US 3926188 A
A three layer laminate drug dispenser comprising a core lamina of a crystalline drug of low water solubility dispersed homogeneously in a polymer matrix of permeability, P, to the drug, the lamina having a thickness, 2t, and a surface area, A, interposed between outer laminas made of a drug release rate controlling polymer of permeability, P', to the drug, each outer lamina having a thickness, t',and the combined, exposed surface area of the outer laminas being A' wherein the expression P T' (1) . >/= 2 t P' and the expression A' P t' (2) k 2>/= 3 . . A t P' k being a constant whose value is dependent upon the geometrical shape of the dispenser.
Description (OCR text may contain errors)
United States Patent 1191 Baker et al.
[ Dec. 16, 1975 1 1 LAMINATED DRUG DISPENSER  Inventors: Richard W. Baker, Bend, Oreg.; Robert M. Gale, San Jose, Calif.
 US. Cl. 128/260; 424/19; 128/213  Int. Cl. A61M 31/00; A61K 27/12  Field of Search 128/156, 260, 268, 2 R,
 References Cited UNITED STATES PATENTS 2,928,770 3/1960 Bardani 424/21 3,184,386 5/1965 Stephenson 424/21 3,416,530 12/1968 Ness 128/260 3,618,604 11/1971 Ness 128/260 3,625,214 12/1971 Higuchi 128/260 3,797,485 3/1974 Urquhart 128/213 3,851,648 12/1974 Brooke 128/260 Primary ExaminerAldrich F. Medbery Attorney, Agent, or Firm-Thomas E. Ciotti; Paul L. Sabatine', Edward L. Mandell 5 7 ABSTRACT A three layer laminate drug dispenser comprising a core lamina of a crystalline drug of low water solubility dispersed homogeneously in a polymer matrix of permeability, P, to the drug, the lamina having a thickness, 2!, and a surface area, A, interposed between outer laminas made of a drug release rate controlling polymer of permeability, P, to the drug, each outer lamina having a thickness, z',and the combined, exposed surface area of the outer laminas being A wherein the expression and the expression A P r 2; (DA 3 I 13 Claims, 5 Drawing Figures U.S. Patent De c. 16, 1975 Sheet 1 of2 3,926,188
DISPENSERS 0F EXAMPLE I TIME HR.)
US. Patent Dec.16, 1975 Sheet2of2 3,926,188
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LAMINATED DRUG DISPENSER BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to a laminated dispenser for dispensing active agents by a diffusion mechanism. More specifically it relates to dispensers comprising a three layer sandwich-type laminate which dispense crystalline drugs of low water solubility.
2. Description of the Prior Art Numerous sustained release dispensers, particularly ones for dispensing drugs, have been developed recently which comprise an active agent which is confined within a polymer and which dispense an agent by a diffusion mechanism in which the agent permeates through the polymer. The aim of these devices is to dispense the drug at a more or less constant rate for a prolonged period of time which results in improved therapy compared to drugs delivered by periodic ingestion of pills, injections or drops. Basically such dispensers are of two types: monolithic and reservoir. In a monolithic device the drug or other active agent is dispersed in a polymer which is permeable to the drug. The time rate of release of agent from such devices has been studied and reported. It is proportional to time A plot of release rate versus time for a monolithic device gives a curve which starts at a high rate and continuously declines. Notwithstanding this varying release rate, monolithic devices have the commercial attractiveness of being inexpensive to make.
T. Higuchi, J. Plzurm. Sci., 50, 874 (I961); T. J. Roseman et al.. J. Plmrm. Sci., 61, 46 (1972); and H. K. Lonsdale. R. W. Baker. Controlled Release of Biologically Active Agents, Ed. C. Tanquery. Plenum Press, New York (1974) In a reservoir device the active agent is confined within a container formed of a polymer which is permeable to the agent. The agent may be neat or combined with a solid or liquid carrier. In copending, commonly assigned applications Ser. Nos. 42,786 and 185,208, filed June 2, 1970 and Sept. 30, 1971, respectively, embodiments of reservoir devices in which the agent release is substantially constant are disclosed. The two basic features of those embodiments which permit such release are: formulating the agent in a liquid or solid carrier whose permeability to the drug is greater than the permeability of the polymer defining the container to the agent; and maintaining the concentration of the agent in the carrier at saturation for the effective dispensing lifetime of the device. For some agents such reservoir embodiments are the only type of diffusion device for dispensing the agent at a practical controlled rate. Such embodiments also provide the advantages of providing a substantially constant release of agent-- which is an important factor as regards efficacy and safety in many therapeutic regimens. The disadvantages of reservoir devices as compared to monolithic devices is economic--the former being more complex and hence more costly to make than the latter.
