US 3880991 A
An article for dispensing drugs is disclosed which is formed from a crystalline polymeric material having a melting point of at least about 100 DEG C. and a drug. The drug is dispersed throughout the polymer and the combination is formed into a solid shape having structural integrity.
Description (OCR text may contain errors)
United States Patent 11 1 1111 3,
Yolles 1 1 Apr. 29, 1975 I lggblgl-IRIC ARTICLE FOR DISPENSING OTHER PUBLICATIONS Shipley. Steroids 5(5): 699-717, May 1965, Effecl l lnvemofl Y You?! Newark. Del. tiveness of Topical Application of a Number of Pro 73 A nee: mm 5.1; 11 M 11mins" 1 pan inure? Ringler. Steroids 7(4); 341-349, Apr. 1966. Efficacy of Topically Applied Progestational Agents" 1 1 Filed! DN- 29. I970 Kincl et 111.. Steroids 8(1): 5-1 I. July 1966, "Inhibi- 21] AppL No: 02.432 tion of Ovulation in the Adult Estrus Rabbit by Vaginal Deposmon" Related U.S. Application Data Doyle et al., Amer. J. Obstet. Gynec.. 101(4):  Continuation-impart o1 Scr. No. 809.946. March 24, 564-568. June 1968. Preliminary Studies on the E1- 1969. abandoned. fect of Hormone-Releasing intrauterine Devices Scommegna et al.. Fertility 8: Sterility 21(3):  U.S. Cl. 424/22; l28ll30; 128/260; 201-210, Mar. 1970. "Intrauterine Administration of 424/19; 424/83; 424/239 Progesterone by a Slow Releasing Device  int. Cl. Afillt 27/12 Cohen et 111., Fertility & Sterility 21(10): 715-723.  Field 01 Search 128/130. 131. 2611;424/14. Oct. 1970. "The Effects 01' an lntracervical 424/16. 19, 22, 28. 78-83. 239 Steroid-Releasing Device on the Cervical Mucus" [561 References Clted Primary Examiner-Shep K. Rose UNlTED STATES PATENTS 2.625.158 11195: Lee =1 128/260 1571 ABSTRACT 3.426.754 2/1969 Biercnhaum elu. 128/156 An article for dispensing drugs is disclosed which is 3.499.445 3/1970 Rccd............... 128/260 formed from a crystalline polymeric material having :1 .50 .877 5/1970 Wcis|.... 128/130 melting point of at least about 100C. and a drug. The 3545-43) 911mm" 23/260 drug is dispersed throughout the polymer and the 3.5115391 2/1971 Sh rt 424/243 combination is formed into a solid shape having struc' 3.5911.1 15 11/1971 Horne...,.......... 128/130 mm in: 1.611.213 11/1971 Shepherd =1 3]. 32/2 5 3.656.483 4/1972 Rudel 1281264 4 Claims. 6 Drawing Figures PAIENIEBAPRZBIBIS 3,880,991
TIMED RELEASE OF ACTIVE INGREDIENT FROM RABBIT I g 2.4 5 1.8- F I G. l j i 1.2-
1 I I 1 I l I l I l I a I 1 I 1 w 0 4 8 I2 I6 20 24 28 32 36 40 TIME IN DAYS O 0 o O O I 020359 20 o 200 2) C5600 0 FIG. 20 FIG. 2b FIG. 26 FIG. 2d
SEYMOUR YOLLES mam ATTORNEY.
l POLYMERIC ARTICLE FOR DISPENSING DRUGS CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of Yolles. Ser. No. 809.946. filed Mar. 24. I969. now abandoned.
BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates broadly to the controlled release of drugs to the bloodstream of mammals and more particularly to a shaped article formed from a crystalline polymer which contains a drug so that the article is suitable for implantation in a mammal to controllably release the drug.
2. Description of the Prior Art Medical science has long recognized the need for methods to controllably release therapeutic agents and other drugs to the blood stream of patients. Recently. a great deal of research has been initiated in attempting to find new release systems to fulfill this need. Several such systems have been recommended.
One common method for obtaining controlled release is to envelop the active substance with coatings which are attacked by digestive juices in the stomach. This technique has been widely used recently for timerclease analgesics. There are some problems with this method. however. such as: (l) it is difficult to obtain the proper distribution of coating thicknesses to give the desired release; and (2) the sojourn time of the coated agent in the digestive tract is relatively short. thereby making this method unsuitable for long-term release.
Another method of obtaining controlled release is to mix the active substance with various binders such as fats. waxes. and natural or synthetic polymers to slow down release. Many of the binders. however. are un suitable for use with many drugs. Furthermore. these combinations of binders and drugs tend to disperse quickly after they enter the body due to the binders solubility in body fluids. the washing effect of. the body fluids and/or the attack of digestive juices. After the binder has been so dispersed. all control over the release of the drug Ia lost.
