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Publication numberUS3892842 A
Publication typeGrant
Publication dateJul 1, 1975
Filing dateOct 16, 1973
Priority dateSep 1, 1971
Publication numberUS 3892842 A, US 3892842A, US-A-3892842, US3892842 A, US3892842A
InventorsZaffaroni Alejandro
Original AssigneeAlza Corp
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Intrauterine contraceptive device for releasing steroid having double bond functionality
US 3892842 A
Abstract
An intrauterine delivery device for the administration of anti-fertility steroid to the uterine cavity comprising a body of non-toxic, biologically inert, polymeric release rate controlling material containing therein an anti-fertility steroid comprising a locally active steroid of the structural formula: WHEREIN A is C-OH, C-OH, C-OR, or C-OR; B is C-OH, C-OR, C-OH, or C-OR; R is the residue of a pharmaceutically acceptable acid or a lower alkyl group; said anti-fertility agent having a sole double bond at the DELTA 1, DELTA 4 or DELTA 5 position or double bonds at the DELTA 1 and DELTA 4 positions when A and B are both RESPECTIVELY; AND, PROVIDED THAT B is not WHEN A is AND THE DOUBLE BOND IS AT THE DELTA 4 POSITION; AND WHEREIN THE DEVICE, WHILE IN THE UTERUS, CONTINUOUSLY METERS THE FLOW OF A CONTRACEPTIVELY EFFECTIVE AMOUNT OF STEROID THROUGH THE MATERIAL AT A CONTROLLED AND PREDETERMINED RATE OVER A PERIOD OF TIME.
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United States Patent 1 1 Zaffaroni 1 INTRAUTERINE CONTRACEPTIVE DEVICE FOR RELEASING STEROID HAVING DOUBLE BOND FUNCTIONALITY [75] Inventor: Alejandro Zaffaroni,Atherton,

Calif.

[73] Assignee: ALZA Corporation, Palo Alto,

Calif.

[22] Filed: Oct. 16, 1973 211 Appl. No.: 406,951

Related US. Application Data [63] Continuation-impart of Ser. No. 176,926, Sept. 1, 1971, abandoned, which is a continuation-in-part of Ser. No. 884,305, Nov. 11, 1969, abandoned, which is a continuation-in-part of Ser. No. 864,175, Oct. 6, 1969, abandoned.

[52] US. Cl. 424/22; 128/130; 128/260; 424/16; 424/19; 424/238; 424/242; 424/243 [51] Int. Cl A6Im 31/00 [58] Field of Search 128/260, 130, 131; 424/16, 424/19-22, 238-243 [56] References Cited OTHER PUBLICATIONS Hohn J. Endocrin, l0:358362( 1954) Direct Proges- Primary Examiner-Shep K. Rose Attorney, Agenl, or Firm-Paul L. Sabatine; Edward L. Mandel] [57] ABSTRACT An intrauterine delivery device for the administration of anti-fertility steroid to the uterine cavity comprising a body of non-toxic, biologically inert, polymeric re- [4 1 July 1,1975

lease rate controlling material containing therein an anti-fertility steroid comprising a locally active steroid of the structural formula:

wherein A is OOH, COH, C-OR, or C-0R; B is C011, C-OR, COH, or COR; R is the residue of a pharmaceutically acceptable acid or a lower alkyl group; said anti-fertility agent having a sole double bond at the A, A or A position or double bonds at the A and A positions when A and B are both respectively; and, provided that B is not when A is and the double bond is at the A position; and wherein the device, while in the uterus, continuously meters the flow of a contraceptively effective amount of steroid through the material at a controlled and predetermined rate over a period of time.

12 Claims, 4 Drawing Figures 1 INTRAUTERINE CONTRACEPTIVE DEVICE FOR RELEASING STEROID HAVING DOUBLE BOND FUNCTIONALITY BACKGROUND OF THE INVENTION This invention relates to a contraceptive intrauterine device and method and more particularly it pertains to an intrauterine device and to a method for the predetermined. continuous and controlled metering of the flow of a contraceptively effective amount of a biologically acceptable antifertility steroid to the female uterus over a prolonged period of time. The steroids useful by the invention are defined hereinafter.

Intrauterine contraceptive devices of various configurations have become an increasingly popular method of birth control. While generally used to avoid systemic effects associated with oral ingestion and also because they are generally reliable when in proper place and retained therein. such devices are frequently expelled by the patient due to uterine contractions. This is a signifi cant problem since the host is often unaware that the device has been expelled. One approach to this problem has been to incorporate a progestational agent in the device in a manner such that a continuous does of the hormone is delivered to the uterus to reduce both the uterine contractility and expulsion of the devices. Reduction of uterine contractility also is helpful in re ducing inflammation and uterine punctures which are sometimes attendant with the use of intrauterine deices. See Doyle ct al. Amer. J. ()brml. Gynecof. Vol. Iii pp. 564 10 568. W68. Also. another disadvantage with these devices and the agent used is the agent is in a high! active form. Thus. if some of the agent delivered by these devices passes into the blood circulation, it gives unwanted progestational actility similar to the same systemic side effects as those produced by oral ingestion For example. the presence therein can lead to disruption of the menstrual cycle. These features tend to diminish the practical usefulness of this type of unti-fcrtility system.

Other investigators have incorporated pro-gestational agents in intrauterine deyices with a view to controlling fertility by the hormonal effect of the progestational agent. Such work has been extended to other drug delivery systems including vaginal inscrts and cervical rings. that is. progestogen releasing rings placed at the head of the cervix. and surgical implants. placed in the uterine area or elsewhere in the body, These systems mainly arc dependent for their results on agent distribution through the circulatory system. and they give rise to the unwanted side effects produced by oral administration. such as weight gain. retention of electrolytes. and the like. Also. these systems must be removed each month for the mens rual period to occur.

2 or the wearer will be likely subjected to the discomfort of break through bleeding. and the like.

In the main. progcstational agents used in these prior studies have been the highly potent synthetic progestational agents such as chlormadione acetate. megestrol acetate, melengestrol acetate. and medroxyprogesterone acetate. and the like. Such compounds are presently active and they have long half-lives in the body and are known to produce systemic progestogen effectsv Even when applied to the uterus or vagina. it is not unreasonable to expect that continuous administration of these highly active compounds may produce some unwanted and undesirable side reactions. One prior art investigator has used progesterone as the progcstational agent in such devices. Sce Scommegna ct al. Intrauterine Administration of Progesterone by a Slow Releasing Device," presented at annual meeting of the American Fertility Society. April I969.

