-aminobutyl) indole acetate, (13 ) sedatives such as reserpine, ehlorpromazine and thiopiopazate, (14) androgenic steroids such as methyl testosterone and fluoxyesterone, (15) estrogenic steroids such as estrone, 17β-estradiol, ethinylestradiol and diethylstilbesterol, (16) progestational agents such as progesterone, melengestrol, chloromadinone, ethisterone, norethynodrel, 19-nor-progesterone, norethindrone, medroxyprogesterone and UcG-hydroxy-progesterone, (17) humoral agents such as the prostaglandin, e.g. (18) antipyretics such as aspirin, sodium salicylate and salicylamide., (19) antispasmodics such as atropine, methanthelin, papaverine and methco-polamine bromide, (20) antimalarial agents such as 4-aminoquinolines, 8-aminoquinolines, chloroquine and pyrimethamine, (21) antihistamines such as diphenhydramine, dimenhydrinate, tripelennamine, perphenazine and carphenazine, (22) cardioactive agents such as hydrochlorothiazide, flumethiazide, chlorothiazide and trol nitrate, such as vitamins, (23) nutrients, (23) amino acids and essential fats, (24) Anti-Parkinsonism agents such as L-dopa, (L-3,4-dihydroxyphenylalanine), (25) anti-hypotensive agents for study use, such as dopamine, 4- (2-aminoethyl) pyrocatechol.

Other drugs having the same or different physiological effect than those listed above may be used in an osmotic dispenser according to the invention. Suitable mixtures of drugs can of course be dispensed with as much ease as single component systems.

The drugs may be in various forms, such as uncharged molecules, constituents of molecular complexes or non-irritating pharmacologically acceptable salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleinate, tartrate or salicylate. For acidic drugs, salts of metals, amines or organic cations may be used, e.g. quaternary ammonium salts. Furthermore, simple derivatives of the drugs, such as ethers, esters or amides, which have desirable retention and release properties, but which are readily hydrolyzed at the pH of the body, can be used, e.g. enzymes.

The amount of drug incorporated into the osmotic dispenser varies greatly depending on the particular drug, the desired therapeutic effect and the length of time it takes for the drug to be released. Since several different embodiments of the dispenser in several different sizes and forms are intended to provide complete dosing systems for therapy for many different kinds of diseases, there is no critical upper limit on drug incorporated in the dispenser. The lower limit will also depend on the activity of the drug and the time period for its release from the dispenser. Thus, it is not practically possible to define an area for the therapeutically effective amount of drug to be released from the dispenser.

So far, osmotic dispensers have been proposed, each capable of releasing active agent concentrations at an osmotically controlled rate over a long period of time.

Typical forms of these osmotic dispensers include a first chamber of relatively impermeable material and containing an active agent and a second chamber of regulated water permeability and containing a solution of an osmotically active solvent exhibiting an osmotic pressure gradient to water. Such devices are designed so that when placed in or functionally exposed to a hypotonic aqueous environment, water is absorbed therefrom by osmosis and diffuses into the solution contained in the second chamber. (For example, by "functionally exposed" is meant that such devices may be provided with their own water supply or separate water chamber contained within the device itself, as in Rose and Nelson, Austral. J. exp. Biol., 33, pages 415-420 (1955), Rose and Nelson, Austral. J. exp. Biol., pages 411-414 (1955).). As the water flows into the second chamber, the volume of the solution contained therein, and in some cases also the volume of the chamber itself, increases, either directly or indirectly creating mechanical pressure or force on the active agent containing the first chamber. Said first chamber is provided with any suitable dispenser head for releasing its active agent content to the external environment of the dispenser, and it is of such a construction that its active volume is inversely proportional to the pressure thus exerted, i.e. it is of such a construction that its volume in use decreases directly in proportion to and as a result of the volume increase in said second chamber. Accordingly, the release rate and amount of active agent released are directly proportional to the volume change in the second chamber, but inversely proportional to the volume change in the first. That is, as the water flows into the device, the volume of the second canister increases and creates a corresponding pressure or force at first, either directly or indirectly, such as by exerting pressure on a separate or common wall portion therein, which wall portion yields for such pressure, or by actuating a movable locking member on one side so as to move into or against the first chamber, or by correspondingly affecting a wall portion defining the first chamber. Thus, the volume of said first chamber is steadily diminished and active agent is compressed continuously with an osmotically controlled rate over a long period of time.

In the descriptions of the patents mentioned below in the subject matter, several active agent osmotic dispensers and of the type described above are described.

