CH634226A5 - ACTIVE SUBSTANCE DISPENSER AND METHOD FOR THE PRODUCTION THEREOF. - Google Patents

Description

The invention relates to an active substance dispenser which releases an active substance of low water solubility by diffusion from a polymer matrix and a process for its production.

Numerous long-term dispensers, particularly those for drug delivery, have been developed in which a drug is encased in a polymer and which deliver the drug through a diffusion mechanism in which the drug penetrates through the polymer. The aim of these dispensers is to ensure that the drug is dispensed at a more or less constant rate over a longer period of time, which results in improved therapy compared to the periodic administration of drugs in the form of pills, injections or drops. There are basically two types of dispensers of this type, namely monolithic dispensers and dispensers of the container type. In a monolithic dispenser, the drug is dispersed in a polymer that is permeable to it. The amount of time that the drug is released from such donors has been the subject of research and reports are available [sh. T. Higuchi, J.Pharm. Sci., 50, 874 (1961); Roseman, T.J. et al., J.Pharm. Sci., 61, 46 (1972); and H.K. Lonsdale, R.W. Baker, "Controlied Release of Biologically Active Agents," Ed. C. Tanquery, Plenum Press, New York (1974)]. The amount dispensed is proportional to time "'72. A dispense-time graph for a monolithic dispenser provides a curve that begins with a large dispense amount and continues to decrease. Regardless of this variable dispense amount, monolithic dispensers have the advantage of being cheap for industry are to be produced.

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In a container-type dispenser, the drug is enclosed in a container formed by a polymer permeable to the drug. The drug can be in pure form or in combination with a solid or liquid carrier medium. Embodiments of dispensers of the container type with essentially constant drug delivery are described in DE-OS 2 054 488 and 2 247 949.8. The two basic features of these embodiments that permit such delivery are that the drug is placed in a liquid or solid carrier medium that is more permeable to the drug than the container confining polymer and that the concentration of the drug in the carrier medium is kept at the saturation point during the effective dispensing time of the donor. For some medicinal products, such container-like embodiments are the only type of diffusion dispenser with which the medicinal product can be dispensed at a controlled rate which is suitable in practice. Such embodiments also offer the advantage of an essentially constant delivery of the drug, an important factor in terms of effectiveness and safety for many types of treatment. The disadvantage of dispensers of the container type compared to monolithic dispensers lies in the economic field: the former are more complex and therefore more expensive to produce than the monolithic dispensers.

The invention has for its object to provide with simple means an economically producible active ingredient dispenser that meets the requirements in a particularly advantageous manner.

The active substance dispenser according to the invention is defined in claim 1.

The method according to the invention for producing the active substance dispenser is defined in claim 8.

Further advantageous features of the invention are characterized in the subclaims.

The invention is explained in more detail below with the aid of schematic drawings of several preferred embodiments of the active substance dispensers, namely dispensers for dispensing medicinal products. It shows:

1 shows a cross section through a medicament dispenser according to the invention.

2 shows a graphic representation of the release rates of the dispensers described in Example 1 below, the release rate in ng / h on the ordinate and the time in h on the abscissa;

3 shows a graphic representation of the release speeds of the dispensers described in Example 2 below, the release speed in ng / h being shown on the ordinate and the time in h being shown on the abscissa;

4 shows a graphic representation of the release speeds of the dispensers described in Example 3 below, the release speed in ng / h being shown on the ordinate and the time in h being shown on the abscissa; and

Fig. 5 is a front perspective view of another drug dispenser according to the invention.

Fig. 1 shows a drug dispenser designated in its entirety with 10. The medicament dispenser 10 is a three-layer laminate in the form of a thin, circular disc with a core layer 11 and two outer layers 12 and 13 on both sides thereof. The core layer 11 is composed of solid particles of a medicament 14 which are dispersed in a polymer matrix 15 . The base mass 15 has one for the medicament 14

Permeability P, and the thickness of the core layer 11 is 2T. The peripheral surface 16 of the core layer 11 delimits its surface A, which is exposed to the surroundings.

The outer layers 12 and 13 each have a thickness t 'and a permeability p' for the medicament 14. The surfaces 17 and 18 of the outer layers 12 and 13 form a surface A 'which is exposed to the surroundings. The surface formed by the axially directed peripheral surfaces of the outer layers 12 and 13 is also exposed, but can be neglected in relation to the surface A '.