Now. it has been unexpectedly found that many of the above disadvantages can be substantially overcome by using a steroid having a double bond as the anti fertility means for interfering with the female reproductive process. The use of double bond steroids for the purpose of this invention. that is. as anti-fertility agents is considered unexpected since many of these steroids are presently free of progestational activity until acted upon in situ. they can act as anti-fertility agents independent of this activity. and many of the steroids are active at concentrations beyond any apparent progestational activity. Also. the steroid used according to the mode and manner of the present invention have the additional adumtage of acting locally. and if any excess is systemically absorbed. the likelihood of unwanted side effects or reactions are substantially decreased since the steroid used is essentially in a presently inactive form. Additionally. it has been unexpectedly found that the anti-fertility steroids used herein can be incorporated into various and different intrauterine devices and released therefrom for interfering with the female reproductive process at essentially acceptable and operable dosage amounts.

SUMMARY OF THE INVENTION Accordingly. it is an object of this invention to pro vide an improved birth control device which locally applies an antifertility locally acting steroid to the uterine walls for cssentailly local effects.

Still another object of the present invention is to provide an intrauterine device containing a biologically acceptable steroid having a double bond that is released by diffusion from the device in an amount effective for anti-fertility effects while simultaneously substantailly avoiding the systemic effects generally known to the art.

Yet still another purpose of the invcntion is to provide an intrauterine device charged with a steroid use ful for interfering with the female animal reproductive process at a local situ while simultaneously avoiding systemic progestational effects.

Another object of this invention is to provide a birth control device containing and gradually releasing an antifertility agent having local fertility controlling ac tivity but stubsantailly no systemic progcstational activity. and wherein the device releases the steroid by a process called diffusion.

in attaining these objects. one aspect of this invention resides in an intrauterine dcvicc for the predetermined wherein A is a member selected from the group consisting of C- OH. C....OH. C-OR. and CWOR; B is a member selected from the group consisting of C-OH. C-OR. C....OH. and C....OR; provided that B is not when A is and the double bond is at the A position; R is a member selected from a pharmaceutically acceptable acid and a lower alkyl group of l to 8 carbons, wherein the alkyl is ethyl. propyl. butyl and the liek. said antifertility agent having a sole double bond at the A, A or A position or double bonds at the A and A positions when A and B are both respectively; and wherein the anti-fertility agent is metered by the polymeric material to the uterus.

Other objects. features and advantages of this inven tion will become more apparent from the following description. drawings and the accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS In the drawings which are not drawn to scale. but rather are se forth to illustrate various embodiments of the invention. there appears as follows:

FIG. 1 is a side elevational view showing an intrauterine device of the loop' type as disclosed in US. Pat. No. 3.250.271. in operative position within the mature female animal uterus.

FIG. 2 is an enlarged perspective view of the bracketed segment of the intrauterine device of FIG. 1. illustrating according to this invention the anti-fertility steroid confined in the lumen of the material of the intrau terine device.

FIG. 3 is an enlarged cross-sectional view of the bracketed segment of the intrauterine device of FIG. 1. illustrating alternative intrauterine devices according to this invention having the anti-fertility uterine acceptable steroid embracing a double bond, distributed in the material of the intrauterine device.

FIG. 4 depicts an intrauterine drug release platform comprised of a release rate material having the useful, pharmaceutically acceptable steroid for interfering with the reproductive process integral therein.

In the drawings and in the specification. like parts in related figures are identified by like numbers. The terms appearing earlier in the specification and in the description of the drawings. as well as embodiments thereof. are further described elsewhere in the disclo sure.

DETAILED DESCRIPTION OF THE INVENTION i wherein A is C'OH. C....OH. C-OR. or C. OR; B is C-OH, C-OR. C....OH. or CWOR; provided that B is not in and the double bond is at the A position; R is the residue of a pharmaceutically acceptable acid or a lower when A is alkyl group; said anti-fertility agent having a sole double bond at the A, A or A position or double bonds at the A and A positions when A and B are both respectively. Symbols A, A and A correspond to unsaturation at the 1,2; 4,5 and 5,6 positions, respectively. The dashed line between the carbon atoms and the hydroxyl, either, or ester functions represent a sub stituent in the H-COflfigUfalliOfl while the solid line between the carbon atom and such functions represent a substituent in the ,B-configuration.

More specifically, the useful steroid anti-fertility compounds of the invention can have the following formula as embraced in the generic formula:

wherein A is a member selected from the group consisting of C-OH. C....OH, OCR and C....OR; and B is a member selected from the group consisting of wherein A is a member selected from the group consisting of C-OH, C....OH, C-OR and C....OR; B is a member selected from the group consisting of C-OH, C-OR, C....OH and C....OR; R [S as previously described, and with the proviso that B is not Representative useful steroids embraced within the above A formula include A -pregnen-3a-ol-2O-one; N-pregnen-FrB-ol-ZO-one; N-pregnenJB-ol-QOB-ol; N-pregnen-3B-ol-20a-ol; A -pregnen-3-one-20a-ol; A-pregnen-3-one-2OB-ol; and the like. These steroids are commercially available and they are fully described in Steroids, by Fieser and Fieser, pages 572 to 573. 1959, published by Reinhold Publishing Corp.

Also, more specifically, the useful steroid antifertility compounds used by this invention also include the following compounds as embraced in the general formula:

when A is CH B wherein A is a member selected from the group consist ing of C-OH, C....OH, C-OR and C:...OR; B is a member selected from the group consisting of C-OH, C-OR, C,...OH and C....OR', and R is as previously described. Representative examples include A-pregnen-3B-ol-20-one; A'-pregnen 3a-ol-20-one; A-pregnen-3-one-20a-ol; A -pregnen-3-one-20i3-ol, and the like. These steroids are commercially available and they are described in Steroids, by Fieser and Fieser, pages 539 to 599, l959, published by Reinhold Publishing Corp.

The useful steroid anti-fertility compounds used by the invention also include the following compounds as embraced in the general formula:

wherein A and B are both C-Ol-l, C....OH and mixtures thereof as represented by A"-pregnen-3-20-dione. These steroids are easily prepared according to teachings in Steroids, by Fieser and Fieser. pages 539 to 599, I959.