SUMMARY OF THE INVENTION provided there is a particular correlation between the respective permeabilities, thicknesses and exposed surface areas of the core lamina and the outer lamina(s).
0 having a permeability, P. to the drug, a thickness, 1,
and an exposed surface area, A, .from which drug is released wherein is greater than about 2 and is at least three times k being a constant whose value is dependent upon the geometrical shape of the laminate.
Preferably is greater than 3 and is at least 10 times L. 1 i P I The laminated drug dispenser of this invention may be in the form of a three layered sandwich or in the form of a concentric laminate. This type of device combines the good drug release kinetics of the reservoir devices with the ease and cheapness of manufacture of monolithic devices.
BRIEF DESCRIPTION OF THE DRAWINGS In the drawings like reference numerals refer to like parts, and:
FIG. 1 is a cross-sectional view of a drug dispenser of this invention;
FIG. 2 is a graphical representation of the release rates of the devices described in Example 1, infra;
FIG. 3 is a graphical representation of the release rates of the devices dese'fibed in Example 2, infra;
FIG. 4 is a graphical Representation of the release rates of tl ie devices descflled in Example 3, infra; and
FIG. 5 l an elevational perspective view of another drug dlfir of this invlition.
DESCRIPTION OF THE PREFERRED EMBODIMENTS FIG. 1 illustrates a drug dispenser, generally designated 10, of this invention. Dispenser is a three layer sandwich-type laminate in the shape of a thin, circular disc comprising a core lamina 11 sandwiched between two outer laminas 12,13. Core lamina 11 consists of solid particles of drug 14 dispersed within a matrix material 15. Material 15 has a permeability, P, and core lamina 11 has a thickness, 21. The edge 16 of core lamina 11 defines the surface area, A, thereof which is exposed to the environment.
Outer laminas 12,13 each have a thickness, t, and a permeability, P, to the drug. Surfaces 17,18 of laminas 12,13 define a combined surface area, A, thereof which is exposed to the environment. (The area defined by the axial edges of laminas 12,13 is also exposed but is negligible relative to area A'.)
Dispenser 10 releases drug 14 at surfaces 16,17 and 18 by a diffusion mechanism. Drug molecules initially dissolve in matrix material 15 and permeate therethrough either to exposed surface 16 or to outer laminas 12,13 and therethrough to exposed surfaces 17,18.
The molecules which reach exposed surfaces 16,17,18 are removed or cleared therefrom through contact with body fluids and/or body tissue. When the respective permeabilities and thicknesses of core lamina 11 and outer laminas 12,13 are correlated as set forth above, that is is greater than about 2, drug will be released from surfaces 17,18 at a substantially constant rate as long as matrix material 15 is saturated with the drug. In contrast, drug is released from edge 16 at a constantly declining rate proportional to time"? However, by correlating the permeabilities, thicknesses and exposed surface areas of core lamina l 1 and outer laminas 12,13 as set forth above, the amount of drug released from edge 16 is substantially less than the amount of drug released from surfaces 17,18. Accordingly, the overall release rate from dispenser 10 is dominated by the release rate of drug from surfaces 17,18 and thus the overall release rate approximates the substantially constant release rate from those surfaces. In this respect, the greater the magnitude of and the greater the difference between the magnitude of the expression and the magnitude of the expression the closer is this approximation. If
is less than 2, the outer membranes do not control the drug release rate which declines proportional to time? If the area of exposed core is too high or the permeability of the core is too high and release of drug from the edge predominates and again the release rate declines proportional to time. In the intermediate region, how ever, which is the subject of this invention, neither of these effects predominates and drug release is almost constant with time. The release rates of these laminates are, of course, not as constant as the release rates of comparable prior art reservoir devices in which the core is not exposed to the environment. However, for many therapies the degree of release rate constancy afforded by these laminates is acceptable. Thus they provide a viable, less expensive alternative to the reservoir devices in such instances.
