|Publication number||US3625214 A|
|Publication date||7 Dec 1971|
|Filing date||18 May 1970|
|Priority date||18 May 1970|
|Publication number||US 3625214 A, US 3625214A, US-A-3625214, US3625214 A, US3625214A|
|Original Assignee||Alza Corp|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (4), Referenced by (240), Classifications (24)|
|External Links: USPTO, USPTO Assignment, Espacenet|
United States Patent 3,184,386 5/1965 Stephenson 3,416,530 12/1968 Ness ABSTRACT: A drug-delivery device for prolongedly delivering drugs to patients according to any predetermined time release profile, e.g., increasing, decreasing, constant, pulsing, sinusoidal, and like patterns of release, is fabricated by applying a drug coating of varying or uniform thickness to a relatively drug-impermeable film soluble in body fluids and thence rolling said coated film about itself in spiral or jeliyroli fashion. Upon administration to the body, the outermost extremities of the film gradually erode at a predetermined rate in body fluids thus exposing coextensive extremities of the drug coating, also soluble in body fluids, and drug is released to the tissues of the body. Suitable design of the drug coating along the spiral, e.g., of varying thickness, etc. provides for the aforesaid release patterns as the device disintegrates.
PATENTEDDEC nan 35251214 INVENTOR. Takeru Higuchi Attorney nnuc-nnuvnav DEVICE BACKGROUND OF THE INVENTION This invention relates to a device for delivering drugs to patients according to a programmed schedule and, more especially, to a device which can deliver drugs according to any desired program of release which may be therapeutically desired.
In the pharmaceutical field, most prolonged or sustained action medicators have had as their objective to release medication at a constant rate. However, many programs of therapy require that the quantity of medication administered vary with time. For example, in antibiotic therapy, it is common to administer a large initial dose of drug followed by smaller doses. Conversely, in desensitizing against allergens, therapeutic regimes often call for dose of the allergen to progressively increase over the time of treatment. More complex regimes, in which the dose of medication varies through periodic high and low points, are also known. In general, these therapeutic programs are practiced by periodically administering different amounts of medication in separate dosage forms. Such practice requires frequent acts by the patient or trained attendant and departures from the therapeutic program often occur. Thus, a need exists for a drug-delivery device that can provide any desired time profile for drug administration.
SUMMARY OF THE INVENTION Accordingly, it is a primary object of this invention to pro vide a device for delivering drugs to patients according to any predetermined time release profile.
In attaining the objects of this invention, one feature resides in the application of a drug coating of varying or uniform thickness to a relatively impermeable film soluble in body fluids. To provide the drug-delivery unit, the coated film is spirally wound or rolled about itself in jellyroll fashion. When the device is physically inserted or implanted in the body or administered via the gastrointestinal tract, the film gradually erodes or dissolves at a predetennined rate in body fluids thus exposing the drug coating. By suitable design of the film and of the drug coating, which itself dissolves in body fluids, one can obtain any desired release pattern including increasing, decreasing, pulsing, constant, sinusoidal, etc.
Other objects, features and advantages of this invention will become more apparent from the following description when taken in conjunction with the accompanying drawings, and wherein like reference numerals are used to indicate like or equivalent parts.
BRIEF DESCRIPTION OF THE DRAWINGS In the drawings:
FIG. 1 is a side view of the coated substrate precursor structure of a drug-delivery device of this invention;
FIG. la is a top view of a drug-delivery device of this invention, formed from the structure of FIG. 1;
FIG. lb is a side view of the structure of FIG. la;
FIG. 2 is a side view of a coated substrate precursor structure of another drug-delivery device of this invention;
FIG. 2a is a top view of another drug-delivery device of this invention, formed from the structure of FIG. 2;
FIG. 2b is a top view of another drug-delivery device of this invention, also formed from the structure of FIG. 2;
FIG. 20 is a side view of the structures of both FIG. 2a and FIG. 2b;
FIG. 3 is a side view of a coated substrate precursor structure of yet another drug-delivery device of this invention;
FIG. 3a is a top view of yet another drug-delivery device of this invention, formed from the structure of FIG. 3;
FIG. 3b is a side view of the structure of FIG. 3a;
FIG. 4 is a side view of a coated substrate precursor structure of still another drug-delivery device of this invention;
FIG. 4a is a top view of still another drug-delivery device of this invention, formed from the structure of FIG. 4;
FIG. 4b is a side view of the structure of FIG. 4a;
DETAILED DESCRIPTION OF THE INVENTION This invention has for its essence an assemblage of relatively impermeable film separating slowly soluble, medicament-containing matrix composition. Referring particularly to FIGS. I and la, a relatively impermeable film 10 is shown which dissolves at a slow predetermined rate in body fluids. The film 10 is coated with a medicament Ill containing matrix composition 12 of constant thickness, which matrix is soluble in body fluids (FIG. I).
