CA1047403A - Process for making a monolithic drug delivery device - Google Patents

Process for making a monolithic drug delivery device

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Publication number
CA1047403A
CA1047403A CA228,740A CA228740A CA1047403A CA 1047403 A CA1047403 A CA 1047403A CA 228740 A CA228740 A CA 228740A CA 1047403 A CA1047403 A CA 1047403A
Authority
CA
Canada
Prior art keywords
active agent
polymer matrix
agent
layer
drug
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
CA228,740A
Other languages
French (fr)
Inventor
Richard W. Baker
Alan S. Michaels
Felix Theeuwes
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alza Corp
Original Assignee
Alza Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alza Corp filed Critical Alza Corp
Application granted granted Critical
Publication of CA1047403A publication Critical patent/CA1047403A/en
Expired legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0034Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0039Devices retained in the uterus for a prolonged period, e.g. intrauterine devices for contraception
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0002Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0048Eye, e.g. artificial tears
    • A61K9/0051Ocular inserts, ocular implants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system

Abstract

ABSTRACT
A process for making a monolithic active agent delivery device com-prising a shaped body of a dispersion of particle active agent, such as a drug, in a polymer matrix, such as ethylene/vinylacetate copolymer, in which the particulate agent is removed, such as by water washing, from the exterior surface of the body to form an agent depleted layer of polymer matrix voided by the removal of the agent, the thickness of the layer being at least 3% of the overall body thickness. Such removal reduces the initial burst of active agent from the device when the device is placed in the environment of use.

Description

~o4741~3 ~ACK~ROUND-OF THE INV~N~ION ;~
Monolithic devices for sustainedly releasing drugs or other active agents are well known in the art. One type of monolithic device consists of a shaped body of particulate, usually solid, drug dispersed uniformly in a polymer matrix -permeable to the drug by diffusion. The polymer matrix may be substantially imperforate and homogeneous in which case the drug dissolves in and permeates through the polymer material itself.
Alternatively, the matrix may be microporous, the pores of which contain a drug-permeable liquid or gel medium, in which case the drug will preferentially dissolve in and permeate through the medium in the pores. It is of course possible to use a polymer matrix which is both microporous and made of a polymer permeable to the drug in which case movement of the drug through the matrix is via a combination of the above described modes.
Another type of monolithic device for use in releasing active agents into aqueous environments, such as drugs into the various cavities of the human body, consists of a shaped body of discrete particulate osmotic solute/active agent depots dispersed in and surrounded by an active agent impermeable but water permeable polymer matrix whose cohesive strength is exceeded by the pressure generating ability of the individual depots. Such devices release their active agent by an osmotic imbibition-bursting mechanism in which water is imbibed osmotically into the depots nearest the exterior surface of the device, thereby dissolving those depots' contents and generating pressure there-within sufficient to cause the surrounding polymer matrix to rupture thus allowing release of the agent therefrom and access by the environment to the next nearest depots and serially so forth. These monolithic "osmotic bursting" devices are the subject matter of commonly assigned Canadian application Serial No. 198.003 filed 04/23/74. ~$

.
. .

IR ~90 ~oD~7~3 These monolithic devices are attractive commercially because they are inexpensive and easily fabricated relative to other devices such as laminated devices or capsule devices. Also, in the case of some drugs, a monolithic device is the only type of device capable of practically and sustainedly releasing the drug at a therapeutically effective rate.
The active agent release kinetics of these monolithic devices exhibit a feature which is often undesirable, namely the release begins at a high rate--called an "initial burst"--which rapidly decreases to a significantly lower rate. The kinetics of monolithic diffusion for a device having a thin rectangular cross-sectional shape (i.e., the device is shaped as a flat slab) may be expressed by the equation : / ~

dt ~ ) in which Mt is the agent released at time, t, C is the agent solubility in the polymer matrix, C is the total concentration of agent in the polymer matrix, C being much greater than C , D is the agent's diffusion coefficient in the polymer matrix and A is the surface area of the device ~both sides). Equations defining the release kinetics of other simple geometries, such as a cylinder and a sphere are also known .

