KR960002188B1 - Method for delivering an active ingredient by controlled time - Google Patents

Abstract

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Description

Method of delivering active ingredient by controlled time release as delivery excipient using active ingredient

The present invention relates generally to delivery excipients used in time release methods for the delivery of active ingredients and to methods for preparing such excipients.

There are many types of controlled release products currently in use for many applications, including pharmaceutical, agricultural and veterinary applications. Generally speaking, the active ingredient demolds over time.

The active ingredient may be a coating material (e.g., spherical, granular, plural coating or pill), a solid solution (e.g., bead, film, bandage or cube), a composition (e.g. spherical, tablet, pill or strip), a container (e.g. , Capsules, empoules or capillaries), and combinations (eg, in liquids, in capsules or pills).

Microencapsulation is the most common method of preparing time release delivery excipients. In general, microencapsulation uses coatings to include active ingredients that are demolded by breaking or dissolving the coating.

The coating or membrane is also semipermeable or porous to allow the active ingredient to be released from the microcapsules.

U. S. Patent No. 4,322, 311 discloses an encapsulation technique for preparing semipermeable or controlled porous microcapsules. The active ingredient and the monomer in the first solution are emulsified in a hydrophobic solvent. Monomers that replenish soluble first monomers in the hydrophobic solvent are added to the emulsion to initiate interfacial polymerization for aqueous droplets. During the reaction, the affinity of the continuous phase for the first monomer is changed by adding a solvent to the continuous phase to change its polarity. This promotes diffusion into the continuous phase from the result of the porous membrane.

Since this patent describes the use of amine monomers, some amine monomers remain encapsulated in microcapsules.

Another encapsulation technique is disclosed in US Pat. No. 4,444,699, where small capsules are made at one time. This method utilizes polycondensation of formaldehyde and melamine or methylol melamine or methylated esters of melamine itself or its low molecular weight polymer in an aqueous excipient, the reaction being carried out in the presence of a polyvalent electrolyte and a salt. . However, this method typically leaves a residue of formaldehyde that will cause health problems.

Examples of other encapsulation techniques are disclosed in US Pat. Nos. 4,324,683, 4,353,809, 4,353,888, 4,353,962, 4,391,909, 4,396,670, 4.407,957, 4,439,488 and 4,464,271. Microcapsules made by this type of process have limited mechanical strength, and all active ingredients are demoulded immediately when the membrane breaks down.

This limited mechanical stability raises the problem of coordinating microcapsules into the medium and also limits the shelf life of such delivery excipients.

Microcapsules also typically contain reactive groups that can cause chemical stability problems.

Other delivery excipients for the active ingredient are disclosed in US Pat. No. 3,985,298, which utilizes methods of infiltrating the active ingredient into and into all or partly liquid cellulose polymer-liquid compositions. The active ingredient demolds from the gel matrix, which shrinks or collapses when the active ingredient is removed. The gel structure is not mechanically strong and thus causes mechanical problems associated with microspheres.

Thus, there is a need for an economical time-release delivery excipient with high mechanical strength that is useful for controlled release applications.

The present invention relates to a method for delivering an active ingredient by a controlled time release.

In another aspect of the present invention, a composition in question useful for the method of the present invention and a method of making the same are disclosed.

In the present invention, a delivery excipient composed of a polymer bead having a porous network having an active ingredient in the porous network is used to provide a controlled time release of the active ingredient. Active ingredients include lubricants, thickeners, wetting agents, pigments, insects and flea repellents, fragrances, vitamins, and other pharmaceutical functional ingredients. Delivery excipients are incorporated into media such as gels, creams, lotions, ointments, liquids and applied to the surface. The active ingredient is again demolded by pressure, diffusion, or volatilization. Thus, excipients are particularly suitable for use for a wide range of applications so that the active ingredient can be demoulded preferably by one or more methods.

The delivery excipient according to the present invention has improved mechanical stability with respect to microcapsules or gel delivery excipients.

The delivery excipient according to the present invention has improved mechanical stability with respect to microcapsules or gel delivery excipients.

The porous network structure of the beads according to the present invention is independent of the osmotic pressure that may occur in the prior art delivery excipients. Increased mechanical stability also allows the preparation, progress and handling of delivery excipients under more severe conditions, such as mechanical agitation that destroy or damage prior art gels or microencapsulated delivery excipients.

Thus, the delivery excipient according to the present invention can be easily incorporated in any medium than the prior art delivery excipient is more difficult and expensive.

When the delivery excipient according to the present invention is polymerized from styrene and divinylbenzene, the delivery excipient is conventionally used for delivery excipients because the styrene divinylbenzene polymer beads consist essentially of hydrocarbons having no benzene and having benzene rings. Has greater chemical stability. Since the styrene divinyl benzene polymer beads do not contain a reactive group, the beads cannot easily perform unnecessary reactions, the beads are stable at a very wide pH range, and the beads are highly resistant to normal oxidation and reduction reactions, The beads are stable at higher temperatures, the beads are not damaged by moisture, and the beads can have a longer shelf life. In addition, unlike some conventional delivery excipients, the styrene divinylbenzene polymer beads according to the present invention do not contain any reactive groups or polymers that cause problems such as toxicity, irritation, etc. when applied to the skin.