The coated film is next spirally wound or rolled about itself in jellyroll" fashion to provide the drug-delivery device 13 of FIGS. Ia and lb.
To use the drug-delivery device of this invention, it is either physically inserted or surgically implanted in the body or is administered via the gastrointestinal tract. As the film is eroded away by the action of either gastrointestinal tissue or other body fluids, the drug matrix layer becomes exposed and it too erodes, thus releasing the drug to the tissues of the body. When the matrix layer is thin, relatively small amounts of medication are released per amount of film eroded. Conversely, if the matrix layer is thick the amount of medicament released will be enhanced. By adjusting the thickness of the matrix or the concentration of drug therein, any desired time release profile can be programmed.
By use of the drug-delivery device of FIGS. la and lb which is comprised of a drug-matrix coating of constant thickness, there is provided a drug dosage unit which can exhibit a constant slow rate of release of drug.
In FIG. 2 a relatively impenneable film I0 is also shown which dissolves very slowly in body fluids. However, in this embodiment the said film I0 is coated with a medicament I1 containing matrix composition 12 of uniformly varying thickness, namely, the drug or matrix layer is spread thin at a proximal end of the surface of the film but uniformly progressively thicker across to the distal end of the surface of the film.
It will thus be appreciated that, depending upon from which end the assemblage is wound about itself, there can be conveniently prepared drug-delivery devices which will provide constantly decreasing slow rate of release of drug (FIG. 2a) or constantly increasing slow rate of release of drug (FIG. 2b). In either event such devices would be identical in side plan view (FIG. 2c).
As described and illustrated above, the drug-delivery device of this invention may be comprised of a drug-matrix layer such as to program any desired time release profile, and two other of such forms are illustrated in FIGS. 3, 3a, 3b, 4, 4a and 4b, with the FIGS. 3 depicting a unit which provides a pulsing release pattern and the FIGS. 41 a unit which provides a sinusoidal release pattern.
Moreover, even though in the FIGS. of the drawing cylindrical structures are shown, it is apparent that flattened (FIG. 5) or other configurations can be easily provided. The drugdelivery device of the invention is also advantageously capped at either end with a material 14 slowly soluble in body fluids so as to prevent even the slightest amount of drug from prematurely exuding out of said ends (see FIG. 6).
In many instances, it is desirable to provide for release of the drug immediately upon administration of the device. This can be achieved by coating the preformed device, as illustrated in any of FIGS. 10, 2a, 2b, 3a, da and 5, with a layer of the matrix 112 containing drug 11. Alternatively, as illustrated in FIG. '7, film It) can be coated with medicament 11 containing matrix composition 12 on both face surfaces thereof. Upon rolling this coated film about itself, the resulting device will bear a drug-containing coating on its exterior surface (FIG. 7a). In either event, the resulting device initially will release drug by dissolution of the exteriorly exposed coating of the matrix. Thereafter, the film will dissolve, eventually releasing drug disposed within the interior of the spirally wound device.
The film or carrier materials 10 are flexible and relatively resistant to erosion in body fluids to provide for medicating action over a prolonged period of time and are preferably polymeric in nature. Exemplary materials include polymers of the following three general classes: (1 those which slowly dissolve in body fluids, for example, gelatin, glycerinated gelatin, formalin treated gelatin, collagen, polyvinylalcohol, and the like; (2) those which hydrolyze in body fluids, for example, the polymeric, essentially linear, dibasic acid anhydrides of the formula:
especially the polyanhydride polymers of sebacic and azelaic acids, polyhydroxyacetic acid such as described in U.S. Pat. Nos. 2,668,162 and 2,676,945, and polysulfite polymers; and (3) polymers cleaved by enzymes present in body fluids. for example, chitin, which is enzymatically cleaved by lysozyme.
The polyanhydride polymers of theabove type (2) can be conveniently prepared by condensing the respective dibasic acids in the presence of SOCl,, benzene and ethyl acetate.
The film or carrier material should be relatively impermeable to passage of the drug by difiusion or leaching. Otherwise, the rate of release of the drug will depend, at least in part, upon diffusion through the film rather than upon erosion of the film and matrix. Selection of appropriate membrane materials will be dependent on the particular drug to be used, and those skilled in the art can readily make the appropriate choices.
Matrix materials used in fabricating the drug coating of constant or varying thickness are soluble in body fluids. The drug matrix substance must erode faster than the film such that, when physically inserted or implanted in the body or administered via the gastrointestinal tract, the film first erodes or dissolves in body fluids thus exposing the drug coating which thence itself erodes or dissolves and hence provides a slow rate of release of drug, albeit the erosion or dissolution is more rapid than that of the film material. In this manner, erosion or dissolution of the film is the rate controlling step for drug administration; for once the film erodes at its predetennined rate, the drug is released relatively rapidly by dissolution of the matrix. Exemplary matrix materials include polyvinylpyrrolidone, water soluble starch, gum acacia, gum tragacanth, or the like, or even those film materials hereinbefore delineated, so long as the requirement is observed that the selected drug matrix substance must erode or dissolve faster than the selected film.