Other researchers have even suggested that drugs be chemically modified to affect their release and absorption into the bloodstream. The degree of difficulty of this method for obtaining controlled release is clear.
More recently. the possibility of somehow ineorporating drugs into polymeric materials to control drug release has been considered. Thus Furuse et al.. U.S. Pat. No. 3.5 14.5 17. teach that suppositories containing spermicidal agents can be formed by blending the agents with low molecular weight polyethylene glycolst Hill. U.S. Pat. No. 3.458.622. teaches that tablets for controlling the release of medicinal agents for up to eight hours can be formed from a blend ofa polymeric vinyl pyrrolidone with a carboxy vinyl hydrophilic polymer; Weil et al.. U.S. Pat. No. 3.469.005. teach that drugs for reducing blood pressure in mammals can be incorporated into solid vehicles such as lactose. corn starch. microcrystalline cellulose. talc. stearic acid. magnesium stearate. gums. etc.; Merabi et al.. U.S. Pat. No. 3.495.000. have found that controlled release matrices can be prepared consisting of! dialdehyde starch and ethyl cellulose. polyvinyl chloride or polyvinylpyrrolidone. but that mixtures of the same starches Lie with other pharmaceutically acceptable polymers such as methylcellulose or carboxymethyleellulose do not yield compositions suitable for controlled release; and Herrmann. U.S. Pat. No. 2.l5$.658. teaches that medical preparations for injection into the body which are flowable above body temperature but solid at body temperature after injection can be made from polymerized vinyl alcohols and their water soluble derivatives and a solvent for such material.
Another technique for incorporating drugs into polymeric matrices is described in Levesque. U.S. Pat. No 2.987.445 and in Endicott. U.S. Pat. No. 3.087.860 These patents teach a drug dispenser formed from synthetic polymers containing solid particles of a waterleachable drug. Usually the polymer matrix is shaped in the form of a pill which is intended to be orally ingested. This drug dispenser is limited. however. to water-soluble drugs and has relatively short release times. ie.. typically 8-l2 hours.
While the above-mentioned patents describe various mixtures of drugs with polymers. Long et al. ha taught another method for constructing a controlled release device from polymers in U.S. Pat. No 3.279.996. Long et al. form a capsule or container from polysiloxane which is intended for implantation. This device has the advantage of making extended timerclease treatment possible. but suffers a disadvantage since the possibility exists that the polysiloxane con tainer will develop pinholes or a rupture resulting in an undesired and potentially harmful large amount of drug being released almost instantaneously.
In spite of all of the work being carried on to find suitable polymeric vehicles for dispensing drugs controllably. to date the incorporation of drugs throughout crystalline polymers shaped to various solid forms which have structural integrity after implantation has not been considered.
SUMMARY OF THE lNVENTlON It has now been unexpectedly found that an intimate mixture of a drug and a crystalline polymeric material can be formed to a solid. shaped article which will unexpectedly exude the drug to the surface of the pol meric article. For purposes of this description. the term exude is used to mean the migration from the interior of the polymeric material to its surface until the surface is covered with a layer of the drug and an equilibrium is established between the surface layer and the drug at the interior of the polymeric material. If the surface layer is partially or totally removed. the equilibrium is destroyed and further amounts of the drug permeate to the surface until equilibrium is reestablished. This cycle will repeat itself until the supply of drug has been exhausted from the polymeric material. The surface layer can be removed in many ways. including but not limited to: rubbing it off; brushing it off; washing it off; dissolving it off; etc.
Relying upon this discovery. a novel article for dispensing drugs has been invented which comprises:
1. a crystalline polymeric material having a high melting point and being formed to a solid shape having structural integrity; and.
2. a drug substantially uniformly and intimately dispersed throughout portions ofthe polymeric mate rial.
There are many advantages to this drug dispensing device over those previously known. For example. this device provides an economical and reliable method for automatically dispensing controlled quantities ofa drug over a short or an extended period of time. Such a device can be implanted within a mammal's body so that it will dispense the required amounts of one or more drugs continuously over extended periods of time without the patient having to rely on periodic injections or oral ingestion of drugs. Once implanted. the dispenser can be forgotten and the patient can rest assured that his body is continuously and automatically receiving the prescribed amount of drug.
A particularly unique advantage of this device is found in the types of therapy where it is desirable to insure that a patient receives a certain amount of a drug. and it is desirable to place control of administering the drug beyond the patient. This obviates the possibility that the patient will forget to administer the drug. it also prevents the patient from deliberately not administering the drug on his own volition. which has heretofore been a serious problem in many types of medical treatment. Once implanted. the drug dispensing devices of this invention are effectively out of the control of the patient.
A most important advantage of the polymeric drug dispenser described herein is the degree of flexibility which can be obtained in administration techiques. As stated above. one suitable method for releasing the drug from this device to a mammals bloodstream is to subcutaneously implant the device. There are many other methods. however. For example. the device can be extruded into the shape of thin spaghetti which can be injected into the bloodstream. or the polymeric material can be formed into various sized spheroids for ingestion or injection by a patient. Additionally. the polymeric material can be formed into hollow tubing suitable for catheters. in short. the dispenser of this invcntion can be formed into limitless solid shapes each suitable for particular methods of controllably releasing a drug to the patient's bloodstream.