The drug dispenser 10 releases the drug 14 on the surfaces 16, 17 and 18 by a diffusion mechanism. Drug molecules initially dissolve in the matrix 15 and penetrate through it either towards the exposed surface 16 or towards the outer layers 12 and 13 and through this towards the exposed surfaces 17 and 18. The molecules which are the exposed surfaces 16, 17 and 18 are removed or removed from them by contact with body fluids and / or tissue. If the respective permeabilities and thicknesses of the core layer 11 and the outer layers 12 and 13 are set in the correlation given above, i.e. in P t '

the correlation - • -, and if this is greater than about 2, but T p less than 3, drugs 14 are released at the surfaces 17 and 18 at an essentially constant rate, as long as the polymer of the base mass 15 is saturated with the drug 14 is. In contrast, drug 14 is released on the peripheral surface 16 at a steadily decreasing speed proportional to the time ~ '/ 2.

However, if one chooses the mutual relationships between the permeabilities P and p ', the thicknesses 2T and t' and the exposed surfaces A and A 'of the core layer 11 and the outer layers 12 and 13 in the manner indicated above, this is the case Circumferential surface 16 amount of drug released is considerably smaller than the amount of drug released at surfaces 17 and 18. Accordingly, the overall release rate of the drug dispenser 10 is dominated by the release rate of the drug 14 on the surfaces 17 and 18 and thus approaches the substantially constant release rate on the surfaces 17 and 18. This approximation is stronger, the greater the amount of

Pf 'P +'

- • - is. If ^ is less than 2, the outer T p regulate T p

Membranes do not membrane the drug release rate and the rate of release generally decreases in proportion to time ~ VI. If the exposed surface A of the core layer 11 is too large or the permeability P of the core layer 11 is too high, the release of the drug 14 at the core layer circumferential surface 16 predominates, and here too the release rate decreases proportionally to the time -'72. In the intermediate area, however, which represents the solution to the problem according to the invention, none of these effects predominate, and the rate of drug release is almost constant over time. The release rates of these laminates are of course not as constant as those of comparable conventional container-type dispensers, the core of which is not exposed to the environment. However, for many therapies the rate of release rate stability offered by these laminates is acceptable. In such cases, they form a useful, less expensive alternative to the dispenser of the container type.

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Fig. 5 shows another drug dispenser according to the invention. The drug dispenser, designated in its entirety by 19, is a concentric laminate of the shape of a cylinder with a cylindrical core layer 20 and an outer concentric layer 21, which covers the axial surface of the core layer 20. The core layer 20, like the core layer 11, has dispersed particles of a medicament 14 in a polymer matrix 15. It is functionally equivalent to the core layer 11. The end faces 22 and 23 of the core layer 20 form their surface A which is exposed from the surroundings. The diameter of the core layer 20 is 2T. The outer concentric layer 21 has a permeability p 'to the medicament 14 and has a thickness of t \. The layer 21 is functionally the same as the outer layers 12 and 13 and can be made of the same materials as these. An axial surface 24 of the layer 21 forms its surface A 'which is exposed to the surroundings. The surface delimited by the radial edge surfaces of the layer 21 is also exposed, but can be neglected in relation to the surface A '.

The medicament dispenser 19 releases medicament 14 on the surfaces 22, 23 and 24 by means of a diffusion mechanism which is the same as that described above in connection with the medicament dispenser 10. The mutual relationships between the thicknesses 2T and t ', the permeabilities P and p' and the exposed surfaces A and A 'of the core layer 20 and the outer layer 21 of the drug dispenser 19, which are required for this drug 14 to be of a substantially constant Speed releases are the same as described above in connection with the drug dispenser 10.

The drug 14 is solid and must have a low water solubility. Low solubility in water is a prerequisite for ensuring that the medicament 14 does not act to any significant extent as a substance that draws water into the core layer 11 from the surroundings of the application site through osmosis. If a significant amount of water is absorbed, the drug 14 can be released instead of by diffusion due to rupture due to osmosis.

This would undesirably affect the drug release rate. The degree of water solubility will depend in many cases on the permeability of the base mass 15 to water. If the base mass 15 is highly permeable to water, the water solubility of the drug 14 should be correspondingly low and vice versa. Drugs that are less than about 4% by weight soluble in water are useful. Drugs with water solubility less than about 1% by weight are preferred.