In e.g. U.S.A. No. 3,776,885 discloses an osmotic dispenser comprising a water-permeable housing which is advantageously rigid and which encloses a first flexible bag of relatively impervious material and containing the active agent, advantageously a medicament, preferably in a medicament. gel-like, paste or other semi-solid state (although an active agent solution or concentrated solution will sometimes be sufficient), and another controlled moisture permeability bag containing a solution of an osmotically active solvent which exhibits an osmotic pressure agent over for water. Said first and second bags are disposed within said water-permeable housing or porous casing so that water enters from the environment through the porous casing or housing and migrates by osmosis into the solution contained in the second bag. The solution in the second bag increases in volume and exerts a mechanical force on the active agent contained in the first bag, which mechanical force in turn pushes the active agent out of the apparatus. To enable the active agent to be squeezed out of said first flexible bag, it is provided with a release means or dispensing head which is suitable for the active agent, which leads to the exterior of the apparatus, e.g. a long plastic tube extending through the porous casing, or duct-like, of fine tubes comprising through them.

IN USA. U.S. Patent No. 3 * 732,865 discloses an osmotic dispenser which comprises a first chamber of relatively impermeable material and containing an active agent and a second chamber containing a solution of an osmotically active solvent exhibiting an osmotic pressure gradient to water. For separating said first chamber from said second chamber and constituting a common wall portion for the two chambers, there is a sliding or movable locking means of impervious material. Whether constructed in one or not, the casing, which constitutes the remaining portion of the second chamber in which the osmotic driving force of the dispenser is developed, consists at least in part of a membrane which exhibits a regulated permeability to water. When placed in a hypotonic aqueous environment, water is absorbed therefrom by osmosis through the membrane and the water diffuses into the solution contained in the second chamber. As the water flows into the second chamber, the solution contained therein increases in volume and exerts a corresponding pressure behind the separating movable barrier. Such pressure serves to drive said locking means forward and into the active agent-containing chamber so as to reduce its volume, and thereby the sliding locking means ejects the active agent out of the apparatus at an osmotically controlled rate for a long period of time. In order to enable the active agent to be pressed out of the first chamber, this is also provided with any suitable dispensing head or means for releasing the active substance to the external environment of the apparatus, e.g. capillary channels through them. An embodiment of the invention described in the latter patent application consists of an active agent osmotic dispenser which comprises a plurality of capsule half shells similar to pharmaceutical hard gelatin half shells, a first and a second half shell being fixed. jointed in capsule form, and a third half-shell, which is frictionally disposed in such a capsule, but which can freely perform a sliding movement therein. The said capsule is thereby divided into the two chambers, the third half shell forming it for these common wall portions.

1 U.S.A. U.S. Patent No. 3,776,896 discloses an osmotic dispenser comprising a first helical chamber of relatively impermeable material and containing an active agent and a second helical chamber containing a solution of an osmotically active solvent exhibiting an osmotic pressure gradient above for water. The two helical chambers are interconnected to form a continuous helical compartment. For separating the first helical chamber from the second helical chamber and constituting a common wall portion for the two chambers, there is a sliding or movable barrier of impermeable material which can move through the helical compartment, advantageously a plastic or glass ball separator. Whether constructed in one or not, the remaining portion of the second chamber in which the osmotic driving force of the dispenser is developed consists, at least in part, of membrane material exhibiting regulated permeability to water. When placed in a hypotonic aqueous environment, water is absorbed therefrom by osmosis through the membrane and the water diffuses into the solution contained in the second chamber. As the water flows into the second chamber, the solution contained therein increases in volume and exerts a corresponding pressure behind the separating movable barrier. Such pressure serves to drive said locking means forward and into the chamber containing the active agent so as to reduce its volume, and the sliding or rolling locking means thereby pushes the active agent out of the apparatus at an osmotically controlled rate for a long period of time. . To enable the active agent to be pressed out of the first chamber, this is provided at its end with any suitable dispensing head or means for releasing the active agent to the external environment of the apparatus, e.g. a capillary channel therethrough. A further feature of the invention of the latter patent application is that an active agent osmotic dispenser and comprising a dispenser according to the above description is enclosed by a relatively rigid, highly permeable housing. The housing serves both as protection for the dispenser and also for limiting expansion of the dispenser due to internal pressure. Alternatively, such expansion can itself be limited by a suitable binding means.