BRIEF DESCRIPTION OF THE DRAWINGS FIG. I is a graphical representation of the controlled release of the steroid progesterone from a device ofthis invention to the bloodstream ofa rabbit;
FIGS. ii (a) (d) are perspective views of some of the variety of shapes of controlled release drug dispenscrs of this invention;
FIG. lll is a perspective view showing the subcutaneous implantation of a controlled release film device of this invention into the back of a rat.
DESCRlPTlON OF THE PREFERRED EMBODIMENTS The polymeric materials used to manufacture the inslant device must be crystalline and must have high melting points so that they won't soften when exposed to fairly high temperatures such as those encountered with human body fluids. Preferably the material will have a melting point of lDC. or more so that the device can be sterilized at high temperatures.
Some examples of suitable polymeric materials include. but are not limited to: polyamides such as nylons; polyolefins such as polypropylene and polyethylene; polyesters such a: polyethylene tcrephthalate; vinyl polymers such as polyvinylidene chloride and polytetrafiuoroethylene; polyacetals; cellulose acetate;
polypeptides; polycarbonates'. polyvinyl ethers and combinations of these.
lt has been found that polymers having a crystalline structure yield the most satisfactory control of drug release. Although the reason for this is not known. it may be because of the long segments of linear polymer chains regularly oriented with respect to one another in crystalline polymers. It is known of course. that crystallinity does have a marked effect on physical properties. See Flory. Paul 1.. Principles of Polymer Chemistry. 5th printing. I966 at pages 49 et seq. It has also been reported in the literature that gaseous diffusion through polymeric membranes is slower. in general, for those polymers having higher degrees of crystallinity than for those with lower degrees of crystallinity. See Michaels. A. S. and Bixler. H. 1.. "Flow ofGases through Polyethylene and Rubbery Polymers" J. Poly. Sci.. vol. 50. 4l3-39 (I96! While melting points can be a good indication of polymer crystallinity. the best evidence is obtained by X-ray diffraction patterns.
Some preferred polymeric materials are polyethylene. polytetrafluoroethylene. and polyethylene terephthalate because they are commercially available. economical. and have the required physiological inert ness required of any materials considered for implantation into the human body. Polyethylene is particularly preferred.
The crystalline polymeric materials described above have drugs incorporated in them to form the article of this invention. The term drug is used in this description in its broadest sense and covers drugs useful to any mammals including. but not limited to. human beings. wild animals. household animals. and animals raised for their meat or other products such as farm animals and cattle. The term drug is further used in describing this invention to include. but not limited to. the following classes of drugs: (I) therapeutic drugs; (2) preventative drugs; and. (3) diagnostic drugs. It should be understood that a variety of classes. subclasses. and specific examples of drugs not expressly mentioned herein are within the scope of this invention. and these other drugs will be well known or easily ascertainable to those skilled in the art.
Some specific examples of drugs which can be incorporated in crystalline polymers to form a device of this invention are described infra.
As is well known. people suffering from sugar diabetes are required to take daily doses of diabetes control agents. insulin or the active ingredients in some of the commercially available control agents such as tolbutamide ("Orinase" by Upjohn). chloropropamide ("Diabinese" by Pfizer) and tolazamide (Tolinase" by Up john) could be dispensed with an article of this invention.
Many drugs are presently being used to treat rheumatoid arthritis and other forms of arthritis. These include. but are not limited to. narcotic pain relievers. gold salts. corticosteroids. adrenocorticotropic hormones phenylbutazone and its derivatives. antimalarials. and indole derivatives. A comprehensive listing of specific drugs used to treat the various forms of arthritis is given in the Aug. l2. i968 edition of Chemicaland Engineering News at pages 54 and 55. which listing is herein incorporated by reference. These drugs could be dispensed with the instant article.
Antibiotics are a further group of drugs which can be dispensed. Some examples of suitable antibiotics include the tetracyclines. penicillan. streptomycin. and aureomycin.
Deworming and distemper drugs such as those given to household pets and/or cattle are another group of drugs capable of being dispensed by the device of this invention. An example ofsuch a drug in phenothiazine.
Sulphur drugs such as sulfisoxazole diolamine ("Gantrisin" by Roche Laboratory). useful in treating urinary tract infections. could also be exuded from a crystalline polymeric article.
Another group ofdrugs suitable for use in the crystalline polymeric articles are the cancer-control agents. An example would be the drugs or combinations of drugs useful for treating leukemia such as the nitrogen mustard p-(di-Z-chlorethyi) amino-phenylbutyrlc acid.
Two further groups of drugs which could be advantageously dispensed with the hereindescribed device are alcohol-addiction control agents and tobacco-smoking addiction control agents.