The useful steroids that can be used in an effective amount for preventing reproduction include the following compounds as embraced in the general formula:

wherein A is a member selected from the group consisting of C....OH, C-or and C....OR; B is a member selected from the group consisting of C-OH, R, C....()H and C....OR, wherein A is as previously defined. Representative examples include A pregnene-3a-ol-20'one; A -pregnene-3a-ol-20/3-ol; and the like. These steroids can be prepared according to techniques set forth in the above references.

The anti-fertility steroid is confined within a polymeric steroid release rate material so that when inserted in the uterus the material continuously meters by diffusion. the flow of an effective amount of the steroid to the uterus of a fertile female capable of species re production. by passage of the agent by diffusion through the polymeric material at a controlled ra These steroids, when applied locally to the uterus. Lit not generate significant unwanted systemic progcstutional activity, and they are therefore useful for releu from devices otherwise known intrauterine devices or intrauterine platforms per se, as an effective. reliable and safe means of birth control.

The above compounds can also be used in the pharmacologically acceptable derivatives thereof, such as the derivatives of their hydroxy or keto groups. Such derivatives should convert to the parent compounds upon release from the intrauterine device or intrauterine platform by enzymatic transformation, pH assisted hydrolysis, and the like. They are used to enhance the release properties of the anti'fertility agent from the uterine capsule. Suitable derivatives include: hydrolizable esters with pharmaceutically acceptable acids, such as the formate acetate, propionate, butyrate. valerate, caproate, hexanoate, heptanoate, caprylate, maleate, citrate, perlargonate, succinate, tartrate, fumarate, malate, aseorbate, sulphate, phosphate and the like; ethers. especially lower alkyl ethers and ketals. Of course, the acyl radical of other organic carboxylic acids containing l to 18 carbons can be used herein. These include the residue of hydrocarbon carboxylic acids. alkanoyl, alkenoyl and the like. These residues are known to the art in U.S. Pat. Nos. 2,873,271, 3,415,818, and the like.

This invention release and use of the disclosed steroids for interfering with the reproductive process at a local level substantially free of systemic progestational effects is both totally unexpected in the light of the prior art and because steroids are known for their structural specificity. That is, the properties of steroids resides therein. The A and A steroids as described immediately above have now been found as useful according to the mode and manner of this invention, and also for releasing from devicesv And, although not wanting to be bound by any other particular theoretical additional explanation for the effectiveness of the present invention, it is noted that especially for steroids having a A and substituted with a 3-ol and ZO-one undergo conversion to progesterone at a 5 percent level. This occurs in the presence of the endometrium enzyme 3,8-ol dehydrogenase-isomerase system and because of the characteristic ofenzyme template specificity this rate of conversion is structure specific and it is not readable on other steorids. Life Sciences, by Sweat and Bryson, Vol. 8, Part li, pages 107 to ll], l969, Pergamon Press, Great Britain. The reported rate of conversion for this compound is substantially beneath the rate needed for the present purpose and because of in situ metabolism. Accordingly, the use of these steroids for fertility control circumscribed within the uterus, without undesired systemic progestational activity. and if some enters it does so in an essentially inactive form, is a novel physiologic means of birth control as provided by the invention. Renzinglons Pharmaceutical Sciences, Fourteenth Edition, pages 1049 to i050, 1970. Mack Publishing Company, Easton, Penna.

The polymeric release rate controlling material can be of suitable shape known to those skilled in the art to promote insertion and retention in the uterine cavity over a short to a prolonged period of time. Alterna tively, the polymeric release rate controlling material can be attached to an intrauterine device or an intrau erine platform which is effective for the short to long .rm ietcntion of said material in the female uterine aiity. ln general. suitable intrauterine devices can be oi'italnetl by distributing the anti-fertility agent in a solid or gel matrix of the polymeric rate controlling material; microencapsulating the agent and then distributing the microcapsules in the polymeric rate controlling 9 material or confining the agent within the polymeric rate controlling material.

With regard to known shapes for promoting retention in the cavity, such devices can take various configurations, such as the conventional Lippes loop", as disclosed in U.S. Pat. No. 3,250,271, Marguiles' spiral," as disclosed in US. Pat. No. 3,200,815. Birnbergs bow," as disclosed in U.S. Pat. No. 3,230,953, and the like. or matrix containing the agent suitably affixed to these conventional intrauterine devices. However, the particular configuration or shape of the device forms no part of the present invention. The main purpose of the device, in this invention, is to provide a depot, carrier, or platform, for the continuous administration of the anti-fertility steroid as defined hereinafter to the uterus at a predetermined and controlled rate. Devices which in themselves are effective birth control means, such as the Lippes loop, have their usefulness enhanced while other shapes are rendered effective in the first instance.

For ease of presentation the invention is described with reference to a specific intrauterine shape, which has arbitrarily been selected to be the loop disclosed by Lippes in U.S. Pat. No. 3,250,271. Another suitable intrauterine device is disclosed in copending application Ser. No. 6l,l4l, filed Aug. 5, 1970, now U.S. Pat. No. 3,675,647, for an invention of Bruce B. Pharriss and Max Anliker. The disclosure of that copending ap plication is relied upon and incorporated herein by reference. However, it will be appreciated that this is in no way to be construed as limiting the teaching of this invention. FIG. 1 generically depicts an intrauterine device nested within a uterine cavity 16. Device 15 is made of a uterine flexible material and it has a memory for retaining its shape in uterine cavity 16. The illustrated uterine cavity 16 is of standard anatomy having sides 23 as well as a fundus uterus 24. A thread 19 is attached to trailing end 17 distant from lead end 18 for manually removing device 15 from uterus 16. Device 15 is seen releasing steroid within female uterus l6. FIGS. 2 and 3 illustrate various embodiments detailing several structures for the loop shaped body as illustrated in FIG. 1.

FIG. 2 illustrates generally, by reference numeral 11, an enlarged segment of an intrauterine device in the shape of a loop." The body 8 of the loop 11 is structured in the form of a container with the anti-fertility solid, steroidal agent it) confined in the lumen 9 of the material of device 15. The release rate controlling walls or surface 12 of device 15 functions to control the rate of release of the anti-fertility steroid 10 to uterus 16. While walls 12 of such device 15 can be of any convenient thickness, satisfactory results can be obtained with thickness of0.0()1 to 0.10 inches and more preferably between 0.005 and 0.05 inches. The diameter of the lumen 10 can be of any convenient size consistent with obtaining reasonable dimension for the overall diameter of the body of device 15. Diameters from 0.05 to 0.2 inch are acceptable. The cross-section of the body 8 can be round or otherwise, with the former preferred for reasons of case of fabrication. The intrauterinc deivce 15 can be fabricated by molding a solid rod of the desired material and overall outside dimension having embedded therein a wire of same diameter as the desired dimensions of the lumen 10. After the molding operation, the wire can be removed resulting in the structure depicted in FIG 2. The device can then be suitably filled with the desired anti-fertility steroidal agent and sealed. The anti-fertility agent. when incorporated into devices ofthe type disclosed in FIG. 2, can be admixed in a suitable carrier, for example, cured silicone, if desired.