' T. Highchi, J. Pharm. Sci., 50, ~74 (1961) T. J. Roseman et al, J. Pharm. Sci., 59, 353 (1970);
T. J. Roseman, J. Pharm. 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) dM
In a plot of the above equation with dtt plotted against t, the release rate in the initial stage of release is extremely high and drops off very quickly to a level markedly below the rate in the initial stage. Corresponding plots for monolithic diffusion devices of other simple geometry, such as a rod-like cylinder or sphere, follow the same general release rate pattern as the simple slab described above.
The release kinetics for monolithic osmotic bursting devices have been found empirically to also exhibit an initial burst which decreases rapidly to a significantly lower rate.
However the release rate plateaus after the initial decrease in the osmotic bursting devices whereas it continuously decreases in the diffusion devices.
In both types of devices this initial burst of active agent may be undesirable because it results in overdosing, toxicity or side reactions, or may not conform to the optimal dosage regimen for a particular active agent.
The initial high level or "burst" in the release rate of active agent from a monolithic device may be reduced by coating the body with a layer of pure polymer matrix. ~ -Such a coated device is taught (the coating is used for a different purpose) in U.S. Patent No. 3,577,512 issued May 4, 1971 to T. H. Shepherd et al. However this coating procedure has the disadvantage of lowering the entire release rate dM
profile (i.e., the entire ~_ vs. t plot) of the device. Such lowering may result in release rates below those required for efficacy. Also, if the device has an irregular shape, it is usually quite difficult to devise a manufacturing procedure to make a continuous, uniform coating on the device in a reproducible manner.
This invention relates to a process for making a monolithic active agent delivery device comprising a dispersion ' ~

~

lV474~3 of solid particulate active agent in a polymer matrix com-prising the steps of forming a dispersion of the solid particulate active agent in said matrix and forming the dispersion into a shaped body adapted for placement in the environment of use of the device, characterized by the addi-tional step of removing the solid particulate active agent from the surface of said body before the body is placed in the environment of use to form an active agent depleted layer of polymer matrix voided by the removal of the parti-culate solid active agent therefrom, said removing accom-plished by washing the body in a liquid which is inert relative to said polymer matrix, the thickness of said layer being at least about 5% of the overall thickness of said body.
In the drawings:
Figure 1 is a vertical, sectional view of a disc-shaped monolithic diffusion type drug delivery device made in accordance with the invention process;
Figure 2 is an enlarged view of a portion of the section of Figure 1 taken along line 2-2 of Figure l;
Figure 3 is a graphic representation of the release kinetics of a prior art monolithic diffusion drug delivery device;
Figure 4 is a graphic representation of the improve-ments in the release kinetics of the device represented in Figure 3 which may be realized by subjecting that device to the process of this invention;
Figure 5 is a graphic representation of the release kinetics of several prior art devices of the same geometry as the device of Figure 3 but having different loadings of active agent; and Figure 6 is a graphic representation of the improve-~ _ 5 _ A~", ments in the release kinetics of the devices of Figure 5 which may be realized by subjecting those devices to the process of this invention;
Figure 7 is a vertical, sectional view of a disc-shaped - 5a -~,'~' lV474U3 monolithic osmotic bursting drug delivery device made by ~he invention process;
Fig. 8 is an enlarged view of a portion of a section of Fig. 7 taken along line 8-8 of Fig. 7;
Fig. 9 is a graphic representation of the release kinetics of a prior art monolithic osmotic bursting drug delivery device; and Fig. 10 is a graphic representation of the improvement in the release kinetics of the device of Fig. 9 which may be realized by treating that device in accordance with the process of this invention.