Closely related are the addictive drug antagonists. if an addictive drug such as heroin, morphine. codeine. neopine. etc. is taken while the blood still contains the antagonist. the addictive drug will pass through the body and be harmless to the taker in the sense that the taker will not experience "a high" and the drug will not be addictive. Such antagonists have offered a very successful method for treating drug addicts while the addiets are at clinics; however. it has been noted that once an addict returns to his original environment. and is out of control of the clinic. he is likely to stop taking the antagonist and resume taking one of the addictive drugs. For this reason. the article of this invention offers unique advantages in treating drug addicts by this method since such an article containing an antagonist could be implanted within the addict's body. thereby giving him no control over the administering ol' the antagonist. This will extend the addict's period ofcure beyond the time that he can actually be confined to a clinic. Some examples of specific drug antagonists suitable for incorporation into the polymeric dispenser include N-ailylnoroxymorphone ("Naloxone") and 2- cyclopropyimethyl-Z'-hydroxy'5.9-dimethyl-6,7- bcnzomorphone (Cyclazocine"). Other drug control agents such as "Methadone can also be used.
Two further groups of closely related drugs are the thyroid gland regulating drugs and weight-control drugs. Here aguln. there is a particular advantage to the use of the polymeric dispenser since such a device can be implanted within the body of the patient and thereby supply the required amount of drug without the patient having any control over this. Also. it is known that these types of drugs are extremely dangerous when taken in large doses. and the use of this device would help assure that an overdose did not get into the patient's bloodstream.
Another group of drugs which could be dispensed are the analgesic drugs. These drugs have little or no therapeutic effect. but serve to lessen or eliminate the severe pain often encountered wth many diseases or operations. For example. in the cases of chest cancer. morphine or codeine are often prescribed. Also. for patients suffering from cancer of the prostate glands. progesterone is often prescribed. One particularly advantageous use ofthe polymeric dispenser would be in serlous surgical operations which result in severe pain to the patient after the operation is completed and the pa ticnt regains consciousness. in these cases. the body is going to be opened for the operation. and a device of this invention containing a pain killer could be inserted into the body during the operation to ease the pain to the patient during the recovery period. Of course. there are many other types of analgesic drugs and many other examples of when such drugs could be used which will be apparent to those knowledgeable in the field of medicine.
Another group of drugs suitable for being dispensed from the polymeric article are the hormone-regulating drugs to aid fertilization or to act as Contraceptives. One preferred embodiment using hormone-regulating drugs is formed using the active ingredients in oral con traceptives. The advantage is that a device containin the active ingredients of oral contraceptives could be designed to last over extended periods of time thereby relieving the taker from a daily routine oforally taking the contraceptives. Suitable exam les of the active ingredients in oral contraceptives include a progestin or a combination of a progestin and an estrogen. For example. a homogeneous dispersion of the active ingredient in Norethindrone" and Mestranol" in a ratio of 201i by weight could be prepared and incorporated into the solid polymeric material. Other examples ol synthetic progesterones and estrogens suitable for use with this invention include: Norethylnodrel. Mcdroxy progesterone acetate. Dimethisterone. Ethynodiol diacetate. Chlormadione acetate. Norethindrone acetate and Ethynyiestradiol.
One particular advantageous embodiment is thrcombination ofan intrauterine device and the article or this invention. This can be prepared by forming a SUll able polymeric material containing an oral contraceptive into the shape of an intrauterine device. The dC\lCL could then be inserted into the uterus of a woman and would offer the double protection of the exuding oral contraceptive and the intrauterine device principle The intrauterine device could have any shape including. but not limited to. a spiral. bow. loop. ring. coil, or trefoil. Besides using contraceptive combinations of steroids in such a device. it would also be possible to use a spermicidal agent such as the tcrpenylphcnyl polyethyethylene ethers described in Furuse. US. Pat No. 3.514.5l7.
Other drugs which can be incorporated in the sys tents of this invention include: drugs for reducing bloorl pressure such as those described in US. Pat. No 3,469,005; pharmaceutical compositions for the control of appetite such as the combinations of am hctrr mines and thioridazines described in US. Pat. No 3.495.005. and. agents for treating psychosis in mammals such as those described in US. Pat. No 3.495.007.
The above listing ofdrugs is not intended to be comprehensive. but merely representative ofthe wide var|- ety of drugs which can be used with this invention Those skilled in the art will know or be able to determine by routine experimentation that many other 5pc cific drugs are also suitable,
The amount of drug dispersed in the polymeric artt Cle will depend. of course. on many factors including the specific drug. the function to be accomplished, lht' length of time it is desired to dispense the drug. the amount ofdrug to be dispensed in a specified time. the size Of the device. and many other factors. in general,
amounts ranging from about 0.5 to about 50'? by weight of the polymeric material can be incorporated. Particularly good results can be obtained with from at least about it) to about 20%.