FIG. 3 illustrates by general reference numeral 13 an enlarged segment of an intrauterine device 15 in the shape of a loop wherein anti-fertility agent It) as illus trated by crystal dots, is distributed throughout the material forming device 15. The material also serves as the matrix for the controlled rate of release of the antifertility steroid 10 to the uterus 16. A device such as depicted in FIG. 3 can be fabricated by adding the steroid to the matrix material in liquid form in a suitable mold and subsequently converting the matrix to a solid or gel by curing or cooling; or by immersing the solid matrix in the agent or a solution of the agent to effect diffusion of the agent into the matrix.

HO. 4 illustrates an intrauterine device 15 or intrauterine platform within a normal, child bearing woman uterus 16. Device 15 is formed of a single piece of ste roid release rate controlling material having a plurality of waves 22 aligned along each side of device 15. Waves 22 serve to both keep the device in uterus l6 and increase the area for releasing steroid 10 from device 15. A string 19 is fixed to hole 27 at trailing end 20, opposite lead end 21 for removing device 15 from uterus 16. Device 15 touches sides 23 and top 24 of uterus 16.

Devices containing the anti-fertility steroid are formed at least in part of a material permeable as by diffusion to the compounds of Formula I to permit passage of these steroids through the release rate controlling walls or release rate controlling body of the device at a relatively low rate. The rate of passage of the steroid through the wall or body is effected by the mechanisms of permeation and diffusion and it is therefore dependent on the pororsity of the Wall or body or the diffusivity and solubility of the agent in the wall or body, as well as on the wall or body thickness. The mechanism by which diffusion is achieved may be ex plained on the basis of an activity or chemical potential gradient wherein the enclosed substance relieves its internal concentration within the device by spreading out into the adjacent medium. As the migrant diffusing steroid is removed from the outer surface of the material of the device by body uterine fluids and tissue absorption and the like. the diffusive action continues through and from the device until the source of the steroid has been substantially consumed. The anti-fertility steroid will have a definite and characteristic rate of passage through the body of the device which will, in effect, establish the dosage rate and amount of agent released from the surface during a given time interval, This means that selection of appropriate materials for fabricating the device will be dependent on the particular anti-fertility agent to be used. By varying the composi tion, porosity, and thickness of the device wall or body, the release rate per area of device can be controlled; for the walls or body of the device act as solubility membranes or diffusion control systems to regulate or meter the flow of anti-fertility steroid from the device to the uterine walls. Thus, devices of the same surface area cna provide different release rates and therefore daily dosages of the steroid by varying the characteristic of the device. The anti-fertility steroid is metered through the walls or body of the device to the uterus of the female patient. with the rate controlled by the composition. porosity. and thickness of the walls or body of the device. In each instance. the device acts as a depot for the storage and continuous release of the steroid to the uterus.

The amount of useful anti-fertility steroid to be incorporated in the deivce to obtain the desired contraceptive effects or interfer with the reproductive process will vary depending upon the permeability or solubility of the particular steroid to be used. the material employed to fabricate the device and the length of time the device is to remain inserted in the uterus. Since this device is designed to control fertility for an extended period of time. such as 1 hour to 3 or more years, there is no critical upper limit on the amount of steroid incorporated into the device as the device per se meters a regulated amount. The lower limit is determined by the fact that sufficient amounts of the steroid must remain in the uterine device to maintain the desired dosage. In order to achieve a contraceptive effect the daily release dosage from the device should be in the range of between 05 and 150() micrograms per day. and preferably between micrograms and 200 micrograms of steroid per day. Thus. for example. using 200z-hydroxypregn-4-en3-one and with an intrauterine device intended to remain in place for one year. and with a release rate of 200 micrograms of 20a-hydroxypregn-4- en-3-one per day. that is for 24 hours. approximately 80 mg of 20oz-hydroxypregn-4-en-3-one would be in corporated in the device. Generally. the devices will contain 0.1 mg or lower to 5000 mg or higher of steroid for release at the desired rate.

Further. depending on the particular species of female patient to be treated. such as mammals, farm animals. such as cows. sheep, goats and the like. the device of the invention releases a fertility suppressing amount of antifertility steroid in the range of about 0.1 microgram to 10 micrograms per kilogram of body weight per patient per day.

The inventions use of steroids for interfering with the reproduction process is achieved essentially without pyrogenic effects frequently associated with a few of these. The pyrogenicity reported in Chem. AhsL, Vol. 57. page 5243h. 1962 for Med. K1in., Vol. 57. pages 305 to 307. 1962; Chem. Absr.. Vol. 55. pages l79l0d. 1961 for Symp. Dem. Ges. Endukz. pages 69 to 75. 1959; Chem. AbsL. Vol. 55. pages l2639c. 1961 for Syrup. Dem. (jes. Endok. Vol. 6, pages 69 to 75, 1959; Chem. Abxh. Vol. 56. pages 9352g. 1962 to Z. Geburr. u. Gyrmek. Beilagel1 fr.. Vol. 157. pages 46 to 54, 1961; Chem. Abst. Vol. 54. page 25136h. 1960 for Trans. Assoc. Am. Phyiz. Vol. 72, pages 54 to 61, 1959; Chem. AbSL. Vol. 54. page 19.951. 1960. for AMA. ARC/i. Internal Med. Vol. 105. pages 701 to 708, 1960; and

ill

Chem. AbsL. Vol. 51, page 7589d. 1957 for]. CHM. En-

docrr'nol. and Memh. Vol. 17. pages 451 to 453. 1957. is attributed to single and multiple massive doses usually 5 mg to 25 mg administered intramuscularly and intravenously with accompanying systemic effects. Ac cording to the mode and manner of the present inven tion, however. the pyrogenicity is avoided by a dose situ response relationship. The present invention slowly and locally releases the steroid in small amounts over a prolonged period of time to overcome the above re ported disadvantages. The objects of this invention are achieved by releasing locally an effective amount of steriod for interfering with the reproductive process from Sug to 150(Iug over 24 hours. That is. the systemic pyi'ogenic effects that accompany the large doses by intramuscular and intravenous administration are beyond the scope of this invention.

