Delayed/sustained release of macromolecules

Claims

What is claimed is:

1. A drug delivery device for the controlled administration of a macromolecular drug, said device comprising:

(a) a pharmaceutically acceptable carrier;

(b) a macromolecular drug having a molecular weight greater than about 1,000 mixed with said carrier; and

(c) an initially partially-hydrated, non-biodegradable, hydrogel rate-limiting membrane, wherein said membrane:

(i) comprises a homopolymer or a copolymer material surrounding said carrier and drug, and

(ii) has an initial water content such that it is substantially non-permeable to said macromolecular drug.

2. The drug delivery device of claim 1 wherein said carrier is saturated with said drug and wherein an excess of said drug in a solid state is disposed in contact with said drug-saturated carrier.

3. The drug delivery device of claim 1 wherein said membrane is initially hydrated to such an extent that it is structurally manipulable.

4. The drug delivery device of claim 1 wherein said membrane comprises a crosslinked HEMA homopolymer.

5. The drug delivery device of claim 1, which is a monolithic reservoir.

6. The drug delivery device of claim 1 wherein said carrier is silicone oil.

7. A device for the delayed/sustained release of a compound, said device comprising:

(a) a macromolecular compound having a molecular weight greater than about 1,000;

(b) a carrier having said macromolecular compound mixed therewith; and

(c) an initially partially-hydrated, non-biodegradable, hydrogel rate-limiting membrane, wherein said membrane:

(i) comprises a homopolymer or a copolymer material surrounding said carrier and macromolecular compound,

(ii) is substantially non-permeable to said macromolecular compound when in said initially partially-hydrated state, and

(iii) is hydratable, when placed in a delivery environment, to become permeable to said macromolecular compound.

8. The drug delivery device of claim 1 useful as an ocular insert.

9. The drug delivery device of claim 1 wherein said membrane is selected from the group of crosslinked and non-crosslinked homopolymers or copolymers consisting of: HEMA, GMA, HEMA/GMA, HEMA/MMA, GMA/MMA, and HEMA/GMA/MMA.

10. The drug delivery device of claim 9, which is a reservoir, wherein said carrier is silicone oil.

11. The drug delivery device of claim 9 useful as an ocular insert.

12. The drug delivery device of claim 1 wherein said macromolecular drug comprises a hydrophilic polypeptide.

13. The drug delivery device of claim 1 wherein said macromolecular drug comprises a luteinizing hormone-releasing hormone analog or a pharmaceutically acceptable salt thereof.

14. The drug delivery device of claim 13 wherein said carrier is saturated with said drug and wherein an excess of said drug in a solid state is disposed in contact with said drug-saturated carrier.

15. The drug delivery device of claim 13 wherein said analog is a luteinizing hormone-releasing hormone agonist or a pharmaceutically acceptable salt thereof.

16. The drug delivery device of claim 13 wherein said analog is a luteinizing hormone-releasing hormone antagonist or a pharmaceutically acceptable salt thereof.

17. The drug delivery device of claim 13 wherein said analog is nafarelin acetate.

18. The drug delivery device of claim 17 wherein said membrane is initially hydrated to a water content of less than about 30%.

19. The drug delivery device of claim 17 wherein said membrane is hydratable to an equilibrium water content of about 35%-45%.

20. The drug delivery device of claim 17 wherein said membrane is hydratable to an equilibrium water content of about 39%.

21. The drug delivery device of claim 13 wherein said analog is aza-Gly.sup.10 nafarelin acetate.

22. The drug delivery device of claim 1 wherein said membrane is hydratable to an equilibrium water content such that it limits the diffusion of said macromolecular drug from said carrier to a delivery environment.

23. The drug delivery device of claim 1 wherein said macromolecular drug is selected from the group consisting of: hormonally active polypeptides, mammalian growth hormones, mammalian growth hormone-releasing hormones, and polypeptides having thymosin activity.

24. A pharmaceutical formulation for controlled release of a luteinizing hormone-releasing hormone analog, said formulation comprising:

(a) a pharmaceutically acceptable carrier;

(b) an effective amount of at least one luteinizing hormone-releasing hormone analog or a pharmaceutically acceptable salt thereof disposed in contact with said carrier; and

(c) an initially partially-hydrated, non-biodegradable, hydrogel rate-limiting membrane surrounding said carrier, said membrane being:

(i) initially hydrated to a water content of about 5% to less than about 30% by weight before placement in a delivery environment, and

(ii) hydratable to an equilibrium water content of about 30% to about 80% by weight when in a delivery environment.