The amount of drug to be dispensed in a specified time. will of course. depend on such factors as the particular application. the particular drug. the age of the patient. etc. in general. what will constitute an effective amount will be known or easily ascertainable by those skilled in the art.
As to what constitutes an effective amount of drug in intrauterine devices. reference is made to the following four articles which disclose the use of progestins and/or estrogens in intrauterine devices:
I. Taubert and Segal. Absorption of Estrogen and Progesterone by Intrauterine Devices." American Journal of Obstetric: and Gynecology. V0. 98. No. l. pp. l26-2l7 (May i967). Studies reported in this journal show that a polyethylene intrauterine device adsorbs progesterone or estrogen. The authors erroneously conclude (as shown by subsequent studies) that an lUD containing either progesterone or estrogen would not have a useful effeet on the endometrium. it should be noted that Taubert et al. did not study the combination of a progesterone and estrogen.
. Doyle and Clewe. Preliminary Studies on the Effect of Hormone Releasing intrauterine Devices. American Journal of Ubslclrics and Gynecology. ll(4 564-8 (June i963). This article reports on the use of progesterones incorporated into Silastic intrauterine devices to prevent expulsion of the intrauterine device and also reported that estrogen primed monkeys demonstrated that the primate uterus responds to hormone impregnated intrauterine devices.
3. Scommegena et al.. "Intrauterine Administration of Progesterone by a Slow Releasing Device. Ferrt'liry and Slcrili'ly 2i. l-2l0 i970). This article confirms the Doyle et al. findings and discloses the use of Silastic intrauterine devices containing progestrone which device is useful as a contraceptive in human females.
. Cohen et al.. "The Effects of an lntracervical Stemid-Releasing Device on the Cervical Mucus". Ferrillly and Sterility 2i. HS-723 (Oct. 1970). This article is directed to a Silastic intrauterine device contanlng a progesterone or an estrogen for use in conception control. These articles are herein incorporated by reference. Much of this type of data is published in the literature or easily determined by routine experimentation. Examples of the published literature on effective amounts of progestin-type steroids. in this case for topical application. can be found at: Shipley. "Effectiveness of Topical Application of a Number of Progestins." Steroids 5(5): 699-7l7. May. 1965: and Ringler. "Efficacy of Topically Applied Progestational Agents." Steroids 7 (4): 341-349. Apr.. i966. in a like manner. the following literature describes ef fective amounts of addictive drug antagonists: Martin. W. P... "Opioid Antagonists." Pharmacological Reviews. vol. l9. no. 4. pages 463-52l (i967) and references contained therein; Freedman. A. M.. "Cyclazocine and Methadone in Narcotic Addiction." The Journal oft/re American Medical Associalion. Oct. l6. i967. vol. 202. pages l9l-l94. Also.
the patents mentioned above often contain data on effective amounts for any particular application.
The dosage administered by this dispenser can be controlled by the size and shape of the article. concentration of the drug in the polymer. surface area. pore size. matching of the polymer and drug. nature of the surroundings. etc. This is a particular advantage where it is desirable to deliver a metered amount of the drug over a specified period of time.
Of course. combinations of drugs and substances in addition to drugs can also be incorporated into the polymeric material. For example. radioactive tracers such as carbonl4. nonradioactive tracers such as barium sulfate. carriers which would transport the drug through skin such as dimethylsulfoxide and dimethylsulfone. water-soluble excipients. etc. could be incorporatcd with certain drugs for particular applications. The amount of auxiliary agent used will depend. of course. on the specific agent. drug and polymer used to fabricate the article as well as the purpose for incorporating the auxiliary agent.
As has been described. the polymeric article dispsenses the drug it contains by exuding it to the surface of the article. The mechanism of how the drug enters the body from the polymer surface is not critical and can be accomplished with a variety of techniques. For example. the article may be placed upon a person's body in contact with the skin so that the particular drug could be absorbed through the person's skin into the bloodstream. An alternative technique is to implant the device within the patient's body at a location where the surface layer of drug will be in contact with any of the various body fluids or tissue so that the drug could be dissolved and/or carried away by such body fluids or rubbed off and absorbed by the tissue. Subcutaneous implantation ofa film drug dispenser under the skin on the back of a rat is shown in H0. ill; a more detailed description of such implantation techniques is presented in the examples. Intramuscular implantation is also contemplated. Still another technique would be to prepare the article for use in the patient's mouth so that the saliva would carry the drug into the body. in certain cases. it might be advantageous to insert the dispenser in other body cavities such as the uterus. Other techniques for getting the material from the surface of the article into the body will be readily apparent to the medical profession.
The dispensing articles described herein can be formed by pre-mixing the polymer. drug and any auxiliary agents to be incorporated with the drug and then following conventional techniques to shape and set the article. For example. the polymer and drug can be mixed together in a suitable solvent until a homogeneous solution is formed. After driving off solvent. the residue can be molded. extruded. etc. to the desired shape. Another method of forming the dispenser might be to compact at elevated pressures a dry mixture of drug and polymer. Also. monomer and drug can be mixed with subsequent polymerization of the monomer.