The particle size of drug 14 is not critical. Particle sizes in the range between 1 and 20 .mu.m are normally used, since they are easy to handle and can be homogeneously dispersed in the base material 15 by conventional methods without difficulty.

The concentration of drug 14 in core layer 11 is important because it can affect the permeability of core layer 11 to drug 14. At high drug concentrations greater than about 25% by weight, the core layer 11 tends to become microporous during the lifetime of the donor 10. This occurs because when drug particles 14 dissolve in the base 15 and diffuse therefrom, 15 empty spaces remain in the base. At such high drug concentrations, the void or void volume is sufficient to make the portion of the core layer 11 cleared of the drug 14 microporous.

Such microporosity causes an increase in the permeability of the core layer 11. Indeed, high drug concentrations provide a way to make the permeability of the core layer 11 significantly greater than the permeability of the outer layers 12 and 13 even if the same polymer is used in both. The drug concentration in the core layer 11 will depend on the desired drug dosage, with higher concentrations resulting in larger doses and / or release over a longer period of time. The concentration is usually between 30 and 75% by weight of the core layer.

The type of drug will depend on the therapy for which the donor is intended. Drugs can be used that produce a localized effect at the site of administration or a systemic effect at a site remote from the site of administration. Such drugs include inorganic and organic compounds, for example sleeping pills, sedatives, antidepressants, tranquillizers, anticonvulsants, muscle relaxants and anti-Parkinson's disease agents, anti-fever and anti-inflammatory agents, local anesthetics, spasmolytics and anti-ulcer agents, prostaglandins, antibiotics , Hormone preparations, estrogen steroids, steroids of the progesterone series, such as for contraception, sym-pathomimetic, cardiovascular, diuretic, anti-parasite and hypoglycemic and ophthalmic agents.

The base mass 15 can be made from a homogeneous and substantially non-perforated, i.e. no artificially produced openings having polymer material or made of a polymer that has been made microporous by conventional methods. In both cases, its permeability to the drug must be known. Examples of essentially non-perforated polymers which can be used are poly (butyl methacrylate), plasticized polyvinyl chloride), plasticized soft polyamide, natural rubber, poly (isoprene), poly (isobutylene), poly (butadiene), polyethylene), Poly (vinylidene chloride), cross-linked poly (vinylpyrrolidone), chlorinated polyethylene), poly (4,4'-isopropylidene-diphenylene carbonate), ethylene-vinyl acetate copolymer, plasticized ethylene-vinyl acetate copolymer, vinylidene chloride-acrylonitrile-Co- polymer, vinyl chloride-diethyl fumarate copolymer, silicone rubbers, in particular the drug-pure poly (dimethylsiloxanes), ethylene-propylene rubber, silicone car bonate copolymers and vinylidene chloride-vinyl chloride copolymer.

Microporous materials have pores that range in size from at least about 10 Â to several hundred microns, but are usually no more than about 100 µm. Examples of materials that can be produced from which microporous structure, are regenerated, insoluble, nichterodierbare cellulose, acylated cellulose, esterified cellulose, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetatdiäthylaminoacetat, poly (urethanes), poly (carbonates), modified insoluble collagen, cross-linked poly (vinyl alcohol), epoxy resins and poly (olefins) or polyvinyl chlorides). These materials can be made microporous by known methods, for example by co-precipitating or leaching out trapped salts, soap micelles, starch or similar materials. See, for example, J.D. Ferry, Chemical Reviews, 18, 373 (1935) and "Synthetic Polymer Membranes" by R.E. Kesting, McGraw-Hill, 1971.

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The outer layers 12, 13 and 21 can be produced from the same polymers that are listed above for the production of the base material 15. The specific polymer selected from this list for the production of the base composition 15 can be the same or different from the selected special polymer for the production of the layers 12, 13 and 21. Preferably, the permeability P for the medicament of the base composition 15 is considerably greater than the medicament Permeability p 'of the outer layers 12, 13 and 21, either due to the degree of drug concentration mentioned above and / or by making the outer layers 12, 13 and 21 from a polymer which is inherently lower in drug permeability than that used to make it the base 15 polymer used.