25. The formulation of claim 24 wherein said analog is a luteinizing hormone-releasing hormone agonist.

26. The formulation of claim 24 wherein said analog is a luteinizing hormone-releasing hormone antagonist.

27. The formulation of claim 24 wherein said analog is nafarelin acetate.

28. The formulation of claim 25 wherein said analog is a nonapeptide or a decapeptide having the formula:

(pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z

or a pharmaceutically acceptable salt thereof, wherein:

V is tryptophyl, phenylalanyl or 3-(1-naphthyl)-L-alanyl;

W is tyrosyl, phenylalanyl or 3-(1-pentafluorophenyl)-L-alanyl;

X is a D-amino acid residue having the formula: ##STR5## wherein R is: (a) a carbocyclic aryl-containing radical selected from the group consisting of naphthyl, anthryl, fluorenyl, phenylanthryl, biphenylyl, benzhydryl and phenyl substituted with three or more straight chain lower alkyl groups; or

(b) a saturated carbocyclic radical selected from the group consisting of cyclohexyl substituted with three or more straight chain lower alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2,2-diphenylmethyl and adamantyl;

Y is leucyl, isoluecyl, nor-leucyl or N-methyl-leucyl; and

Z is glycinamide or --NH--R.sub.1,

wherein R.sub.1 is lower alkyl, cycloalkyl, fluoro lower alkyl or has the formula: ##STR6## wherein R.sub.2 is hydrogen or lower alkyl.

29. The formulation of claim 28 wherein:

V is tryptophyl or phenylalanyl;

W is tyrosyl;

X is 3-(2-naphthyl)-D-alanyl or 3-(2,3,6-trimethylphenyl)-D-alanyl;

I is leucyl or N-methyl-leucyl; and

Z is glycinamide, NHEt or has the formula: ##STR7##

30. The formulation of claim 24 wherein said luteinizing hormone-releasing hormone analog is (pyro)Glu-His-Trp-Ser-Tyr-3-(naphthyl)-D-alanyl-Leu-Arg-Pro-Gly-NH.sub.2 or a pharmaceutically acceptable salt thereof.

31. The formulation of claim 30 comprising an ocular insert containing 2.0 mg of said luteinizing hormone-releasing hormone analog suspended in 0.2 ml of a silicone oil carrier, wherein said membrane is a 0.5% EGDMA-crosslinked HEMA homopolymer having an initial water content less than or equal to 29%.

32. The formulation of claim 24 wherein said luteinizing hormone-releasing hormone analog is (pyro)Glu-His-Trp-Ser-Tyr-3-(naphthyl)-D-alanyl-Leu-Arg-Pro-aza-Gly-NH.sub .2 or a pharmaceutically acceptable salt thereof.

33. The formulation of claim 32 comprising a reservoir device containing 30.0 mg of said luteinizing hormone-releasing hormone analog suspended in 0.3 ml of a silicone oil carrier, wherein said membrane is a 0.5% EGDMA-crosslinked HEMA homopolymer having an initial water content less than or equal to 29%.

34. The formulation of claim 24, wherein the luteinizing hormone-releasing hormone is an analog of natural luteinizing hormone-releasing hormone, in which the 6-position residue is changed from Gly to a D-amino acid.

35. A formulation according to claim 34, wherein the D-amino acid is D-Ala, D-Lue, D-Phe or D-Trp.

36. A formulation according to claim 34, wherein the D amino acid is D-Leu.

37. A formulation according to claim 34, wherein the D amino acid is D-Trp.

38. The formulation according to claim 24, wherein said carrier is selected from the group:

(a) aqueous systems;

(b) solvents;

(c) solid substrates;

(d) unpolymerized monomers or comonomers;

(e) xerogels;

(f) partially hydrated hydrogels; and

(g) fully hydrated hydrogels.

39. The formulation according to claim 38, wherein said carrier is silicone oil.

40. A drug delivery device for the controlled administration of a macromolecular drug, said device comprising:

(a) a pharmaceutically acceptable carrier;

(b) a macromolecular drug having a molecular weight greater than about 1,000 disposed in contact with said carrier; and

(c) an initially partially-hydrated, non-biodegradable, hydrogel rate-limiting membrane, wherein said membrane:

(i) comprises a homopolymer or a copolymer material surrounding said carrier, and

(ii) has an initial water content such that it is structurally manipulable.

41. The drug delivery device of claim 40 wherein said macromolecular drug is selected from the group consisting of: hormonally active polypeptides, mammalian growth hormones, mammalian growth hormone-releasing hormones, and polypeptides having thymosin activity.

42. The formulation of claim 24 wherein said hydrogel comprises a copolymer of:

(a) 50-100 mole % HEMA;

(b) 0-50 mole % MMA;

(c) 0-10 mole % crosslinking agent; and

(d) 0.01-5 mole % polymerization initiator.

43. The formulation of claim 24 wherein said hydrogel comprises a copolymer of:

(a) 75-100 mole % HEMA;

(b) 0-25 mole % MMA;

(c) 0-5 mole % crosslinking agent; and

(d) 0.01-2 mole % polymerization initiator.