Any of the drugs used to treat the body can be incorporated in the drug layer of the drug-delivery device of this invention. Drug is used herein in its broadest sense as including any composition or substance that will produce a pharmacologic response.
Suitable drugs for use in therapy with the device of the invention include without limitation:
l. Protein drugs such as insulin;
2. Desensitizing agents such as ragweed pollen antigens, hay fever pollen antigens, dust antigen and milk antigen;
3. Vaccines such as smallpox, yellow fever, distemper, hog cholera, fowl pox, antivenom, scarlet fever, dyptheria toxoid, tetanus toxoid, pigeon pox, whooping cough, influenzae, rabies, mumps, measles, poliomyelitis, Newcastle disease, etc.;
4. Antiinfectives, such as antibiotics, including penicillin, tetracycline, chlortetracycline bacitracin, nystatin, streptomycin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, and erythromycin; sulfonamides, including sulfacetamide, sulfamethizole, sulfamethazine, sulfadiazine, sulfamerazine, and sulfisoxazole; anti-virals including idoxuridine; and other antiinfectives including nitrofurazone and sodium propionate;
5. Antiallergenics such as antazoline, methapyrilene, chlorpheniramine, pyrilamine and prophenpyridamine;
6. Antiallergenics such as hydrocortisone, cortisone, hydrocortisone acetate, dexamethasone, dexamethasone 2lphosphate, fluocinolone, triamcinolone, medrysone, prednisolone, prednisolone 2l-phosphate, and prednisolone acetate;
7. Decongestants such as phenylcphrine, naphazoline, and tetrahydrazoline;
8. Miotics and anticholinesterases such as pilocarpine, eserine salicylate, carbachol, diisopropyl fluorophosphate, phospholine iodide, and demecarium bromide;
such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine;
l0. Sympathomimetics such as epinephrine;
l l. Sedatives and Hypnotics such as pentabarbital sodium, phenobarbital, secobarbital sodium, codeine, (abromoisovaleryl) urea, carbromal;
l2. Psychic Energizers such as 3-(2-aminopropyl) indole acetate and 3-(2-aminobutyl) indole acetate;
13. Tranquilizers such as reserpine, chlorpromayline, and thiopropazate;
l4. Androgenic steroids such as methyltestosterone and fluorymesterone;
15. Estrogens such as estrone, l7 B-estradiol, ethinyl estradiol, and diethyl stilbesterol;
l6. Progestational agents such as progesterone, megestrol, melengestrol, chlormadinonc, ethisterone, norethynodrel, l9- nor-progesterone, norethindrone, medroxyprogesterone and 17 B-hydroxy-progesterone;
l7. Humoral agents such as the prostaglandins, for example PGE PGE and PGF l8. Antipyretics such as aspirin, sodium salicylate, and salicylamide;
l9. Antispasmodics such as atropine, mcthantheline, papaverine, and methscopolamine bromide;
20. Antimalarials such as the 4-aminoquinolines, 8- aminoquinolines, chloroquine, and pyrimethamine;
21. Antihistamines such as diphenhydramine, dimenhydrinate, tripelennamine, perphenazine, and chlorophenazine;
22. Cardioactive agents such as dibenzhydroflumethiazide, flumethiazide, chlorothiazide, and aminotrate;
23. Nutritional agents such as vitamins, essential amino acids and essential fats.
Other drugs having the same or different physiological activity as those recited above can be employed in drug-delivery devices within the scope of the present invention.
Drugs can be in various forms, such as uncharged molecules, components of molecular complexes, or nonirritating, pharmacologically acceptable salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate, tartrate, salicylate, etc. For acidic drugs, salts of metals, amines, or organic cations (e.g., quaternary ammonium) can be employed. Furthermore, simple derivatives of the drugs (such as ethers, esters, amides, etc.) which have desirable retention and release characteristics but which are easily hydrolyzed by body pH, enzymes, etc., can be employed.
The amount of drug incorporated in the drug-delivery device varies widely depending on the particular drug, the desired therapeutic elTect, and the time span for which it takes the film barrier and matrix material to erode or dissolve. Since a variety of devices in a variety of sizes and shapes are intended to provide complete dosage regimes for therapy for a variety of maladies, there is no critical upper limit on the amount of drug incorporated in the device. The lower limit too will depend on the activity of the drug and the time span of its release from the device. Thus it is not practical to define a range for the therapeutically effective amount of drug to be released by the device.