Materials having the ability to control the rate of release of steroid by diffusion in the desired range is herein defined as a release rate controlling material". These materials are those polymers which. in addition to being permeable to and compatible with the antifertility agent and uterine environment. are non-toxic. biologically inert. Exemplary materials include hydro phobic polymers such as plasticized or unplasticized polyvinylchloride. plasticized nylon. plasticized soft nylon. plasticized polyethylene terphthalate. natural rubber. C -C olefins. eg. polyethylene, polyisoprene. polyisobutylene. polybutadicne; silicone rubbers, espe cially the medical grade polydimethylsiloxanes. described in US. Pat. NO. 3.279.996. hydropilic polymers such the hydrophilic hydrogels of esters of acrylic and methacrylic acid (as described in US. Pat. Nos. 2.967.576 and 3.220.960. and Belgian Pat. No. 701.813). modified collagen. crosslinked polyvinylalcohol. and cross-linked partially hydrolyzed polyvinyl acetate. Polymeric materials that tend to be irritating can be used but should be coated with a non-irritating polymeric coating. When plasticizers are used to im part flexibility to the polymer. various non-toxic plasti cizers known to the art can be employed. such as longchain fatty amides. higher alcohols, and high boiling csters such as ditisooctyl) sebacate or di(2cthyl hexyl) phthalate. and the like.

The intrauterine device of the invention is easily fabricated as previously discussed in connection with the description of FIGS. 1 through 4. Using FIG. 3 as an example. steroid is mixed with the matrix material. which can be in solid, semi-solid. or gel-solid form at the time. and distributed therethrough by ballmilling. calendering. stirring. shaking. or the like standard processing means. Where the compound is chemically compatible with monomers or prepolymers used to form the matrix, the agent particles can he added at this earlier stage and thematrix formed in situ. The matrix mate rial. however made and having the agent distributed therethrough, can then be formed to a solid shape by molding, casting. pressing. extruding. drawing. or like processes and conventional techniques. Depending on the material used to form the matrix. curing may be necessary at this stage. This ability to shape the matrix into devices of assorted shapes such as tubes, loops. rods. disks. rings and other highly reproducible shapes of controllable composition. results in ready fabrication of devices with closely controlled characteristics.

Those skilled in the art can readily determine the rate of permeability of a steroid through a polymeric material or selected combinations of polymeric materials. One embodiment that has been found to be eminently well suited is to cast or hot press a film of the material to a thickness in the range of 2 to mils. The film is used as a barrier between a rapidly stirred (e.g. r.p.m.) saturated solution of the agent containing ex cess compound and a rapidly stirred solvent bath. both maintained at constant temperature (typically 37C). Samples are periodically withdrawn from the solvent bath and analyzed for agent concentration. By plotting agent concentration in the solvent bath versus time. the permeability constant P of the membrane is determined by the Ficks First Law of Diffusion.

.46 Slope of plot )1 wherein Q cummulative amount of agent in solvent in micrograms at Q 2 cumulative amount of agent in solvent in microgram at 1 t elapsed time to first sample, i.e., Q

1 elapsed time to second sample, i.e., Q

A area of membrane in cm C saturation concentration of agent in solution It thickness of membrane in cm.

By determining the slope of the plot. i.e., Q (1 t and solving the equation using the known or measured values of A, C, and h, the permeability P constant in cm /time of the material or membrane for a given com pound is readily determined. Of course, this permeability constant is an inherent characteristic of the material for a given compound. Using the above technique, the permeability constant P for select membrane and steroid can be determined. These data can then be employed to design a device of the invention to release the anti-fertility steroid to the uterus in the desired dosage range. Similarly, this experimental procedure or others known to those skilled in the art can be used to determine release rates for matrices and combinations of matrices and matrix with microcapsules of suitable polymeric materials as above disclosed in order to design intrauterine devices of this invention. These examples and like examples can be used to determine the rate of steroid release through different steroid release rate controlling materials are known to the art in J. Pharm. 500.. Vol. 52, pages N45 to 1149, I963; ibid., Vol. 53, pages 798 to 802, 1964; ibid., Vol. 54, pages 1459 to 1464, I965; ibid., Vol. 55, pages 840 to 843, and 1224 to l236, i966; Encyl. Polymer Sci. TechnoL, Vol. 5 and 9, pages 65 to 82 and 794 to 807, 1968; the references cited therein and the like.

Alternatively, in certain cases equation [I below can be employed to design the intrauterine device of this invention with out the use of any experimental data by computations well known to those skilled in the art of polymer permeation. See for example, Advances in Separation and Purzficaliun," Chapter 5. A. S. Michaels, entitled Principals of Membrane Permeation Theory and Practice" (lnterscience Publishers, NY. 1968). initially. of course, it is necessary to select the specific shape and size and thereby establish the surface area of the device and. also, the anti-fertility steroid and uterine acceptable materials which are to be used.

For a compound represented by Formula I having a molecular weight under ca. 900, for example A' -pregnene-3a-ol-20-one, the diffusion coefficient in most non-glassy polymers will be in the range of l X l cm /sec. to 5 X cm lsec. at female mammalian body temperature. in such cases the specific permeation flux of the compound which is defined as the product of the permeation flux .1, and the film thickness. I, through the polymer is given by the equation: J I C* D. wherein J is the permeation flux; C* is the concentration of the compound in the polymer when in saturation with the solid compound; D is the diffusivity of the compound in the polymer, and I is the film thickness of the polymer wall. The saturation concentration in a particular polymer is ascertainable with good accuracy if the solubility of the compound in an organic liquid of chemical constitution similar to that of the poly mer is known. For example, the solubility of a particular compound in poly(vinyl acetate) will be nearly the same as its solubility in ethyl acetate; in polyethylene, nearly the same as in octane or cyclohexane, etc.

Thus, the solubility of A -pregnene-3a-ol-20-one in polyethylene at C is estimated to be about 2 gm/IUOO gm. Hence, the specific permeation flux of A -pregnene-3a-ol-20-one through low density polyethylene can be calculated to be: Jt= (2 X 10 gm/gm) (l X 10 cm /sec) 2 X [0 cm /sec wherein C* is 2 X 10 gm/gm; D is assumed to be l X 10" cm lsec.