Another method of forming the drug dispensers is to soak a previously shaped piece of polymeric material in a solution of the drug to be incorporated. and subsequently drying the surface ofthe article. This technique must be distinguished. however. from simply dipping a polymeric article in a solution to coat the surface of the article with a substance. in the soaking technique of this invention. the conditions. i.e. solvent. polymer. temperature. etc.. must be carefully chosen to insure that the active ingredient penetrates deeply into the polymer matrix instead of remaining only on the surface or penetrating a small distance below the surface as a coating does. One way to accomplish the desired deep penetration is to choose a solvent which causes the polymer to swell in the solution of drug. Some sol vents cause swelling at room temperatures; others require elevated temperatures. Once the polymer has swollen. solvent and active ingredient can penetrate deeply into the polymer matrix. With rapid cooling. the polymer returns its non-swollen condition trapping solvent and active ingredient within it. if the solvent chosen is highly volatile. while the active ingredient is not. the solvent can be driven out ofthe article by continuous pumping. i.e. exposing the article to reduced pressures. Those skilled in the art will be able to select appropriate conditions for carrying out this technique.
Other methods for making the polymeric dispensing articles will be apparent to those skilled in the art.
An important feature of the dispenser. which results from the way it is prepared, is that there is a substantially intimate dispersion of drug throughout polymer. This is to be contrasted with a foraminous plastic matrix containing discrete solid particles of a drug only within the voids. such as described in US. Pat. Nos. 2.937.445 and 3.087.860. in these patented systems. drug release is predicated upon water or other liquids leaching the drug from the voids; in the dispenser of this invention. drug release is predicated upon exudation of the drug to the polymer surface.
Another important feature of the dispenser. which also results from the way it is prepared. is that the dispcnser has "structural integrity." This means that the shaped dispenser will remain intact after prolonged exposure to body fluids. Although it is difficult to list all of the factors which contribute to the structural integrity. some include: substantial non-solubility and non-swellability in water or body fluids; relatively high tensile strengths; and good elongation at break and tensile modulus. Additionally. the polymeric matrices of this invention do not soften appreciably at temperatures as high as 100C. as many of the prior art waxy binders do.
A test to establish structural integrity ls as follows. The shaped drug carrier is immersed in distilled water at 37C. for 7 days. After this perlod. weight loss ofcarrier and dimensional changes of carrier should be less than l% of their original values. The polymeric matrices of this invention meet this test.
The shape of the dispenser will depend on its in tended use. Any shape is within the scope of this invention. Some possible and preferred shapes are illustrated in FIG. ll wherein (a) illustrates a film. (b) illustrates a contraceptive intrauterine device known as the Lippes Loop. (c) illustrates a piece of hollow tubing suitable for implantation or for use as a catheter. and (d) illustrates various sized solid spheroids which could be injected into a patient or orally ingested by the patient. Other shapes contemplated but not shown include solid sphagetti-like" and fiber-like configurations and a mesh configuration which would be expected to minimize the possibility of a device subcutaneously implanted causing blood clotting.
The drug dispenser can be also be shaped as a body organ or any part thereof. For example. an artificial heart valve could be formed from a polymer Containing a drug which would lessen rejection of the new valve. Those skilled in the art will know many other organ shapes to which the drug dispenser could be formed.
As is evident from the forgoing discussion. the article of this invention has many uses. all of which fall within the general utility of dispensing drugs to mammals.
The following examples serve to further illustrate the invention. All parts and percentages are by weight. unless otherwise specified.
EXAMPLE I A WOMAN'S lNTRAUTERlNE DEVlCE MOLDED FROM POLYETHYLENE RESlN IMPREGNATED WITH AN EFFECTIVE AMOUNT OF A CONTRA- CEPTIVE PROGESTlN AND ESTROGEN COMBI- NATION Eighty parts of polyethylene resin as fine powder is dissolved in 320 parts of boiling toluene. Twenty parts ofa mixture of norethindrone H.048 parts) and mestranol (0.952 parts) is added slowly with stirring to the refluxing polyethylene-toluene solution. When the solution has cleared indicating homogeneity. the volatile solvent toluene is removed by flash distillation at reduced pressure. The residue consists of an intimate dispersion of norethindrone-mestranol in polyethylene. The hot. semi-solid mass is formed into solid Shapes having the geometry of any of the well-known intrauterine devices by conventional polyethylene molding techniques. Each is suitable for intrauterine insertion into the uterus of a woman to dispense effective amounts of the norethindrone-mestranol contraceptive combination. Analysis ol'a device reveals that the composition consists substantially of parts polyethylene and 20 parts of a mixture of norethindrone and mestranol.