The active agent osmotic dispenser disclosed in U.S.A. U.S. Patent Nos. 3,995,631 and 4,343,756, include a chamber of 8 143318 regulated water permeability and containing a solution of an osmotically active solvent exhibiting an osmotic pressure gradient to water, which chamber contains a flexible bag of relatively impervious material and containing an active agent and provided with a means or dispensing head for releasing said active agent into the external environment of the dispenser.

The flexible bag is disposed within said chamber so that as water penetrates from the external environment through the permeable walls of the chamber and, by osmosis, migrates or diffuses into the solution contained therein, it increases in volume thereby creating a mechanical compression or flat compressive force on the flexible bag, which force in turn bounces the active agent out of the apparatus at an osmotically controlled rate over a long period of time.

The osmotic dispenser suggested in the above article by Rose and Nelson is also capable of delivering drug solution at a relatively constant rate. This injector consists of three chambers and a clamping means for retaining a semi-permeable membrane. The driving force of the injector depends on the saturated aqueous solution of Congo red osmotic pressure developed against water. This solution is contained in a partially collapsed rubber chamber and is separated from another water chamber by a semipermeable cellophane membrane.

The partially collapsed bag is placed in a glass ampoule, the drug chamber of the apparatus being the space between the Congo red bag and the glass ampoule. The ampoule is also provided with a drug release means and when the drug chamber is filled with a drug solution, water by osmosis will move into the Congo red solution thus expanding the rubber chamber and providing the mechanical force to eject the drug from the apparatus.

The chamber of the aforementioned active agent osmotic dispensers, which chamber contains the solution of the osmotically active solvent in which the osmotic drive of the devices in question is developed, consists at least in part of a membrane which exhibits regulated water permeability. Such a membrane can be made from many different kinds of materials which are permeable or semi-permeable to solvent (water) but not to the solute, ie. materials suitable for the construction of an osmotic cell. Typical membranes are isotropic membranes such as of non-plasticized cellulose acetate, plasticized cellulose acetate, reinforced cellulose acetate, cellulose di and tri-acetate, ethyl cellulose, anisotropic reverse osmosis membranes typically made of cellulose acetate; silicone rubber, polyurethanes, natural rubber and hydrolyzed ethylene / vinyl acetate copolymers. Isotropic membranes have less water permeability than anisotropic membranes. For both types of membranes, an increase in the acetate content of the cellulose acetate polymer decreases water permeability. In apparatus whose surface areas of membranes are relatively limited, it is preferred to use semi-permeable membranes which allow relatively rapid water transfer. Thus, in such embodiments, the anisotropic membranes are preferred. In addition, for drug depot applications as described above, the membranes are biologically inert, non-irritating to alveolar vasculature and non-allergenic. This is also for such applications the other materials from which the dispensers for local use are made. For best results, the membrane must be substantially impervious to passage of the osmotically active solute so that loss thereof is prevented. form of a solution. Accordingly, there are several drawbacks to the handling of such osmotic apparatus, e.g. wastage and loss of active ingredient as well as their storage options, since drug-containing solutions generally have a relatively short storage time, and many chemical substances in prolonged dissolved storage undergo chemical degradation. The use of solutions in osmotic apparatus furthermore sets an absolute upper limit on the concentration of active agent which can be administered with a given volume of the solution. This last limitation is of great importance when considering the limitations of the total size of such appliances. In addition, solutions of a drug or other active agent have an adverse tendency to be released from an osmotic apparatus by simple leaching.

The object of the invention is to provide an osmotic dispenser which does not have the aforementioned disadvantages and which at the same time can achieve a more constant release rate for the active agent than with a corresponding dispenser in which the active agent is present in a completely liquid solution.

This is achieved with the present active agent osmotic dispenser, comprising a first chamber of relatively impermeable material, which chamber contains an active agent and is provided with means for releasing the active agent to the environment of the dispenser, and a second chamber of controlled permeability to water. said second chamber containing a solution of an osmotically active substance exhibiting an osmotic pressure gradient to water, said two chambers being constructed such that the first chamber decreases in volume due to a volume increase of the solution in the second chamber by absorption of water herein by osmosis, whereby as water flows into the dispenser in its tendency to osmotic equilibrium with the environment, active agent is continuously extruded at an osmotically controlled rate over a long period of time, characterized by the active agent being in a form other than 143318 of completely liquid solution .

According to the invention, it is preferred that the active agent is in the form of a gel, cream, paste, slurry, dispersion, suspension, emulsion or a thickened liquid having a viscosity of at least 1000 centipoise at 20 ° C.

If desired, one or more additional constituents such as surfactants, antioxidants, preservatives and / or disperse, inert, particulate solid or gelling agents may be incorporated into the active agent.