FIG. 5 illustrates another drug dispenser, generally designated 19, of the invention. Dispenser 19 is a concentric-type laminate in the shape of a cylinder comprising a cylindrical core lamina 20 and an outer concentric lamina 21 which covers the axial surface of core lamina 20. Core lamina 20, like core lamina 11, comprises particles of drug 14 dispensed within a matrix material 15. It is functionally equivalent to core lamina 1 1. The ends 22,23 of core lamina 20 define the surface area, A, thereof which is exposed to the environment. Core lamina 20 has a diameter, 2!. Outer concentric lamina 21 has a permeability, P, to the drug and has a thickness, t. Lamina 21 is functionally identical to laminas 12,13 and may be made from the same materials as the latter. The axial surface 24 of lamina 21 defines the surface area, A, thereof which is exposed to the environment. (The area defined by the radial edges of lamina 21 is also exposed but is negligible relative to area A'.)
Dispenser 19 releases drug 14 at surfaces 22,23,24 by a diffusion mechanism identical to that described above with respect to dispenser 10. The correlations between the thicknesses, permeabilities and exposed surface areas of laminas 20,21 of dispenser 19 required to permit dispenser 19 to release drug at a substantially constant rate are the same as those described above. with respect to dispenser 10.
Drug 14 is solid (crystalline) and should have a low water solubility. Low water solubility is a requirement so that the drug does not function to any significant extent as an osmotic attractant to imbibe water from the use environment into core lamina 11. If substantial water is imbibed, the drug 14 may be released by an osmotic bursting mechanism rather than a diffusion mechanism. This would affect the release rate of drug in an undesirable manner. The degree of water solubility will in many-instances depend on the permeability of matrix material 15 to water. If material 15 has a high permeability tovwater, the water solubility of the drug should be correspondingly low and vice versa. Drugs which are less than about 4% by weight soluble in water are preferred.
The particle size of drug- 14 is notcritical. Particle sizes in the-range of l to 20p. will normally be used since they are easy to handle and may be readily dispersed homogeneously in matrix material by conventional techniques.
The loading of drug 14 in core lamina 11 is important because it may affect the permeability of core lamina 11 to the drug. At high drug loadings (greater than about 25% by weight) lamina 11 has a tendency to become microporous over the. devices lifetime. This occurs because as drug particles 14 dissolve in matrix 15 and diffuse therefrom, voids are left in the matrix. At such high drug loadings, the void volume is sufficient to make the portion of lamina 11 which has been v depleted of drug microporous. Such microporosity will cause the permeability of core lamina 11 to increase. Indeed, high drug loadings provide a means for making the permeability of the core lamina 11 substantially greater than the permeability of the outer laminas even though the same polymer is used in both. The drug loading of lamina 11 will'depend upon the drug dosage regimen desired, with higher loadings providing greater dosages and/or more sustained release. Usually the loading will be in the range of 30 to 75% by weight of the core lamina.
The nature of the drug will depend upon the therapy for which the device is intended. Drugs which produce a localized effect at the administration site or a systemic effect at a site remote from the administration site may be used. Such drugs include inorganic and organic compounds, for example, drugs which act on the central nervous system such as hypnotics and sedatives, psychic energizers, tranquilizers, anticonvulsants, muscle relaxants and anti-parkinson agents, antipyretics and anti-inflammatory agents, local. anesthetics,
anti-spasmodicsand antiulcer agents, prostaglandins,
anti-microbials, hormonal agents, estrogenic steroids, progestational steroids, such as for contraceptive purposes, sympathomimetic drugs, cardiovascular drugs, diuretics, anti-parasitic agents, hypoglycemic drugs and ophthalmic drugs.
Matrix material 15 may be made from a polymeric material which'is homogeneous and substantially imperforate (i.e., it has no man-made perforations) or it may be made from a polymer which has been made microporous by conventional techniques. In either instance its permeability to the drug should be known. (Known techniques are available to determine the permeabilitiesof such materials. See for instance US. Pat. No. 3,710,795.) Examplesof substantially imperforate polymers which may be used are poly(butylmethacrylate), plasticized poly(vinylchloride), plasticized soft nylon, natural rubber, poly(isoprene), poly(isobutylene), poly(butadiene), poly(ethylene), poly(vinylidene chloride), cross-linked poly(vinylpyrrolidone), chlorinated poly(ethylene), poly(4,4-isopropylidene diphenylene carbonate), ethylene-vinylacetate copolymer, plasticized ethylene-vinylacetate copolymer, vinlyidene chloride-acrylonitrile copolymer, vinyl chloride-diethyl fumerate copolymer, silicone rubbers, especially the medical grade poly(dimethylsiloxanes), ethylene-propylene rubber, silicone-carbonate copolymers and vinylidene chloridevinyl chloride copolymer.