DETAILED DESCRIPTION OF THE INVENTION
Fig. l depicts a disc-shaped monolithic diffusion type active agent delivery device, generally designated 10, comprising a particulaté
active agent 11, such as drug, dispersed in a polymer matrix 12.
The particles of agent 11 may be liquid, semi-solid or solid but are preferably solid.
"Active agents" as used herein include those compositions of matter which when dispensed in their environment of use produce a predetermined, beneficial and useful result. Such agents include for example pesticides, herbicides, germicides; biocides, algicides, rodenticides, fungicides, insecticides, anti-oxidants, plant growth promotors and inhibitors, preservatives, surfactants, disinfectants, catalysts, fermentation agents, nutrients, drugs, plant minerals, sex sterilants, plant hormones, air purifiers, micro-organism attenuators and the like.
"Drug" as used herein broadly includes physiologically or pharmacologically active substances for producing a localized effect at the administration site or a systemic effect at a site remote from the administration site: Such drugs include inorganic and organic compounds, for example, drugs which act on the central ~0474l)3 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-spasmodics and antiulcer agents, prostaglandins, anti-microbials, hormonal agents, estrogenic steroids, progestational steroids, such as for contraceptive purposes, sympathomimetic drugs, cardiovascular drugs, diuretics, antiparasitic agents, hypoglycemic drugs and ophthalmic drugs.
In the osmotic bursting devices the active agent must either itself be water soluble to the extent that the osmotic pressure of a saturated solution thereof exceeds the osmotic pressure of the external environment of use or it must be mixed with a compatible osmotically effective solute such as an inorganic or organic salt capable of generating such an osmotic pressure. Such pressure provides the necessary driving force by which the osmotic bursting mechanism is effected. Methods of calculating or measuring osmotic pressure are well known. See for example, S. Glasstone, Textbook of Physical Chemistry, MacMillan & Co., London (1960).
As indicated above, in the monolithic diffusion devices the polymer forming the polymer matrix may be substantially imperforate and homogeneous or microporous. Such polymers and matrixes are described in commonly assigned Canadian application Serial No. 152,938 filed 09/29/72.
Polymers for forming the osmotic bursting devices are described in commonly assigned Canadian application Serial No. 198,003 fi~ed 04/23/74.
In the diffusion devices the concentration of active agent dispersed in the polymer matrix will primarily depend upon the desired dosage level for the device. Normally the concentration of active agent will be in the range of 5 to 70 weight ~ based on the polymer matrix. Its particle size will usually be in the rànge of 0.1 to 100 microns.

~0474U3 In the osmotic bursting devices the active agent depot loading (which depends on the size and number of depots) is important.
The depots will usually comprise 5% to 70% by weight of the device.
In this range sufficient polymer is present to adequately encapsulate the depots and maintain the device's integrity after a substantial amount of the agent depots have been released. The depot size will usually range between 0.1 and 100 microns in diameter.
The shape of the device made from the above described active agent/polymer dispersions will depend on the intended environment of use. In most environments complex shapes will be unnecessary and thus for convenience and economy the device will have a simple shape such as flat disc, a cylindrical rod, or a sphere.
For specific embodiments such as an embodiment intended for use in the eye to release an ophthalmic drug therein, the device will usually be in the shape of a flat disc, oval, ellipse or kidney.
The device will be sized according to the environment and desired dosage. Drug delivery devices for implanting in the body will be sized in accordance with the dimensions of the implant site. For instance for ocular inserts for inserting in a cul-de-sac of the eye the device will normally have a length of 4 to 20 mm, a width of 1 to 15 mm and a thickness of 0.1 to 4 mm and will usually contain 1 to 200 mg ophthalmic drug.
The active agent/polymer dispersions may be formed by mixing the two components by conventional techniques. Likewise, the dispersions may be formed into shaped bodies by conventional techniques such as solvent casting, extruding, roll milling, melt pressing, cutting, punching and the like.
After the dispersion if formed into the desired shape ~this may be its final form for introauction into the use environment , ~74(~3 or some intermediate form such as a large sheet or roll) but before it is placed in the environment of use, the particles of active agent are removed from the exterior surface layer of the body in accordance with the process of this invention. This may be done by washing the body with a liquid which is inert relative to the polymer matrix ~in other words the liquid should not deleteriously affect the polymer matrix either physically or chemically such as by dissolving, disintegrating, or chemically reacting with the matrix). For convenience and economy the wash liquid will usually be aqueous, with water being preferred.
In a diffusion device the washing of the device causes active agent which is dissolved in the polymer matrix at the surface to diffuse into the wash liquid which in turn causes agent particles located near the surface to dissolve into the polymer and be diffused therefrom. In the case of the osmotic bursting devices the washing causes any agent at the surface to be dissolved and water to be imbibed by the encapsulated agent depots causing them to burst and release their contents. In both types of devices this washing ultimately results in the active agent being depleted from a surface layer of desired thickness. In the device shown in Figs. 1 and 2 the drug has been depleted from a layer, designated A, at the exterior surface of the device leaving voids 14. The number and size of the voids in the matrix will depend on the concentration and particle size of the dispersed active agent. In this regard it has been observed that the voids tend to irreversibly shrink, i.e., the porosity of the layer decreases, if the device is permitted to dry after the washing. This phenomenon is believed to make the layer of a dried device act more like a coating of pure matrix in that it may be less permeable to the agent than the remainder of the matrix. In any event voids 14 affect the release kinetics of device 10 .
lQ474(~3 because they form preferred pathways (indicated by small arrows) for the active agent to diffuse along.
Figs. 7 and 8 illustrate a monolithic osmotic bursting active agent delivery device, generally designated 15, which has been prewashed in accordance with the invention process. Device 15 comprises discrete active agent/osmotic solute depots 16 encapsulated within a polymer matrix 17. As shown in Fig. 8 the prewashing has depleted the active agent depots from a layer, designated B, at the surface of the device leaving voids 18. Voids 18 are similar to voids 14 of device 10 except that voids 18 are substantially interconnected due to the bursting mechanism by which the active agent was released.
The process conditions of the wash, e.g., time and temperature, will be selected to provide an agent depleted layer of predetermined thickness. Given a desired layer thickness the wash temperature and time will depend on the particular polymer and active agent invoIved. In a diffusion device wash times may be shortened by employing temperatures at which diffusion is enhanced. In an osmotic bursting device wash times may be shortened by using temperatures at which water imbibition by the depots is enhanced. In almost all instances this means that elevated temperatures (above ambient temperature) below the matrix melt temperature and below that which might adversely afect the agent in any manner will shorten the wash time. For most polymers and agent wash temperatures in the range of about so& to about 60 C may be used advantageously. For both types of devices it is desirable to carry out the wash with agitation to ensure good clearance of the released agent from the exterior of the device.
Although any degree of prewashing will improve the release ~inetics of the device, it is desirable to remove active agent from a layer which represents at least about 5~ of the total thickness or diameter of the device. Usually the thickness of the layer will comprise 1~74(~3 about 5~ to about 25% of the overall thic]cness or diameter. It should be understood that in most devices the layer appears at both sides or both edges of the device and that the above percentages relate to only a single appearance of the layer. In other words in a spherical device the layer would appear at both énds of a diameter and thus the total diametrical drug depleted portion of the device would represent at least about 10% of the entire diameter.