An intrauterine device designed to release micrograms of A pregnene-3a-ol-2Oone per day. or 3 X 10 grams/day. which has an external surface area of 5 cm if comprised of low density polyethylene, must therefore have an external membrane wall thickness of:

of 0.3 millimeters l 2 mils) wherein 86,400 is the number of seconds in a day; 3 X 1'0 is the cm grams of pregnenolone to be released per day and 5 cm is the external surface area of the device. Thus, using this technique it can be determined that an intrauterine device having a surface area 5 cm and made of a polyethylene film 12 mils thick, will release 30 micrograms of A -pregnene-3A-ol-2O-one per day.

The following examples will serve to illustrate the invention without in any way being limiting thereon; as these examples and other examples will become apparent to those versed in the art in the light of the present disclosure, drawings and accompanying claims.

EXAMPLE 1 An intrauterine device is fabricated of low demsity commercially available polyethylene tubing of circular cross-section, measuring 7 cm in extended length and 3 mm outside diameter having a total external surface area of about 5 cm. The device has a shape ofa hollow coil of total curvature of 480 and outside coil diameter of 2 cm having a bore of 2.4 mm diameter through its entire length. A 12 month supply of A' -pregnene-3a-ol- 20-one is inserted into the device. The amount is computed to be:

(30 X 10 mg/day) (365 days/yr) 11 milligrams Since the density of the steroid is of the order of 1.2 gm/cc, the volume occupied by the compound is about 0.0] cc which can be easily inserted as a core in the above device. An amount in the order of 10 percent to 30 percent in excess of l i milligrams can be used. if desired, to insure adequate delivery during the time pe riod.

The ends of the uterine acceptable device are sealed using polytetrafluoroethylene plugs and cyanoacrylate adhesive commercially available as Eastman 9l0. The device can be used for conception control by surgical insertion into each uteirne horn of a I20 pound ewe. Each intrauterine device rleeases and supplies approximately 30 micrograms of the steroid per day for a pcriod in excess of one year. lt is highly preferred that the device be placed in both uterine horns in order to insure that conception is prevented.

EXAMPLE 2 The procedure set forth in Example 1 was repeated in the present example, except that the steroid used in these examples was 3B,2OBdihydroxypregn-S-ene. BB-hydroxypregn--en-20 one or 3B-20a-dihydroxy pregn'S-ene.

EXAMPLE 3 Twenty-five milligrams of A pregnene-3a-ol-20a-o| are inserted into a hollow tube of low density polyethyl ene cm in length and having an inside diameter of 2.6 mm and an outside diamter of 3.0 mm. The tube is sealed on the same manner in Example 1 above. An intrauterine device in the shape of a Lippes loop is then fabricated from ethylenevinylacetate copolymer (84 percent ethylene. l6 percent vinylacetate) by injection molding. having a total straightened length of 4.5 inches. The length of polyethylene tubing prepared above is secured to the body of the loop with cyanoacrylate Eastman 910 adhesive. This device can be used to control conception of a 150 pound ewe by insertion through the cervical os into the uterus. The device will release approximately 60 micrograms of steorid per day for a period in excess of 1 year. Ethylene vinylacetate copolymer as used for the fabrication of the intrauterine device does not constitute a part of this invention. Ethylene vinyl acetate copolymer used in manufacturing drug delivery devices, including intrauterine devices. is the invention disclosed and claimed in copending United States Patent application Ser. No. 80.531. filed Oct. 14. 1970. now abandoned. and United States Patent application Ser. No. 28l.446. filed on Aug. l7. 1972. Both of these applications are assigned to the same assignee of this invention. and they are incorporated herein by reference.

EXAMPLE 4 Uterine devices providing effective fertility suppression are prepared by repeating the procedure of Examples l to 3. with substitution of the steroid cyclopentaphenanthrene by each of the following anti-fertility agents:

3B,2OB-dihydroxypregn-5-ene 38.20a-dihydroxypregn-5-ene ZOa-hydroxypregn-5-en-3-one ZOB-hydroxypregn-5en-3-one pregn'S-enJJO-diOne EXAMPLE 5 Uterine devices providing effective fertility suppression are prepared by repeating the procedure of Examples l to 3. with substitution of the steorid cyclopentaphenanthrene by the following anti-fertility agent:

3B-hydroxypregnl cne-2U-one EXAMPLE 6 Uterine devices providing effective fertility suppression are prepared by repeating the procedure of Exam ples l to 3, with substitution of the steroid cyclopenta' phenanthrene by each of the following anti-fertility agents:

3B-hydroxypregn-4-en-ZO-one 3B acetoxypregni-en-Zdone 16 3B.20B-dihydroxypregn-4-ene 3B,20a-dihydroxypregn-4-ene 20a-hydroxypregn4-en-3-one ZOa-acctoxypregn-4-en 3-onc 20a-hydroxypregn-4-en-3-one ZOB-acetoxypregn-i-en-3-one EXAMPLE 7 Uterine devices providing effective fertility suppression are prepared by repeating the procedure of Examples l to 3, with substitution of the steroid cyclopentaphenanthrene by the following anti-fertility agent:

A"'-pregnen-3.20-dione EXAMPLE 8 An intrauterine device made according to Examples i to 4 and shaped like a wavy triangle is made from film. release rate silicone polymer charged therethrough with 3a,20(3diacetoxypregn-4-ene. The device will release 25 to 30 micrograms of the esterified steroid per day for controlling fertility.

This invention provides a reliable means of fertility control. By releasing selected pharmaceutically acceptable anti-fertility steroids to the uterus or to the uterine horns. the desired local effect is achieved without obtaining unwanted and possibly toxic systemic progestational activity, and other side effects which attainment is unexpected in the light of the prior art. And. while the invention has been described with reference to certain preferred embodiments thereof. and wherein the improvement is described in details. those skilled in the art will appreciate that various modifications. changes, omissions and substitutions can be made without departing from the spirit of the invention. It is intended. therefore. that the invention be limited only by the scope of the following claims.

I claim:

1. An intrauterine device adapted for insertion and placement in a uterine cavity for the administration of a pharmaceutically acceptable antifertility steroid to the cavity, said device comprising a matrix formed of a non-toxic biologically inert polymeric release rate controlling material containing a locally. contraceptively active steroid and permeable to the passage of the steroid. having the structural formula:

wherein A is a member selected from the group consisting of 00H. C...OH, C-OR and C...OR: B is a member selected from the group consisting of C-Ol-l. CWOH. OCR and C...OR; R is a member selected from the group consisting of the acyl moiety of a pharmaceutically acceptable acid of l to l8 carbons and a lower alkyl of l to 8 carbons. said steroids having a sole double bond at A A or A positions, with a double bond at the A and A position when A and b are both provided that B is not when A is and the double bond is at the A* position, and wherein the device when placed in a uterus, meters the flow of an effective amount of the steroid up to l500 micrograms per day for an antifertility effect through the material at a controlled and continuous rate over a pro longed period of time, essentially without systemic progestational effect.