Microporous materials have pores which range in size from at least about 10 A to several hundred microns, but usually not more than about 100 microns. Examples of materials from which microporous structures may be made are regenerated, insoluble, nonerodible cellulose, acylated cellulose, esterified cellulose, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate diethylaminoacetate, poly(urethanes), poly(carbonates), modified insoluble collagen, cross-linked poly(- vinyl alcohol), epoxy resins and poly(olefins) or poly(- vinylchlorides). These materials may be made microporous by well known procedures such as coprecipitation or leaching out incorporated salts, soap micelles, starch or like materials. See, for example, J. D. Ferry, Chemical Reviews, 18, 373 (1935), and In: Synthetic Polymer Membranes, by R. E. Kesting, McGraw-Hill, 1971.
Outer laminas 12,13 may be made from the same polymers as matrix material 15, provided, of course, that the permeability of the material 15 to the drug is greater than the permeability of the material forming laminas, 12,13. It will be appreciated that either of outer laminas 12,13 may be made from a drugimpermeable material. In such an instance, the effective thickness (the maximum thickness through which the drug must permeate to reach a permeable outer lamina) of core lamina 11 will be twice that of an embodiment in which both laminas 12,13 are drug permeable and the exposed outer lamina surface area from which drug is released will be half that of an embodiment in which both laminas 12,13 are drug permeable. It is also within the scope of this invention to make laminas 12,13 from different polymeric materials of different drug permeability and to make them of different thicknesses.
The shape and size of the dispenser of this invention will depend upon the environment in which it is intended to be used. If the dispenser is intended to be implanted or inserted, its size and shape will be compatible with the size and shape of the implantation or insertion site. For instance, if it is intended to be used as an ocular insert, it will be sized and shaped for insertion and retention in the eye. Likewise, if intended for insertion in other body cavities, such as the vagina, uterus, mouth and gastrointestinal tract, it will be sized and shaped accordingly. In most instances it will be acceptable to employ regular shapes. As indicated above, the value of k in the expression will depend on the geometrical shape of the dispenser. For three-layered sandwich elliptical shaped dispensers such as dispenser 10, k has a value of 4. Its value for other sandwich-type dispensers of regular geometrical shape may be calculated, (e.g., for a circle it is 8). For cylindrical concentric laminate dispensers such as are listed above as useful for dispenser 19, k has a value of /s. The value of k for other concentric laminates of other cross-sectional shapes (e.g., hexagonal, square, elliptical) may be calculated.
The sandwich-type laminates of this invention may be manufactured according to well-known techniques. Depending upon the particular polymers comprising the core lamina and outer laminas, the laminate may be bonded together with or without binders. Various binders are well known in the art. See for instance the Encyclopedz'a of Polymer Science and Technology, John Wiley & Sons, Vol. 8, 1968. If a binder is used, it, of course, should be compatible with the polymers constituting the laminas and should not affect or interfere with the drug permeation through the laminas or alter the drug deleteriously in any manner. Conventional laminating machines and techniques may be used, with the particular temperatures and pressures employed varying with the polymers involved. The laminates may be formed as continuous sheets and the dispensers of this invention cut or punched therefrom by known techniques. The concentric-type laminates of the invention may also be formed by well-known techniques such as coextrusion.
While the dispensers have hereinabove been described as dispensers for releasing drugs for human or animal therapy, it will also be appreciated that they may be used to release other active agents in other environments, provided such agents are solid and have low water solubility as described above. Such active agents include, for example, pesticides, herbicides, germicides, biocides, algicides, rodenticides, fungicides, insecticides, anti-oxidants, plant growth promoters and inhibitors, preservatives, surfactants, disinfectants, catalysts, fermentation agents, nutrients, plant minerals, sex sterilants, plant hormones, air purifiers, microorganism attenuators and the like.
EXAMPLES The following examples illustrate the dispensers of this invention and their performance relative to dispensers outside the scope of the invention as defined herein, and are not intended to limit the scope of the invention in any manner.