The dimensions and shape of the dispenser depend on the environment in which it will be used. If the donor is to be implanted or inserted, its dimensions and shape must be compatible with the dimensions and shape of the implantation or insertion site. If, for example, it is to be used as an ophthalmic insert, its dimensions and shape must be selected so that it can be inserted into the eye and retained there. If it is to be used in other body cavities, for example in the vagina, in the uterus, mouth and gastrointestinal tract, it must be designed with the appropriate dimensions and shape. In most cases it will be possible to use a regular formula. The minimum value of depends on the geometric shape of the A

Donors. With elliptical three-layer laminate

A '

Donors, e.g. for donor 10, -r- has the minimum value

A.

A '

2.75. The minimum value for - with other laminate dispensers

A

with a regular geometric shape is, for example, 2 in the case of a circular disk. In the case of cylindrical concentric laminate dispensers, such as at donor 19

A '

■ j- the minimum value of 15.5.

The composite laminates according to the invention can be produced by known methods. Depending on the special polymers that form the core layer and the outer layers, the layers can be bonded to one another with or without binders to form the laminate. Various binders are known. See, for example, Encyclopedia of Polymer Science and Technology, John Wiley & Sons, Vol. 8.1968. If a binder is used, it should of course be compatible with the polymers forming the layers and not affect or disrupt the migration of the drug through the layers or adversely affect the drug in any way. Conventional lamination devices and processes can be used, the temperatures and pressures used in the individual case changing with the polymers in question. The laminates can be produced as endless webs from which the dispensers according to the invention are cut or punched out according to known methods. The concentric laminates according to the invention can also be produced by known methods, for example by extruding them together.

While the donors have been described above as dispensers for dispensing drugs in the treatment of humans or animals, it is clear that they can be used to release other agents in other environments, provided that such substances are solid, as indicated above and have low water solubility. Such active ingredients include, for example, pesticides, herbicides, germicides, biocides, algicides, rodenticides, fungicides, insecticides, antioxidants, plant growth-promoting and inhibiting agents, preservatives, surface-active agents, disinfectants, catalysts, fermentation agents, nutrients, vegetable minerals, plant infertility agents Hormones, air purifiers and agents to weaken microorganisms.

In the following examples the donors according to the invention and their performance are compared with donors not falling under the invention.

example 1

A. A physostigmine donor, e.g. used to deliver physostigmine for eye treatment was prepared as follows: 50 parts of physostigmine with a particle size of about 5 (in which 50 parts of ethylene vinyl acetate copolymer (Elvax 40 ') were processed in a rubber mill to give a homogeneous mixture The mixture was melt-pressed into a 200 (in thick film. This film was then placed in a vacuum hot laminator and coated on both sides with a 150 (in thick film made of ethylene-vinyl acetate copolymer ('Elvax 40'). The three-layer laminate obtained was used to make the same Ellipses

5.8 mm x 13.5 mm punched out. P, P ', A and A' were determined for these elliptical donors and from them the

P t 'A'

Values for the expressions 4 • - ^ and ^ arithmetically determined

1 p A

telt. These values are listed in Table 1 below.

B. Exactly the same physostigmine dispensers were made in accordance with Part A described above, except that the outer layers were each 75 µm thick. The data for these donors are also shown in Table 1 below.

C. For comparison, exactly the same physostigmine donors were made in accordance with Part A described above, except that the thickness of the outer layers was 13 µm each. The data for these donors are also shown in Table 1 below.

Table 1

P

(mg / cm2-h)

P '

(mg / cm2-h)

A

(cm2)

A '

(cm2)

P t 'Tp'

A 'A

1A

230

70

0.0650

1.23

4.93

18.92

1B

230

70

0.0650

1.23

2.46

18.92

IC

230

70

0.0650

1.23

0.43

18.92

The release rates of dispensers A, B and C were determined by placing individual dispensers in polymer mesh bags and hanging the mesh bags on a vertically up and down rod in vessels in which 50 ml of buffer solution was stirred at 37 ° C . The physostigmine concentration in the buffer was measured at regular intervals by UV analysis, the buffer being replaced after each measurement. The physostigmine release rates were calculated from the measured values. In the diagram of FIG. 2, these release speeds in jxg / h were plotted against the time in h. From the graphic representation in FIG. 2 er5

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It turns out that the release rate of the donor B is considerably more constant than that of the donor C and that it is even more constant with the donor A than with the donor B. This shows the amount shown in Table 1.

P t '

increase in expression - • -.

T p

Example 2

Two sets of chloramphenicol dispensers were made according to the general procedure used for Dispenser A of Example 1. The core layer was made from 66 parts of chloramphenicol with a particle size of about 5 µm and 34 parts copolymer and was 125 µm thick. The thicknesses of the outer layers were 50 and 17.5 µm respectively. The data for these two included Sets 2A and 2B are listed in Table 2 below.