In one embodiment of the present active osmotic dispenser, the active agent is solid or semi-solid at storage temperature, advantageous at room temperature, and is liquid at the temperature of the potential site of use of the osmotic dispenser, usually body temperature. In a preferred embodiment, the active agent is dispersed or dissolved in not completely liquid solution in an inert carrier. If desired, one or more additional ingredients, such as a surfactant, antioxidant and / or dispersed, inert, particulate solid filler, may be incorporated with the active agent and carrier.

The worked-up form of the active agent may comprise an active agent which is dispersed, suspended or emulsified in a carrier which is usually, but not necessarily liquid at the storage temperature of the present dispenser, advantageous at room temperature. The form of the active agent used in the present dispenser may assume physical properties such as a solid or semi-solid or a thickened liquid. However, it is preferred that the active agent be in a form exhibiting the properties of a semi-solid and preferably only to some extent the properties of a relatively high viscosity liquid, e.g. a liquid having a viscosity of at least 1000 centipoise at 20 ° C. Of course, for certain contemplated uses of the present dispenser, it is possible, but less advantageous, to use the active agent in liquid forms having lower viscosities. When using the active agent in forms intended for local use, the dispenser according to the invention is characterized in that it improves handling ease as there is little or no possibility of wasting or loss of active ingredient from the apparatus, thereby ensuring uniform dosage at all times. after the fabrication of the apparatus. In addition, in forms of the active agent in which the active agent is not completely in solution, the tendency for chemical degradation of the active agent is significantly reduced, and such non-solution forms are also characterized by a greatly improved storage stability compared with active agents in in the form of liquid solutions which usually have a relatively short storage time. Further, by removing the natural solubility constraints of active agents in the form of solutions, higher concentrations of active agent can be administered from the same composition volume with the forms of active agent used in the invention, and there is significantly less tendency for the active agent. the work in solid or semi-solid or high viscosity forms is washed out by the apparatus in embodiments for local use. Thus, with the dispenser according to the invention, active agent can be administered in doses within a wide range, while observing natural limits for the total size.

Forms of active agent containing an active agent worked up in a form other than complete liquid solution may consist of the active compounds or compositions themselves, provided that such compounds or compositions may be forced out of the apparatus due to the osmotic pressure developed therein. However, the worked-up form of the active agent usually comprises an active agent in combination with a carrier. In the dispenser according to the invention, any suitable carrier for the active agent can usually be used. However, when the present dispenser is to be used for drug depot applications, the carrier must be biologically inert, non-irritating to body tissue and non-allergenic.

A variety of such carriers are available, including such liquids as water, alcohols such as ethanol, propylene glycol, glycerol, polyethylene glycols of various molecular weights, etc., mineral oil, vegetable oils such as corn oil, peanut oil, cottonseed oil, etc., and solids such as is converted into liquids at the temperature of the potential use of the apparatus, i.e. the body temperature in the case of drug depot applications, such as those listed below.

In addition, according to the invention, it has been found that considerable advantages can be obtained by using the active osmotic dispenser in the form in a form which is solid or semi-solid at storage temperature and liquid at the temperature of the potential site of use of the osmotic dispenser. Using such form of the active agent, the present dispenser exhibits superior handling properties, as there is no possibility of wasting or loss of active ingredient from the apparatus, thereby ensuring uniform dosing after the manufacture of the apparatus. In addition, as was the case with the non-dissolution vapors, the solid forms of the active agent are characterized by the absence of chemical degradation and by a greatly improved storage stability compared to liquid, the active agent containing solutions which usually have a relatively short shelf life. Similarly, a higher concentration of active agent may be administered from the same composition volume compared to the use of solutions, and there is no tendency for the solid forms of the active agent to be leached by the apparatus in local application embodiments. Thus, with these latter embodiments of the dispenser according to the invention, doses of active agent can be administered within a wide range, while simultaneously observing natural limits for the total size.

The forms of active agent which are solid or semi-solid at the storage temperature and liquid at the temperature at the potential site of application of the apparatus may also consist of the active compounds themselves or compositions exhibiting such properties, or may, again, more commonly, include an active agent in combination with a carrier exhibiting the above properties. The selection of an active agent or carrier to achieve the desired result, of course, depends primarily on the temperature of the environment in which the apparatus is intended to be finally used, since the storage temperature is often a matter of choice. The dispenser according to the invention is preferably designed for storage at room temperature with final use of it in an environment of greater temperature than room temperature. It should be noted that it falls within the scope of the invention to have forms of active agent which advantageously have storage temperatures below room temperature, e.g. refrigerator temperature, as well as forms that have storage temperatures above room temperature. A particularly advantageous use of the osmotic dispenser according to the invention is in the field of administering drugs to humans and other mammals, such as cattle. In such applications, the temperature at the potential point of use of the dispenser is, of course, body temperature.