To demonstrate that a contraceptive combination nl drugs could be released. polyethylene implants prepared as described above except shaped as films instead of lUD's were subcutaneously implanted into the backs of rabbits. Trace amounts of radioactive tagged ingredients were used with the norethindronemestranol combination. Measurements of the disintegrations per minute with scintillation counting equipment of samples of rabbit blood and urine demonstrated that effective amounts of the contraceptive combination were being released from the device to the rabbits bloodstream.
EXAMPLE ll FLEXIBLE POLYETHYLENE TUBlNG CONTAIN- lNG AN ADDlCTlVE DRUG ANTAGONIST Eighty parts of polyethylene resin as Vs inch cubes and 20 parts of N-allyl-noroxymorphone are blended on a steam heated two-roll rubber mill. This mixture is then placed in a conventional twin screw extrudcr and extruded into flexible tubing of me inch diameter This tubing can be subcutaneously implanted into various parts of a drug addict's body. and when so im planted will release the N-allyl-noroxymorphone to the addict's bloodstream. Alternatively. the tubing could be extruded as a hollow catheter and implanted by catheterization techniques.
EXAMPLE lll POLYETHYLENE FlLM IMPLANTS CONTAINING PROGESTERONE Eight grams of powdered polyethylene resin and two grams of progesterone together with a trace of radioactive tagged progesterone are dissolved in 250 milliliters of hot xylene. The clear solution is evaporated down to about one-hall'ol'its original volume and the remainder is poured onto glass plates where the solvent is allowed to evaporate. The remaining solid mixture is placed in an oven at iOOC. for 2 hours to drive off remaining solvent.
Films are formed by placing the dried solids between two sheets of aluminum foil and pressing at 150C. and 5,000 p.s.i. for five minutes in a Carver press. The films are formed with a circular shape having a diameter of 3-4 inches and a thickness OH to 6 mils. lfdesired. the
Table II presents progesterone release data obtained from the urine samples collected. As can be seen. each of the rabbits was receiving daily dosages of progester' one from the implant over the period of testing.
After the test period. each of the four rabbits was killed by intracardiac injection of l,l .l-trilluoro-2- bromo-Z-chloroethane. The implants were recovered by dorsal incision. inspected and placed as found into paper envelopes. There was very little visible tissue reaction. Small amounts of clear fluid were found in the "tissue" pouch around the implant.
The removed implants were weighed and subsequently dissolved in xylene so that a final radioactive count and weight loss after 60 days could be checked.
pressing technique is repeated to make the films more l The results are shown in Table III.
TABLE l DPM 'lml. Final Rabbit initial Rabbit lm lunt of blood after Wci ht Alter Rabbit Weight. kg. Weig t. gm. 48 hours 43 ays, kg.
A 2. 0.2488 8 3.5 B 2.]! 0.2500 5 3.4 C [.84 0.2592 34 3.2 D L94 0.2I03 l4 3.l
' disintegration: per minute TABLE II Urine counts. accumulated DIM 1'rri0d.... 24 hr. 48 hr. 00 hr. 7th day Hth day Nth day 25th day 29th day 30th day 1mm 001.818 [,iOLMS LlTLNB 1.373.908 i.tT3,46B Lti'ltfltitl 820,013 1,136.91! 1,405.03 1.565.123 2.080.088 2,2,680 2.507.57lt B30, LMJJW 1.850.887 LUlLlZi LBULNl L'H'Lttiil l.8'. .5.l.'.l 657.006 "24.97! i. HD3323 1,233,723 1.630. 758 1,673.07! i. BOJ. l2?
Sea the tollowin (Percent.
cultttod lrom radioactive count alter 80 days:
TABLE ill #1 Active Ingredient Delivered BKiWeight By Residual Count Final implant Residual Count ethod Method Rabbit Weight. grn. After 60 days. DPM 0 days 60 days C 0.2l30 835.000 89A 76.4
uniform. EXAMPLE IV A polyethylene film prepared as described above was cut into one-inch squares. Four of these one-inch squares were subcutaneously implanted into the backs of four rabbits. Each film section weighed approximately 250 milligrams and contained about milligrams of progesterone. After implantation. the rabbits ere placed in metabolism cages.
Release of progesterone into the blood stream of the rabbits was monitored by radioactive counting of blood samples taken periodically from the hearts and 24-hour urine samples. The release ol'progesterone for one rabbit is shown in HO. 1 plotted as milligrams of active ingredicnt delivered per day.
Table l presents the initial and final rabbit weights for the period of testing. the implant weights. and the radioactive count of blood samples 48 hours after implantation. As can be seen from the radioactive count of blood samples. the progesterone was being released by the implant to the rabbits bloodstream.
POLYETHYLENE FILM IMPLANT CONTAlNlNG THE DRUG ANTAGONIST CYCLAZOCINE A subcutaneous implant in the form of polyethylene film is prepared as in Example lll except that 207: cyclazocine with a trace of radioactive tagged cyciazo cine is used as the active drug. Cyclazocine is an addictive drug antagonist.