Example 1 A. A physostigmine (Eserine) dispenser, such as might be inserted in the eye to dispense Eserine thereto, was made as follows. Fifty parts Eserine (particle size approximately 5 microns), and 50 parts of ethylene/vinyl acetate copolymer (brand name, Elvax 40) were mixed homogeneously on a rubber mill. The resulting mixture was melt pressed into a 200 micron thick film. This film was then placed in a vacuum/heat laminator and a 150 micron thick sheet of ethylene/vinyl acetate copolymer (brand name, Elvax 40) was laminated to each side of it. Duplicate 5.8 mm X 13.5 mm ellipses were punched from the resulting three layer laminate. P, P, A and A, for these elliptical dispensers were determined and the values for the expressions were calculated therefrom and are reported in Table 1 below.
B. Duplicate Eserine dispensers were made in accordance with part A above except that the outer laminas were each 75 microns thick. The data for these dispensers are also reported in Table 1 below.
C. For comparison, duplicate Eserine dispensers were made in accordance with part A above except 8 that the outer laminas were each 13 microns thick. The data for these dispensers are also reported in Table 1 below.
The release rates of the dispensers of A, B and C were determined by placing individual devices in polymer mesh bags and suspending the bags from a vertically reciprocating bar into vessels containing 50 ml water stirred at 37C. The Eserine concentration in the water was measured at regular intervals by UV analysis, the water being changed after each measurement. Eserine release rates were calculated from the measurements. FIG. 2 is a plot of these release rates versus time. As indicated by the plots of FIG. 2, the release rate of the dispensers of B is substantially more constant than that of the dispensers of C and that of A is even more constant than B. This is a reflection of the increasing value of the expression P r P as reported in Table 1.
Example 2 Two sets of chloramphenicol dispensers were made by the general procedure of Example 1A. The core lamina was made from 66 parts chloramphenicol (particle size approximately 5 microns) and 34 parts copolymer and was 125 microns thick. The outer laminas were 50 microns thick and 17.5 microns thick, respectively. The data for these two sets, designated 2A and 2B, are reported in Table 2 below.
Table 2 P P A A P I r k (A' )2 (cm (cm t P A 2A 16 0.1 1.23 4.5 605 2B 90 16 0.1 1.23 l 6 605 The release rates of dispensers 2A and 2B were determined by the procedure described in Example 1. FIG. 3 is a plot of these release rates versus time.
Example 3 Table 3 P P A A P I k A 2 (cm) (cm I P A The release rates of dispensers 3A and 3B were determined by the procedure described in Example 1. FIG. 4 is a plot of these release rates versus time.
Modifications of the dispensers described herein which are obvious to persons of skill in the art are intended to be within the scope of the following claims.
1. An active agent dispenser comprising a laminate of:
a. a core lamina of particles of a crystalline active agent of low water solubility dispersed in a solid material having a permeability, P, to the agent, the core lamina having a thickness 2t, and an exposed surface area, A, from which agent is released, and being partially covered by;
b. at least one outer lamina made of an active agent release rate controlling polymer having a permeability, P, to the agent, a thickness, 1, and an exposed surface area, A', from which agent is released wherein is greater than about 2 and is at least three times .L'... r P
10 is greater than 3 and is at least 10 times L. r P I 4. The drug dispenser of claim 2 wherein P is substantially greater than P.
5. The drug dispenser of claim 4 wherein P is substantially greater than P because of the porosity of the core lamina caused by the quantity of drug therein.
6. The drug dispenser of claim 2 wherein the drug initially comprises 30 to by weight of the core lamina.
7. The drug dispenser of claim 2 wherein the solubility of the drug in water is less than 4% by weight.
8; The drug dispenser of claim 2 wherein the drug is chloramphenicol, physostigmine or hydrocortisone, and the dispenser is sized and shaped for insertion in the cul-de-sac of a human eye.
9. The dispenser of claim 1 wherein the dispenser is a three layer sandwich-type laminate, said core lamina being sandwiched between a pair of said outer lamina.
10. The dispenser of claim 9 wherein the laminate has the geometrical shape of a thin circular disc and k is 8.
11. The dispenser of claim 9 wherein the laminate has the geometrical shape of a thin elliptical disc and k is 4.
12. The dispenser of claim 1 wherein the dispenser is a concentric-type laminate, said outer lamina being outerly concentric to said core lamina and covering the axial surface of said core lamina.
13. The dispenser of claim 12 wherein the laminate is cylindrical in shape and k has a value of Ma.