44. The formulation of claim 24 wherein said membrane is selected from the group of crosslinked and non-crosslinked homopolymers or copolymers consisting of: HEMA, GMA, HEMA/GMA, HEMA/MMA, GMA/MMA, and HEMA/GMA/MMA.

45. The formulation according to claim 24, wherein said membrane comprises a 0.32% EGDMA-crosslinked homopolymer of HEMA.

46. The formulation according to claim 24, which is a reservoir device.

47. The formulation according to claim 24 useful as an ocular insert.

48. The device of claim 7 wherein said membrane is hydratable to an equilibrium water content at which it limits the diffusion of said macromolecular compound from said carrier to a delivery environment.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the controlled release of macromolecules, particularly hydrophilic macromolecules. More specifically, it relates to the delayed/sustained release of pharmaceutical compositions, particularly polypeptides such as luteinizing hormone-releasing hormones ("LH-RH"), mammalian growth hormones, mammalian growth hormone-releasing hormones, polypeptides having thymosin-like activity, and the analogs thereof. Specifically, the invention relates to drug delivery devices having an initially partially-hydrated, non-biodegradable hydrogel rate-limiting membrane. These delivery systems, which may include ocular inserts and implantable devices, delay the release of macromolecules until after placement in a delivery environment, and then facilitate a sustained, preferably zero-order release thereof.

2. Background Information

The sustained release of active agents is known to be of value. Particularly in the administration of certain pharmaceuticals, long-term drug delivery has been shown to be most effective in that constant serum levels are obtained and patient compliance is improved. Delaying the release of such agents is also desirable in that an immediate release upon placement in the delivery environment can result in unacceptably high initial concentrations of a drug at the situs of implantation or use.

The examination of synthetic hydrogels for potential biomedical applications (including potential use in certain drug delivery devices) has given rise to various theories regarding mechanisms of diffusion. Lee, Jhon and Andrade have proposed that there are three classes of water in hydrogels, using polyHEMA (hydroxyethyl methacrylate) as their model [Nature of Water in Synthetic Hydrogels, J. Colloid & Interface Sci., 51 (2): 225-231 (1975)]. The first 20% of hydrogel water content, called "Z water", was said to be bound to the polymer matrix. The next 10-12% of water content, called interfacial or "Y water", is partially affected by the polymer matrix. Any additional water imbibed by the gel is relatively unaffected by the polymer matrix; it is called bulk or "X water".

The Lee, et al. model was expanded upon by Kim, Cardinal, Wisniewski and Zentner [Solute Permeation Through Hydrogel Membranes: Hydrophilic vs. Hydrophobic Solutes, ACS Symposium Series (Water in Polymers), 127 (20): 347-359 (1980)]. They concluded that the diffusion coefficients for hydrophilic solutes through hydrogel membranes depends on molecular size and water content; permeation in pure polyHEMA and in polyHEMA crosslinked with a low mole percent of ethyleneglycoldimethacrylate ("EGDMA") was via the pore mechanism, i.e., through the bulk-type water. Hydrophobic solutes were said to diffuse via both pore and partition mechanisms, i.e., respectively through the bulk-type water, and through the interfacial-type and bound-type water. Neither article, however, included any suggestion as to how such diffusion characteristics might be applied to the design of a delayed/sustained delivery device.

Wood, Attwood and Collett have described a model for diffusion of the small hydrophobic molecule salicylic acid (the solute) in hydrogels [The influence of gel formulation on the diffusion of salicylic acid in polyHEMA hydrogels, J. Pharm. Pharmacol., 34: 1-4 (1982)]. Radioactively labelled salicylic acid was added to a HEMA monomer solution and polymerized in situ. The water contents of the resulting gels were measured. Diffusion was measured by quantifying migration of the solute to a gel placed in contact with the sample gels. It was concluded that diffusion occurred primarily through the polymer's pores via the hydrating liquid at higher levels of hydration (more than 31%). At hydration levels below 31%, diffusion was said to occur by dissolution of the solute within the polymer segments; crosslinker concentration did not have any significant effect on diffusion. This was correlated to a change in pore size proportional with percent hydration. Wood, et al. did not, however, offer any teaching as to the effects of percent hydration on delayed/sustained release of hydrophilic macromolecular compositions. For another treatment of the interaction of pore size and diffusion, see Wisniewski and Kim [J. Membrane Sci., 6: 299-308 (1980)].

Controlled and sustained release compositions are known in the art for progesterone. [See Mack, et al., Topics in Pharm. Sci., pp. 265-275 (1983). ] A variety of devices have been described, for example, in the article by Cardinal, Kim, Song, Lee and Kim [Controlled Release Drug Delivery Systems from Hydrogels: Progesterone Release from Monolithic, Reservoir, Combined Reservoir-Monolithic and Monolithic Devices with Rate Controlling Barriers, AIChE Symposium Series, 77: 52-61 (1981)].

