US3926188A - Laminated drug dispenser - Google Patents

Laminated drug dispenser Download PDF

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Publication number
US3926188A
US3926188A US523720A US52372074A US3926188A US 3926188 A US3926188 A US 3926188A US 523720 A US523720 A US 523720A US 52372074 A US52372074 A US 52372074A US 3926188 A US3926188 A US 3926188A
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United States
Prior art keywords
drug
dispenser
lamina
agent
laminate
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Expired - Lifetime
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US523720A
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English (en)
Inventor
Richard W Baker
Robert M Gale
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Alza Corp
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Alza Corp
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Publication date
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Priority to US523720A priority Critical patent/US3926188A/en
Priority to GB4228975A priority patent/GB1477813A/en
Priority to DE2549856A priority patent/DE2549856C2/de
Priority to IT69740/75A priority patent/IT1050619B/it
Priority to CA239,459A priority patent/CA1056685A/en
Priority to JP50136148A priority patent/JPS6059203B2/ja
Priority to SE7512744A priority patent/SE439432B/xx
Priority to CH1472575A priority patent/CH634226A5/de
Priority to MX161923A priority patent/MX158868A/es
Priority to FR7534821A priority patent/FR2290891A1/fr
Priority to MX6132A priority patent/MX158867A/es
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Publication of US3926188A publication Critical patent/US3926188A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time

Definitions

  • 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
  • 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.
  • 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.
  • Such dispensers are of two types: monolithic and reservoir.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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;
  • FIG. 5 l an elevational perspective view of another drug dlfir of this invlition.
  • 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.
  • 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.
  • drug is released from edge 16 at a constantly declining rate proportional to time"?
  • the amount of drug released from edge 16 is substantially less than the amount of drug released from surfaces 17,18.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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-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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Eserine particle size approximately 5 microns
  • ethylene/vinyl acetate copolymer brand name, Elvax 40
  • 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.
  • 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.
  • An active agent dispenser comprising a laminate of:
  • 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
  • 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.
  • 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.
  • 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.

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  • Engineering & Computer Science (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Ophthalmology & Optometry (AREA)
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US523720A 1974-11-14 1974-11-14 Laminated drug dispenser Expired - Lifetime US3926188A (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
US523720A US3926188A (en) 1974-11-14 1974-11-14 Laminated drug dispenser
GB4228975A GB1477813A (en) 1974-11-14 1975-10-15 Sustained release dispensers
DE2549856A DE2549856C2 (de) 1974-11-14 1975-11-06 Wirkstoffspender und Verfahren zu seiner Herstellung
IT69740/75A IT1050619B (it) 1974-11-14 1975-11-06 Erogatore a cessione prolungata particolarmente per medicamenti.. e procedimento per la sua fabbricazione
JP50136148A JPS6059203B2 (ja) 1974-11-14 1975-11-12 積層型ディスペンサ−の製造法
CA239,459A CA1056685A (en) 1974-11-14 1975-11-12 Active agent dispenser and process for making same
SE7512744A SE439432B (sv) 1974-11-14 1975-11-13 Forfarande for framstellning av en anordning for avgivande av ett aktivt medel med lag vattenloslighet genom diffusion ur ett polymerskelett
CH1472575A CH634226A5 (de) 1974-11-14 1975-11-13 Wirkstoffspender und verfahren zu seiner herstellung.
MX161923A MX158868A (es) 1974-11-14 1975-11-14 Dispensador de agente activo
FR7534821A FR2290891A1 (fr) 1974-11-14 1975-11-14 Support destine a liberer lentement un corps actif, en particulier un medicament, et sa fabrication
MX6132A MX158867A (es) 1974-11-14 1975-11-14 Procedimiento para hacer un dispensador de agente activo

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JP (1) JPS6059203B2 (es)
CA (1) CA1056685A (es)
CH (1) CH634226A5 (es)
DE (1) DE2549856C2 (es)
FR (1) FR2290891A1 (es)
GB (1) GB1477813A (es)
IT (1) IT1050619B (es)
MX (2) MX158867A (es)
SE (1) SE439432B (es)

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US5466233A (en) * 1994-04-25 1995-11-14 Escalon Ophthalmics, Inc. Tack for intraocular drug delivery and method for inserting and removing same
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SE7512744L (sv) 1977-05-15
SE439432B (sv) 1985-06-17
FR2290891A1 (fr) 1976-06-11
DE2549856A1 (de) 1976-05-20
FR2290891B1 (es) 1978-11-10
CA1056685A (en) 1979-06-19
IT1050619B (it) 1981-03-20
GB1477813A (en) 1977-06-29
CH634226A5 (de) 1983-01-31
JPS5170807A (es) 1976-06-18
MX158868A (es) 1989-03-27
JPS6059203B2 (ja) 1985-12-24
DE2549856C2 (de) 1985-01-03
MX158867A (es) 1989-03-27

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