The active agent is usually used in the form of a medicament which is dispersed or dissolved in not completely liquid solution in an inert carrier when using the dispenser as a drug depot. A variety of biologically inert, non-irritating and non-allergenic suitable carrier materials, including those exemplified in the following table, are known.

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Table

Carrier Composition Mp ° C

Cocoa butter Triglycerides of oleic acid, palmitic acid and 30-35 stearic acid 'Cotomar' a Partially hydrogenated cotton seed oil 35-39 Hard butter S-70-XXb Triglycerides 36.5 'Suppositol' H, S, T & Rc Hydrogenated coconut oil triglyceride 34-38, 5 "Wecobee" w, R, S, M & FSd Triglycerides Derived from Coconut Oil and 31.7-40.5 Pa lmekæmeo lie "witepsol '^ H, W, S & Ee Triglycerides of c12_ci8 fatty acids 32-44

Polyethylene Glycols 600, 1000, 1540, Linear Polymers of Ethylene Oxide 38-49 4000 and 6000 "Polymeg" 1000 and Polytetramethylene Ether Glycol 38 2000 * ~ "Myrj1 Polyoxyl (40) Stearate USP 38-43" Tween '^ 1 ^ 1 Polyethylene- ( 4) sorbitan monostearate 35-39 "MYRj'Qo Polyoxyethylene (50) stearate 36" bRIj "58 Polyoxyethylene (20) -cetyl ether 38" bRIj "76b Polyoxyethylene (10) stearyl ether 38" BRIj "78 Polyoxyethylene (20) -stearyl ether £ 38

Protector & Gamble b Best Foods C Fritz Wetz (four types that vary in melting range with H being the lowest and R as the highest melting product) ^ Drew (different types varying in terms of melting range and in terms of melting range) e Dynamite Nobel (different types that vary in melt range but all have a narrow melt range)

Union Carbide (blends of different polymers used to prepare suppositories) ® Quaker Oats b Atlas 14 143318

The amount of active agent incorporated in the worked-up form of the active agent varies widely depending on the particular active agent, the particular carrier used and the desired dose to be administered by the dispenser. Thus, there is no lower limit on the amount of active agent to be combined with the carrier, nor is there an upper limit other than the physical limitation of a given carrier. Accordingly, it is not practicable to define a range of the amount of active agent to be incorporated into the inert carrier. However, in a typically worked-up form of active agent, the carrier contains from ca. 5 to approx. 80% by weight of active agent, preferably from ca. 35 to approx. 75% by weight.

In the worked-up form of the active agent, a surfactant is usually advantageously incorporated to enhance its physical stability.

The surfactant must be inert to the active agent as well as biologically inert, and hence nonionic surfactants are preferred. Examples of non-ionic surfactants include sorbitan monostearate, sorbitan monooleate, polyoxyethylene (20) sorbitan monooleate and polyoxyethylene (40) stearate. Several active agent and surfactant combinations have been found to be particularly effective, e.g. sorbitan monostearate has been shown to be effective in stabilizing suspensions of tetracycline, while polyoxyethylene sorbitan monooleate has been found suitable for use with chloramphenicol.

A preferred area for the surfactant is typically between about. 0.1 and 1.0% by weight, based on the total mixture.

The worked-up forms of the active agent in the dispenser according to the invention may, if desired, contain an antioxidant for preventing degradation during prolonged storage periods, usually in an amount of from approx. 0.01 to approx. 2% by weight, based on the active agent. Any of the antioxidant-approved antioxidants can be used in this amount, and by way of example only, mention should be made of: tert-butyl-4-methoxyphenol (mixture of 2- and 3-isomers), 2,6-di-tert. butyl p-cresol, propyl gallate, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquine), norihydroquaiacetic acid (NDGA) and ascorbyl palmitate. Use of other preservatives, such as methylparaben, propylparaben, sorbic acid, etc., are also considered in the forms of the active agent contained in the present dispenser.