Microporous membranes (some including hydrogels) have been used as rate-limiting barriers for such devices, including implants, ocular inserts, coated intrauterine devices and the like, e.g., as described in U.S. Pat. Nos. 3,416,530 (to Ness--entitled "Eyeball Medication Dispensing Tablet"); 3,551,556 (to Kliment, et al.--entitled "Carriers for Biologically Active Substances"); 3,618,604 (to Ness--entitled "Ocular Insert"); 3,828,777 (to Ness--entitled "Microporous Ocular Device"); and 4,548,990 (to Mueller, et al.--entitled "Crosslinked, Porous Polymers for Controlled Drug Delivery").

In U.S. Pat. No. 3,993,072 (to Zaffaroni--entitled "Microporous Drug Delivery Device") and in its parent patents 3,948,254 (entitled "Novel Drug Delivery Device") and 3,854,380 (entitled "Drug-Delivery System"), drug delivery systems are disclosed including a solid inner matrix containing a drug and surrounded by a wall formed of a polymeric membrane (the '072 and '254 patents call for a microporous membrane, the pores of which contain a drug-release-rate-controlling medium).

Some sustained release devices have been described for the delivery of hydrophilic macromolecules, such as polypeptides. For example, European Patent Application Publication No. 0,092,918 (to Churchill, et al.--entitled "Continuous Release Formulations") describes the continuous release of, e.g., luteinizing hormone-releasing hormone, growth hormones and growth hormone releasing factor, from a hydrophobic/hydrophilic non-crosslinked copolymer in which the hydrophobic component is biodegradable and the hydrophilic component may or may not be biodegradable. The composition is described as being capable of absorbing water to form a hydrogel when placed in an aqueous, physiological-type environment.

These prior devices depend on the relationship between the drug's diffusivity in the reservoir, its diffusivity in the delivery environment, and its diffusivity through the membrane. In other words, the diffusivity through the membrane has to be the least of the three, in order for the membrane to serve as a rate-limiting barrier. They all generally rely on Fick's First Law of Diffusion, in which the flux of a solute through a membrane is related to the area and thickness of the membrane, the permeability coefficient of the solute for that membrane material, and the concentration of the solute.

In attempts to apply the prior art relating to hydrogel-based delivery devices to macromolecules, it was discovered that none of the prior devices solve the following problems:

(i) Such devices release macromolecules as soon as the device is in place.

(ii) Such devices cause an initial spike of drug release in the delivery environment.

(iii) Such devices are difficult to handle during implantation, due to their flexibility.

(iv) Non-hydrated (or xerogel) devices are relatively fragile as compared to hydrated hydrogel devices, in that their rate controlling membranes are quite brittle and tend to chip or crack when handled (e.g., during implantation), potentially destroying the sealed reservoir environment required for zero-order release.

The present invention solves all of the foregoing problems through the use of an initially partially-hydrated, non-biodegradable, hydrogel rate-limiting membrane surrounding a suitable carrier and a macromolecular composition.

SUMMARY OF THE INVENTION

Devices are disclosed for the delayed/sustained release of macromolecules having a molecular weight greater than about 1,000, including the administration of macromolecular pharmaceutical compositions. The devices include a carrier, e.g., a pharmaceutically acceptable carrier, saturated with, and containing excess solid of, the macromolecular composition. An initially partially-hydrated, non-biodegradable, hydrogel rate-limiting membrane formed of a homopolymer or a copolymer (a "[co]polymer") material surrounds the carrier. The devices of the invention are provided with the membrane being only partially hydrated; i.e., sufficiently hydrated to be non-brittle, but hydrated only to such an extent that the devices remain structurally manipulable and are substantially non-permeable to the macromolecular composition prior to placement in the delivery environment.

The devices useful in the invention include surgical implants, suppositories, vaginal inserts and ocular inserts of the reservoir-, monolithic-, monolithic reservoir-, and monolithic with rate controlling barrier layer-types. They all have in common the use of a hydrogel rate-limiting membrane to control the release of the active agent(s) contained therein; in the monolithic-type device, the carrier also serves as the rate-limiting membrane.

In one aspect, the invention covers a pharmaceutical formulation designed for delayed/sustained release of an effective amount of a drug over an extended period of time, wherein the formulation comprises at least one hormonally active, water-soluble polypeptide in an effective amount greater then a conventional single dose, suspended in a carrier (e.g., silicone oil or a [co]polymer) and surrounded with a membrane (e.g., initially partially hydrated, crosslinked or non-crosslinked [co]polymers including hydroxyet