2. An intrauterine device adapted for insertion in the uterine cavity for administration of a pharmaceutically acceptable antifertility steroid. said device comprising a matrix formed of a nontoxic biologically inert polymeric release rate controlling material containing 0.l mg to 5 g of a locally, contraceptively active steroid and permeable by diffusion to the passage of the steroid having the structural formula:

Gil B CH wherein A is a member selected from the group consist ing of C-OH, C...OH, C-OR and CHOR; B is a member se lected from the group consisting of a lower alkyl of l to 8 carbons and the acyl group of a pharmaceutically acceptable carboxylic acid of l to 18 carbons, and wherein the device when placed in a uterus, meters the flow of an effective amount of the steroid up to 1500 mircograms per day for an antifertility effect through the polymeric material at a controlled and continuous rate over a prolonged period of time essentially without progestational effects,

3. An intrauterine device adapted for insertion in a uterine cavity for administration of a pharrnaceutically acceptable antifertility steroid to the cavity, said device comprising a matrix formed of a nontoxic biologically inert polymeric release rate controlling material con taining 0,1 mg to 5 g ofa locally, contraceptively active steroid and permeable by diffusion to the passage of the steroid having the structural formula:

wherein A is a member selected from the group consisting of C-OH. C...OH, C-OR and C...OR; B is a member selected from the group consisting of C-OH, C-OR, C...OH and CWOR; R is a member se lected from the group consisting of a lower alkyl of l to 8 carbons and the acyl group of a pharmaceutically acceptable acid of l to 18 carbons, and with the proviso that B is not when A is and wherein the device when placed in a uterus, meters the flow of an effective amount of the steroid up to 1500 micrograms per day for an antifertility effect through the material at a controlled and continuous rate over a prolonged period oftime essentially without systemic progestational effects.

4. An intrauterine device adapted for insertion in the uterine cavity for administration of a pharmaceutically acceptable antifertility steroid, said device comprising a matrix formed of a non'toxic biologically inert polymeric release rate controlling material containing therein 0,] mg to 5 g ofa locally, contraceptively active steroid and permeable by diffusion to the passage of the steroid having the formula:

wherein A is a member selected from the group consisting of C-OH, CWOH, C-OR and (,.,()R; B is a member se lected from the group consisting of OOH, COR, C...OH and C...OR; R is a member selected from the group consisting of lower alkyl of l to 8 carbons and the acyl group ofa pharmaceutically acceptable organic carboxylic acid of l to l8 carbons, and wherein the device when placed in the uterus me ters the flow of an effective amount of the steroid up to 1500 micrograms per day for an antifertility effect through the material at a controlled and continuous rate over a prolonged period of time essentially without systemic progestational effect.

5. An intrauterine device adapted for insertion in the uterine cavity for administration of a pharmaceutically acceptable antifertility steroid to the cavity, said device comprising a matrix formed of a non-toxic biologically inert polymeric release rate controlling material containing therein O.l mg to g of a locally, contraceptively active steroid and permeable by diffusion to the passage of the steroid of the formula:

wherein A is a member selected from the group consisting of C...OH, COR and C...OR; B is a member selected from the group consisting of V C-OH, C-OR, C...OH and C...OR; and R is a member selected from the group consisting of a lower alkyl group of l to 8 carbon atoms, and the acyl radical of a pharmaceutically acceptable carboxylic organic acid of l to 18 carbons, and wherein the device when placed in the uterus meters the flow of an effective amount of the steroid up to 1500 micrograms per day for an antifertility effect through the material at a controlled and continuous rate over a prolonged period of time substantially without systemic progestational activity.

6. An intrauterine device adapted for insertion in the uterine cavity for administration of a pharamceutically acceptable antifertility steroid to the cavity, comprising a matrix formed of a non-toxic biologically inert polymeric release rate controlling material containing therein Oil mg to 5 g ofa locally. contraceptively active steroid and permeable by diffusion to the passage of the steroid having the formula:

wherein A and B are selected from the group consisting (-OH, CmOH, C-OR and CWOR', and R is a member selected from the group consisting of a lower alkyl of l to 8 carbons and the residue of a pharmaceutically acceptable organic carboxylic acid containing from I to [8 carbon atoms, and wherein the device, when placed in the uterus, meters the flow of an effective amount of the steroid up to l500 micrograms per day for an antifertility effect through the material at a controlled and continuous rate over a prolonged period of time substantially without systemic progestational ac tivity.

7. An intrauterine device adapted for insertion and piacement in a uterine cavity, said device comprising a reservoir surrounded by a wall formed of a non-toxic, biologically inert polymeric release rate controlling material permeable to the passage of steroid by diffusion with the reservoir eontianing an antifertility steroid of the structural formula:

is B

wherein A is a member selected from the group consisting of C-OH, C...OH, C-OR and C...OR; B is a member se lected from the group consisting of C-OH, C...OH, C-OR and C...OR; R is a member se lected from the group consisting of the acyl moiety of a pharmaceutically acceptable acid of l to [8 carbons and a lower alkyl of l to 8 carbons, said steroids having a sole double bond at A N or A positions, with a double bond at the A and A position when A and B are both and provided that B is not when A is maceutically acceptable antifertility steroid to the cavit said device comprising a reservoir surrounded by a wall formed of a non-toxic biologically inert polymeric release rate controlling material permeable to the passage of steroid by diffusion. with the reservoir containing 0.1 mg to g of a locally. contraceptively active steroid and having the structural formula:

wherein A is a member selected from the group consisting of C-OH. CHOH. C-OR and CmOR; B is a member selected from the group consisting of a lower alkyl of l to S carbons and the acyl group of a pharmaceutically acceptable carboxylic acid of l to 18 carbons. and wherein the device. when placed in a uterus. meters the flow of an effect amount of the steroid up to i500 micrograms per day for an antifertility effect through the material at a controlled and continuous rate over a prolonged period of time essentially without progestational effects.