In view of possible incorporation into the worked-up forms of the active agent, there are also dispersed, inert, particulate solids. These particulate solids are usually incorporated in amounts of from ca. 0.5 to 5% by weight, based on the active agent, to increase the stability of the product by providing a high solids content. When low concentrations of drug or other active agent are used, an inert solid, such as submicroscopic silicon dioxide or bentonite, can also be added as a gelling agent to prevent precipitation in the worked-up form of the active agent. prolonged storage of the device.

Although parts of the foregoing description have been directed primarily to active agent forms which are solid at room temperature and liquid at body temperature, it is clear that the basic principles apply equally to the applications of the present osmotic dispenser, where this is placed in other environments to release a composition with a given active ingredient.

Thus, when the dispenser in question is e.g. used in a polymerization reaction to release polymerization catalysts in the reaction vessel at a controlled rate over a long period of time, the active agent composition may comprise the polymerization catalyst dispersed in polymeric material identical to that polymerized in the vessel and this preparation is of course solid at room temperature. and usually liquid at the polymerization reaction temperature.

The invention is further illustrated by the following examples with reference to the drawing which shows an embodiment of the osmotic dispenser according to the invention.

Example 1 40 g of polyethylene glycol 600 containing 8 mg of butylated hydroxytoluene are mixed with 60 g of tetracycline hydrochloride. The obtained paste is well mixed and then ground in an ointment mill to provide a uniformly active composition of 3 viscous paste-like or cream-like consistency. 10 cm of the active composition is then placed in the active agent chamber in an osmotic dispenser constructed in accordance with FIG. 4 of U.S. Patent Application No. 106,130. The dispenser used in this example is shown in the drawing, in which the dispenser 1 comprises a housing 2, a support ring 3, an opening dispensing head 4, a movable locking member 5, a porous membrane holder 6, an O-ring 7, a porous, threaded provided end cap 8 and a semi-permeable membrane 9, and as shown in the drawing, the dispenser contains a saturated solution of osmotically active solute and a non-dissolving active agent designated 11.

Example 2 1200 mg of tetracycline hydrochloride and 800 mg of a 6 ': 4 mixture of polyethylene glycol 600 and polyethylene glycol 1000 containing 8 mg of sorbitan monostearate and 0.16 mg of 2,6-di-tert-butyl-p-cresol are mixed at 39 ° C at which temperature the glycol mixture is a clear viscous liquid. Then the mixture is ground twice in an Asra mill, heated again, and poured into the active agent chamber in an osmotic dispenser constructed in accordance with the drawing.

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He then lets the active composition cool to room temperature, which solidifies to a stable state. The osmotic dispenser is then placed in an aqueous solution at ca. 38 ° C, and the active composition again melts into liquid form and is forced out of the apparatus through the dispenser head by means of the osmotic pressure developed in the chamber with the osmotically active solute as a result of water from the environment by osmosis penetrating therein.

Example 3 600Qmg of chloramphenicol, 5000mg of cocoa butter and 44mg of Tween® OO (polyoxyethylene (2Q) sorbitan monooleate USP) were mixed at 39 ° G, ground twice in an Asra mill, heated again and poured into it. for active agent compartments in an osmotic dispenser constructed in accordance with the embodiment illustrated in Fig. 1 of U.S. Patent Application No. 106,131 The active composition is again a solid; substance at room temperature and readily released through the dispenser's head as a result of the osmotic pressure developed in the apparatus when placed in an aqueous environment at about 38 ° C.

Example 4

An active preparation containing 13000 mg of tetracycline base (vacuum dried), 13Q00 mg of cocoa butter and 104 mg, fSpan® (sorbitan monostearate ASP) is prepared by proceeding as in Example 3 and poured into the active agent chamber in an osmotic dispenser. constructed in accordance with FIG. 1 of U.S. Patent Application No. 106,130. The composition obtained is again solid at room temperature and storage stable at this temperature and again a readily dispensable liquid at approx.

38 ° C,

Example 5

An active preparation containing 1000 mg of cocoa butter, 1200 mg of sulfisoxazole, 8.8 mg of paroxyl (sorbitan monostearate), and 0.2 mg of 2,6-di-tert.-butyl-β-cresol is prepared by proceeding as in Example 3 and poured into the active agent chamber in an apparatus identical to that used in Example 3. Essentially the same results are obtained as in the previous Examples 2-4.

The osmotic dispenser can be made in any convenient form for either physical insertion or implantation into the body, or for administration through the gastrointestinal tract, or for insertion into any desired environment. The dimensions of the apparatus may vary widely and are not of significant importance. The lower limit of the size of the apparatus is determined by the amount of the special active agent to be applied to the surroundings to produce the desired effect.