To prepare the drug-delivery device of the invention, the drug is mixed with the matrix material either at ambient or elevated temperatures to form a settable mixture. The settable mixture, whether a dispersion or true solution, is then simply spread on the film substrate in constant or varying thicknesses (see the FIGS. of the drawing) and allowed to set, for example, by drying or hardening. The coated film is next spirally wound or rolled about itself in jellyroll to provide the subject device.
In applying the drug-containing matrix to the film, the drug release profile of the device is determined. in most instances, a matrix of uniform drug concentration is applied over one entire surface of the film, at a constant or varying thickness. However, the matrix can be printed onto the film in various patterns, providing different rates of drug release. In addition, different portions of the film can be coated with matrix portions having different drug concentration. in each of these ways, the rate of release of drug from the device can be controlled and a wide variety of release patterns obtained.
The drug-delivery device can be fabricated in any convenient shape for either physical insertion or implantation in the body or for administration via the gastrointestinal tract. Dimensions of the device can thus vary widely and are not of controlling importance. The lower limit of the size of the device is governed by the amount of the particular drug to be supplied to the body to elicit the desired pharmacologic response, as well as by the form the dosage unit takes, for example, implantate, suppository, peroral pellet, oral bolus, vaginal pessory, buccal or sublingual lozenge, ocular insert (e.g. as described in US. Pat. No. 3,416,530), the like. Likewise with respect to the upper limit on the size of the device. One of the prime advantages of the dosage form of the invention over the capsule types of the prior art is that any inadvertent flaw in the protective film barrier will not suddenly release the entire drug content. Another advantage, if used as an implantate or the like, is the total disappearance of the film barrier when its function has been completed. Likewise as regards the drug matrix material.
It too will be appreciated that the principle of providing any predetermined time release profile can be embodied in devices other than drug-delivery devices, namely, in any device where it is desired to provide for the prolonged release of any active ingredient according to any desired release pattern.
While there have been shown and described and pointed out the fundamental novel features of the invention as applied to the preferred embodiment, those skilled in the art will appreciate that various modifications, changes, and omissions in the drug-delivery device illustrated and described can be made without departing from the spirit of the invention. It is the intention, therefore, to be limited only by the scope of the following claims.
What is claimed is:
l. A drug-delivery device for prolongedly delivering drugs according to any predetermined time release profile comprised of a spirally rolled substrate, said substrate being comprised of a relatively drug impermeable, flexible film erodible in body fluids and being coated with a drug-containing matrix composition, which matrix itself is erodible in body fluids.
2. The drug-delivery device as defined by claim 1, wherein the matrix composition is more rapidly erodible in body fluids than said film.
3. The drug-delivery device as defined by claim 1, wherein the drug is uniformly distributed throughout the matrix composition.
4. The drug-delivery device as defined by claim 3, wherein the drug coating is of constant thickness along the spiral.
5. The drugelivery device as defined by claim 3, wherein the drug coating is of varying thickness.
6. The drug-delivery device as defined by claim 3, wherein the thickness of the drug coating increases along the spiral.
7. The drug-delivery device as defined by claim 3, wherein the thickness of the drug coating decreases along the spiral.
8. The drug-delivery device as defined by claim 3, wherein the drug coating is of sinusoidal thickness along the spiral.
9. The drug-delivery device as defined by claim 5, wherein the film is comprised of a polymeric material which slowly dissolves in body fluids.
10. The drug-delivery device as defined by claim 3, wherein the film is comprised of polymeric material which hydrolyzes in body fluids.
11. The drugdelivery device as defined by claim 3, wherein the membrane is comprised of polymeric material which is cleaved by enzymes present in body fluids.
112. The drug-delivery device as defined by claim 1 bearing an external coating of said drug-containing matrix composition.
13. A device for prolongedly delivering active ingredient to a given fluid environment according to any predetermined time release profile comprised of a spirally rolled substrate said substrate being comprised of a relatively active ingredient impermeable, flexible film erodible in a given fluid environment, said fllm being coated with an active ingredient containing matrix composition, which matrix itself is erodible in said given fluid environment.
14. The method of prolongedly delivering drug to a patient according to any predetermined time release profile comprising administering to said patient the drug-delivery device as defined by claim ll.
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|U.S. Classification||424/424, 424/484, 424/472, 424/443, 424/433, 424/426, 424/436, 424/427, 424/434, 424/435|
|International Classification||A61K9/70, A61M31/00, A61K9/20, A61D7/00|
|Cooperative Classification||A61D7/00, A61M31/002, A61K9/2072, A61K9/2086, A61K9/70|
|European Classification||A61M31/00D, A61D7/00, A61K9/20K4, A61K9/70, A61K9/20K|