9. An intrauterine device adapted for insertion in the uterine cavity for administration of a pharmaceutically acceptable antifertility steroid. said device comprising a reservoir surrounded by a wall formed of a non-toxic biologically inert polymeric release rate controlling material permeable to the passage of steroid by diffusion. with the reservoir containing U.l mg to 5 g of a lo- Cally. contraceptively active steroid having the strucural formula:

wherein A is a member selected from the group consist ing of C-OH. C...OH. C-OR and C...OR'. B is a member selected from the group consisting of OOH. C-OR. C...OH and C...OR; R is a member se lected from the group consisting of a lower alkyl of l to 8 carbons and the acyl group of a pharmaceutically acceptable acid of l to 18 carbons. and with the proviso that B is not when A is and wherein the device. when placed in a uterus. meters the flow of an effective amount of the steroid up to 1500 micrograms per day for an antifertility effect through the material at a controlled and continuous rate over a prolonged period of time essentially without systemic progestational effects.

10. An intrauterine device adapted for insertion in the uterine cavity for administration of a pharmaceutically acceptable antifertility steroid, said device comprising a reservoir surrounded by a wall formed of a non-toxic biologically inert polymeric release rate controlling material permeable to the passage of steroid by diffusion, said reservoir containing 0.l mg to 5 g of a locally. contraceptively active steroid having the structural formula:

Cili

wherein A is a member selected from the group ct'msisting of C-OH. C...()H. C-OR and CmOR; B is a member selected from the group consisting of C-OH. C-OR. CmOHland C...()R; R is a member selected from the group consisting of lower alkyl of l to 8 carbons and the acyl group of a pharmaceutically acceptable organic carboxylic acid of l to l8 carbons. and wherein the device, when in the uterus. meters the flow of an effective amount of the steroid up to i500 micrograms per day for an antifertility effect through the material at a controlled and continuous rate over a prolonged period of time essentially without systemic progestational effect.

ll. An intrauterine device adapted for insertion in the uterine cavity for administration of a pharmaceutically acceptable anti-fertility steroid to the cavity comprising a reservoir surrounded by a wall formed of a uterine acceptable non-toxic biologically inert polymeric release rate controlling material permeable to the passage of steroid by diffusion with the reservoir containing (H mg to 5 g of a locally. contraceptively active steroid of the formula: C111 B CH wherein A is a member selected from the group consisting of C..,OH C-OR and C.. OR, B is a member selected from the group consisting of C-OH, C-OR, C...OH and C..OR: and R is a member selected from the group consisting of a lower alkyl group of l to 8 carbon atoms and the acyl radical of a pharmaceutically acceptable carboxylic organic acid of l to 18 carbons. and wherein the device. when placed in the uterus. meters the flow of an effective amount of the steroid up to 1500 micrograms per dayfor an antifertility effect through the material at a controlled and continuous rate over a prolonged period of time substantilly without systemic progestational activity.

12. An intrauterine device adapted for insertion in the uterine cavity for administration of a pharmaceutically acceptable antifertility steor id. the device comprising a reservoir surrounded by a wall frmed ofa nontoxic biologically inert polymeric release rate controlling material permeable to the passage of steroid by dif fusion, said reservoir containing 0-.l mg to 5 g of a lo callycontraceptively active steroid of the formula:

wherein A and B are selected from the group consisting COH. CHOH. C-OR and CmORyand R is a member selected from the group consisting of a lower alkyl of l to 8 carbons and the residue of a pharmaceutically acceptable organic carboxylic acid containing from l to 18 carbon atoms, and wherein the device, when placed in the uterus. meters the flow of an effective amount of the steroid up to 1500 micrograms per day for an antifertility effect through the material at a controlled and continuous rate over a prolonged period of time substantially without systemic progestational actlvity.

Non-Patent Citations
Reference
1 *Hohn et al., J. Physiol., III:174-183(1950) "The Response of the Rabbit's Endometrium to Uterine Implants of Progesterone and Other Steroids".
2 *Hohn J. Endocrin, 10:358-362(1954) "Direct Progestational Action of Progesterone and Certain Related Steroids on the Endometrium of the Rhesus Monkey".
3 *Robson et al., J. Physiol., 115:313-316(1951) "Response of the Cat's Endometrium to Implantation of Different Steroids".
4 *Sweat et al., 8(II):107-111 Jan. 15, 1969, Life Sciences "Conversion of Pregnenolone to Progesterone by Human Endometrium in Vitro".
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4016270 *Oct 31, 1975Apr 5, 1977Alza CorporationMethod for treating dysmenorrhea with a uterine therapeutic system
US4018919 *Jul 16, 1975Apr 19, 1977Eli Lilly And CompanySequential contraceptive method using two types of progestational agents
US4314557 *May 19, 1980Feb 9, 1982Alza CorporationDissolution controlled active agent dispenser
US4857049 *Aug 5, 1986Aug 15, 1989Kortum, Inc.Method and apparatus for inducing immunological and resistant response in mammary glands
US4906475 *Feb 16, 1988Mar 6, 1990Paco Pharmaceutical ServicesEstradiol transdermal delivery system
US6436069Mar 25, 1996Aug 20, 2002Advanced Animal Technology LimitedSubstance delivery device
US6569464 *Mar 30, 2001May 27, 2003Council Of Scientific & Industrial ResearchAntifertility agent comprises coelomic fluid extract which is obtained from an Indian earthworm, Pheretima posthuma, belonging to the phylum, Annelida
US8361272Jun 27, 2007Jan 29, 2013Ferring B.V.Polyurethane elastomers
US8361273Sep 6, 2012Jan 29, 2013Ferring B.V.Polyurethane elastomers
US8460707Mar 26, 2012Jun 11, 2013Ferring B.V.Stabilised prostaglandin composition
US8491934Jul 28, 2005Jul 23, 2013Ferring B.V.Stabilised prostaglandin composition
US8524254Oct 15, 2007Sep 3, 2013Ferring B.V.Bioresorbable polymers
US8557281Jul 13, 2010Oct 15, 2013Ferring B.V.Water-swellable polymers
US8628798Aug 10, 2012Jan 14, 2014Ferring B.V.Water-swellable polymers
US8709482May 31, 2013Apr 29, 2014Ferring B.V.Stabilised prostaglandin composition
Classifications
U.S. Classification424/432, 604/515, 604/57, 128/833, 514/179, 424/486
International ClassificationA61F6/00, C07J7/00, A61F6/14, A61K9/00, A61M31/00
Cooperative ClassificationC07J7/007, A61F6/142, A61K9/0039, A61M31/002
European ClassificationA61F6/14B, A61M31/00D, A61K9/00M8D, C07J7/00B2B