Table 2

P p 'A A' p, A,

(mg / cm2-h) (mg / cm2-h) (cm2) (cm2) - ■ - -r-

T p A

Release speeds plotted in (ig / h versus time in h.

s Example 3

Two sets of hydrocortisone dispensers were made according to the general procedure used for Dispenser A of Example 1. The core layer was made from 60 parts hydrocortisone with a particle size of about 2 µm and 40 parts copolymer and was 150 µm thick. The thicknesses of the outer layers were 50 and 17.5 µm respectively. The data for these two, sentences labeled 3A and 3B are listed in Table 3 below.

Table 3

P P 'A A' p, A,

(mg / cmz-h) (mg / cm2-h) (cm2) (cm2) —- -r-

T p A

3A 72 1.9 0.1 1.23 25.3 12.3

3B 72 1.9 0.1 1.23 8.8 12.3

S2A 90 16 0.1 1.23 4.5 12.3 25

2B 90 16 0.1 1.23 1.6 12.3

The release rates of dispensers 2A and 2B were determined according to the procedure described in Example 1. 3, these are 30

The release rates of dispensers 3A and 3B were determined according to the procedure described in Example 1. 4, these release speeds are plotted in (ig / h against the time in h.

s

1 sheet of drawings

Claims (9)

634226 1. active substance dispenser which releases an active substance with low water solubility by diffusion from a polymer matrix, the dispenser (10; 19) being a laminate, from a) a core layer (11; 20) with a thickness 2T of solid active substance particles (14) dispersed in a polymer matrix (15) with an active substance permeability P and b) at least one of the core layer (11; 20) partially covering outer layer (12, 13; 21) with a thickness t 'of a polymer regulating the release rate of the active substance (14) with an active substance permeability p', so that the core layer (11; 20) has an exposed surface A and the outer layer (en) (12, 13; 21) have an exposed surface A ', characterized in that P t ' 2. Active substance dispenser according to claim 1, characterized in that the active substance (14) is a medicament. 2nd PATENT CLAIMS 3. active ingredient dispenser according to claim 2, characterized in that the dispenser (10; 19) is designed according to dimensions and shape so that it can be inserted into the tear sac of a human eye. - • - ^ 3 T p ' A ' and that the quotient - such a not- A ter 2 lies that the active substance (14) is released to a much greater extent through the outer layer (s) (12, 13; 21) than directly from the core layer, so that its release rate is close to zero order . 4. Active ingredient dispenser according to one of claims 1 to 3, characterized in that P is considerably larger than p ', preferably because of the porosity of the core layer (11; 20), which is caused by the amount of active ingredient (14) contained therein. 5. Active substance dispenser according to one of claims 1 to 4, characterized in that the active substance (14) initially makes up 30 to 75% by weight of the core layer (11; 20). 6. Active substance dispenser according to one of claims 1 to 5, characterized in that the dispenser (10) is a three-layer laminate, in which the core layer (11) is arranged between two outer layers (12, 13), the laminate preferably having the geometric shape a thin circular disc and A ' - è 2 A is or the laminate preferably has the geometric shape of a thin elliptical disc and A ' - è 2.75 A is. 7. Active substance dispenser according to one of claims 1 to 5, characterized in that the dispenser (19) is a concentric laminate, the outer layer (21) of which is arranged concentrically with the core layer (20) and covers the axial surface thereof, the laminate preferably being circular cylindrical and A ' - è 15.5 A is. 8. The method for producing an active substance dispenser according to claim 1, characterized in that a) a core is a solid layer with a thickness of 2T from a mixture of solid active substance particles, the water solubility of which is low, and a polymer with an active substance Permeability P is produced and b) at least part of the outside of the core is laminated with at least one outer layer with a thickness t 'of a polymer which regulates the release rate of the active substance and has an active substance permeability p', so that the core layer has an exposed surface A and the outer layers) overall have an exposed surface A ', wherein P t ' - ■ - è 3 T p ' A ' and, in addition, the quotient - not one A has a value below 2 that the active substance (14) is released to a much greater extent through the outer layer (s) (12, 13; 21) than directly from the core layer, so that its release rate is close to zero order . 9. The method according to claim 8, characterized in that a drug is used as the active ingredient.