Pieces of a film prepared as above were cut into two centimeter square areas. Some pieces were weighed, combusted and radioassayed to provide a measure of the concentration of radioactivity present in each piece. Other pieces of the same film were implanted subcutaneously in the backs of rats under light ether anesthesia. The stab wounds were sutured and re mained so until the end of the experiment at which time the wounds were reopened and remaining implants were removed for final radioassay,
The rats were placed in Acme metabolism cages for 62 days for the spearation and collection of urine and samples. Total daily urinary radioactivity was measured daily for the first ten days and every four days thereafter. This was accomplished by liquid scintillation techniques and the data was reported as "q: of dose excreted per day and also as cumulative it: of dose. The final radioassay indicated that all of the cyciazocine was released from each device in each rat. The results are presented in Table IV.
tween sheets of aluminum foil on a Carver press at 140C. lC.. and l30C.. all at I0.000 p.s.i.
Samples oi films prepared in this manner were implanted into the backs of rats and cyclazocine release was monitored by radioassay. implant and radioassay techniques were the same as those described in Exam pie IV.
The results are presented in Table V.
TABLE IV Percent eyeinocina released, cumulative Day ..12|i601811101112131415101111111120 /t.....11.11 111.1 111.0 21.5 26.7 27.7 110.2 45.4 to: 51.0 52.1 saa 114.0 511 50.4 511.5 47.2 111.11 514.11 5111.11 11.... 1.11 11.11 .6 111s 11.4 111.1 111.: 21.11 24.! was 21.2 11.0 no 211.: am 30.11 arr as 33.11 31.1 11.5 is! 111.: 20.0 21.11 n1 24.11 25.11 no 2&5 no 31.11 $3.0 34s ass 311.7 31.11 38.) 411.0 41.1
See the following table:
Eat and implant data Initial rat. initial implant weight, gm. weight. gm. Initial DPM 1175 111312 mm 1100 0.1371 232.22% can 0.1m 2111.000
-- ll V 111A.111.'1| 411 11. t-Hm 'rlm 1 .1. .14 s1 1111"1,
y l l t 6 l 1 in ll 1; 11 1.1 1- 1 1 14.11 11 6. 1 It." I114 "1.1 1!.11 HLU I11! 111 '111 .11! I11 11 in l .l. 1
l J.| I V I.' H'Lfi i '2.) ii," 11L! 1'1, H1 ll, |I, l't l"l I". I! II 1 1 i ll. l |1.l I I HLS III I I ll,\ |l.l 11.41 l1l I 1 It! i 1 ll,l II! I l Illm VFW-8V4 at ll11 1111 l l 4 '1 b I It I I11 11 4 11111 hit 1, 4 I11 4 1111.11 "IA 11! H |1..-l 1. '1 I :o.
11 1! 1 1:11 1 .1 1-..1 w 11 11,11 '11. M. 1-14 1-11 H H g 1 11.11 41 1 .1 1 1 11,1 11.. 1'11 .11 a. m "-111 "'u'f- 111-11 |'r|'s.|-| .it i|1l"( I 1 11 1 l I 1. 1.1 I y t l 1 I 1 I Al 1 11 1'1 1 1 -11-- 1 1 1 I 1.
4 .1 v 1 1 l1 1 l l l What is claimed is:
45 1. An intrauterine device for controllably dispensing an effective contraceptive amount of a progestin and an estrogen comprising a molded solid shaped intrauterine device having structural integrity containing an effective intrauterine dosage amount each ola proges- EXAMPLE V tin and an estrogen in combination uniformly and inti- IMPLANT PREPARED FROM A POLYACTIDE FILM CONTAINING CYCLAZOCINE Six grams of poiylactide with a molecular weight of about 40.000 prepared from L(-) lactide according to Example I of British Pat. No. l.040.i6B is dissolved in 250 milliliters ol'chioroform. Three grams of tributylcitrate and 2.25 grams of cyclazocine are added to the hot stirred solution. This is followed by the addition of S milliliters of a trace of radioactive cyclazocine to monitor drug release. The solution is evaporated to about one-half its original volume and poured onto glass plates. The residue on the plate is air-dried for 20 minutes and oven-baked at lOO'C. for one-half hour. Films are prepared by pressing the dried material bemateiy dispersed throughout a crystalline polyethylene resin.
2.The device of claim I wherein the progestin is norethindrone and the estrogen is mesrranol.
3. A method for preventing contraception which comprises inserting into the uterus an intrauterine do vice for controllabiy dispensing an effective contraceptive amount ola progestin and an estrogen comprising a molded solid shaped intrauterine device having structural integrity containing an effective intrauterine dosage amount each of a progcstin and an estrogen in combination uniformly and intimately dispersed throughout a crystalline polyethylene resin.
4. The method of claim J for preventing contraception wherein the progestin in the uterine article is norethindrone and the estrogen is mestranoi.
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