EXAMPLES
The invention process and the improvement in release kinetics realized by using it are further illustrated by the following examples.
Example l A. A monolithic diffusion device such as might be used to dispense a drug intrauterinely is made by mixing 20 parts progesterone (5-10 micron particle size) into a methylene chloride solution of 80 parts ethylene~vinyl acetate copolymer ~the drug loading is approximately 20~ by volumej. This mixture is cast into a 0.2 cm thick sheet from which a rectangular body having a total surface area of 1 cm is cut. This rectangulai body is placed in a simulated uterine environment where it releases progesterone by diffusion. This release is monitored, the plot of which is shown in Fig. 3. As seen in Fig. 3 the initial release rate of progesterone is in the neighborhood of 150 ~g/day and drops off rapidly during the first lO0 days to about 40 ~g/day after which the release curve slowly and continuously declines until the solid progesterone is exhausted.
B. Three rectangular bodies of a progesterone/ethylene-vinyl acetate copolymer dispersion are prepared as in A. Each is washed in water at 50 C; the first until a drug free surface layer 0.020 cm thick is formed; the second until a drug free layer 0.033 cm . . .
' 1()474(~3 thick is formed; and the third until a drug free layer 0.0~7 cm thick is formed. Each device is then placed ln the simulated uterine environment as described in A and the progesterone release therefrom is monitored and plotted, the plots of which are shown in Fig. 4.
As shown by these plots the i'nitial release rate relative to the unwashed device is decreased respectively by about 30%, 60% and 70 in the washed devices. Also the release rate during the major portion of the device's lifetime (c.a. 100 days to 500 days) is not significantly decreased by the washing.
Example 2 - A. A device identical with that of Example lA and two other devices identical to the same except in drug loading (one contained half the amount of progesterone and the other contained double the amount of progesterone) are prepared and tested as in Example lA. Their release plots are illustrated in Fig. 5.
B. Three devices identical to those of A are prepared and prewashed in water at 50 C until a 0.047 cm thick drug-free laye'r is formed in each. These washed devices are then tested as in Example lA. Their release plots are shown in Fig. 6.
i As is readily seen by comparing Figs. 5 and 6 the washing eliminated the initial burst in the progesterone release while not significantly affecting the release rate over the bulk of each devlce's lifetime.
Example 3 A. An osmotic bursting device such as might be used to dispense drug to the eye is made by mixing 30 parts pilocarpine nitrate with 70 parts of ethylene/vinyl acetate copolymer on a laboratory rubber mill. The well-dispersed mixture which contains pilocarpine nitrate particles with an average diameter of between 1 and 10 microns is then pressed into a flat film 500 microns thick from which an - -- ~.04741~3 ellipse-shaped body 13.5 mm by 6.5 mm is cut. This body is placed in simulated lachrymal fluid at 37 C where it releases pilocarpine nitrate by an osmotic bursting mechanism. This release is monitored, the plot of which is shown in Fig. 9. As seen in Fig. 9 the initial pilo-carpine nitrate release rate is about 175 ~g/hour and drops off rapidly during the first 25 hours to about 25 ~g/hour.
B. Five devices identical to those of A are prepared and soaked in water at 37 C for 15, 30, 60 and 120 minutes and 24 hours respectively. Each device is then tested as in A. Their pilocarpine nitrate release plots are shown in Fig. 10. As shown by these plots the washing decreases the initial release rate by about 20%, 40%, 50%, and 90% respectively. Also, there is little variation in release rate between the unwashed and washed devices after 25 hours.
Example 4 Osmotic bursting ocular inserts are made by dispersing 30 parts tetracycline hydrochloride in 70 parts ethylene/vinyl acetate copolymer (Elvax 220) on a rubber mill, melt pressing the dispersion into a ~lat film 500 microns thick and cutting 13.5 mm x 5.8 mm ellipses therefrom. Individual ellipses are washed 0, 15, 30, 60 and 120 minutes respectively, in water at 50C, dried and then placed in simulated lachrymal fluid. The average tetracycline hydrochloride release over the first 7 hours of release is respectively 26-, 18, 17, 12 and 9 ~g/hour.
Example 5 Inserts were made and tested as in Example 4 except that a different ethylene/vinyl acetate copolymer (Elvax 40) was used.
The average tetracycline hydrochloride release over the first 7 hours is, respectively, 25, 15, 12, 9 and 6 ~g/hour.

t~r~lQ ~rh)

Claims (7)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for making a monolithic active agent deliv-ery device comprising a dispersion of solid particulate active agent in a polymer matrix comprising the steps of forming a dispersion of the solid particulate active agent in said matrix and forming the dispersion into a shaped body adapted for placement in the environment of use of the device, character-ized by the additional step of removing the solid particulate active agent from the surface of said body before the body is placed in the environment of use to form an active agent depleted layer of polymer matrix voided by the removal of the particulate solid active agent therefrom, said removing accomplished by washing the body in a liquid which is inert relative to said polymer matrix, the thickness of said layer being at least about 5% of the overall thickness of said body.
2. The process of claim 1 characterized in that said liquid is water.
3. The process of claim 1 characterized in that the polymer matrix is an ethylene/vinyl acetate copolymer and the washing is carried out at about 50°C to about 60°C.
4. The process of any of claims 1, 2 and 3 characterized in that said device is a diffusion type device and said washing is carried out at an elevated temperature at which diffusion of the agent from the matrix is enhanced.
5. The process of any of claims 1, 2 and 3 characterized in that the device is an osmotic bursting type device and the washing is carried out at an elevated temperature at which imbibition of said liquid by the active agent is enhanced.
6. The process of any of claims 1, 2 and 3 characterized in that the thickness of the layer is about 5% to 25% of the overall thickness of the body.
7. The process of any of claims 1, 2 and 3 characterized in that the active agent is a drug.
CA228,740A 1974-06-07 1975-06-06 Process for making a monolithic drug delivery device Expired CA1047403A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US477297A US3923939A (en) 1974-06-07 1974-06-07 Process for improving release kinetics of a monolithic drug delivery device

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CA1047403A true CA1047403A (en) 1979-01-30

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US (1) US3923939A (en)
JP (1) JPS6043327B2 (en)
CA (1) CA1047403A (en)
CH (1) CH611160A5 (en)
DE (1) DE2525061C2 (en)
FR (1) FR2273515A1 (en)
GB (1) GB1477545A (en)
IT (1) IT1036192B (en)
MX (1) MX3007E (en)
SE (1) SE405803B (en)

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US3923939A (en) 1975-12-02
GB1477545A (en) 1977-06-22
JPS6043327B2 (en) 1985-09-27
FR2273515B1 (en) 1980-02-15
DE2525061A1 (en) 1976-01-02
IT1036192B (en) 1979-10-30
JPS5112920A (en) 1976-01-31
FR2273515A1 (en) 1976-01-02
CH611160A5 (en) 1979-05-31
SE405803B (en) 1979-01-08
MX3007E (en) 1980-01-28

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