If a delivery excipient is prepared according to the present invention, the active ingredient is entrapped in the porous network during the polymerization of the beads. Thus, unlike the method of absorbing the active ingredient into the already formed matrix, the active ingredient in the delivery excipient of the present invention has a substantially uniform concentration throughout the porous network.

This uniformity allows for a more controlled time release of the active ingredient from the porous network over time. Furthermore, the delivery excipient of the present invention allows for sustained demolding over a period of time compared to the overall demolding when the membrane of the microencapsulated delivery excipient is broken.

Another advantage of the delivery excipients prepared according to the present invention is that no unreacted monomers are actually present. Therefore, in the microencapsulated delivery excipient, it is difficult to remove unreacted monomer because it is encapsulated with the active ingredient inside the membrane. This problem is particularly acute for some prior art delivery excipients that use urea-formaldehyde microcapsules that cause severe health problems.

It is therefore an object of the present invention to provide a delivery excipient for delivering the active ingredient by controlled time release over a period of time.

These and other objects and advantages of the present invention will be apparent to those of ordinary skill in the art related to the detailed description of the preferred embodiments described below.

According to the invention, the active ingredient is demolded from the porous network by a controlled time release.

An active ingredient is defined as a functional ingredient or ingredient that is demolded from the porous network to perform a certain function.

For example, when the active ingredient is a drug used to treat skin diseases, the active ingredient may be an anti-infective agent (such as antibiotics, fungicides, tooth or home insecticides, or anti-infective agents such as iodine), anti-inflammatory agents, anti-inflammatory drugs, astringents, antiperspirants, keratin It consists of chemicals and caustics, keratin softeners, redness agents, sunscreen agents, colorants, viscous agents, protective agents and detergents. In addition to being used for the treatment of skin diseases, the active ingredients are coagulated in various forms of other applications such as cosmetics, cosmetics and cosmetics, and the active ingredients are used together in the body such as gels, creams, lotions, ointments and liquids.

Delivery excipients containing active ingredients include hand creams, acne products, deodorants, antiperspirants, baby powders, milk powders, lip ice creams, lipsticks, baby creams and lotions, mouse washes, toothpastes, therapeutic face creams and lotions, shampoos, shaving creams It is used in beauty products such as pre and save lotions, hair loss agents and hair care products. The active ingredient consists of the carrier and the reagent used by the carrier to deliver the reagent and the reagent is a functional ingredient.

Thus, for example, a reagent is a solid component suspended in a reagent. Thus, the active ingredient is to be interpreted to encompass the full range of possible compositions or materials as long as the active ingredient is retained in the porous network of the porous beads according to the invention.

Delivery excipients according to the invention can be prepared by polymerizing one or more polymers by free radical suspension polymerization. It is dissolved in a pair of comonomers or monomers, also active inert porogens, to form a solution suspended in one phase or a solvent incompatible with the solution. One example of a phase or solvent is water stabilized with an additive. After the solution is suspended in the phase, the solution and the phase are stirred to form a plurality of droplets of the solution suspended in the phase. After forming the plurality of droplets, the monomers or monomers in the plurality of droplets are activated to initiate a polymerization in which one monomer is crosslinked, or two or more monomers are polymerized to form a network with the porogen retained in the porous network. To form a porous bead having.

This activation is initiated by an initiator that can be dissolved in the monomer solution.

Activation is also initiated by an energy source such as radiation. Inert porogens act as internal diluents during polymerization to introduce macroporous structures, such as porous networks or desired sponges, into post-processed delivery excipients.

Inert porogens should not react with the monomers present during the polymerization or should not interfere with the polymerization. Beads of delivery excipients may or may not swell in inert porogens.

After formation of the porous beads, the beads are separated from the phase and subjected to one or more purification, such as washing, to remove any unreacted monomers or impurities from the beads. Purification of the beads should not be designed to remove porogen from the porous network for each bead. After purification, the beads are dried to obtain a powder, such as powder, consisting of beads containing porogen in a porous network that acts as an active ingredient when the beads are used as a time release delivery excipient.

The preparation of the present invention is designed to control the porosity and particle diameter of the beads, which are actually considered spherical. Under the same polymerization conditions, porosity is increased by increasing the measured or theoretical crosslinking degree or by increasing the porogen concentration in solution. The increase in porosity increases the weight percent of porogen that can be retained in the beads and the surface area of the beads.

In order to reduce the particle diameter under the same polymerization conditions, the stirring or concentration of the dispersant in the bed must be increased. By controlling the porosity and particle diameter of the beads, delivery excipients suitable for use in the methods of the present invention are produced. In general, the beads preferably have a diameter of about 10 to 100 microns and a calculated crosslink greater than about 10%.

The active ingredient should be comprised between about 5 and 60% by weight of the total weight of the delivery excipient consisting of the composition or polymer beads and the active ingredient.

To determine if the composition has sufficient mechanical strength to be used as a delivery excipient to provide controlled time release of the active ingredient, the composition is wet tested. If the composition has a calculated crosslink density and active ingredient concentration so that virtually all active ingredient can be demolded from the porous network when the active ingredient is placed in a solvent where the active ingredient can be dissolved for a time sufficient to wet the beads, The composition can be used in the method of the present invention.

The wetting test is carried out by weighing a dry sample of the test substance containing the initial amount of the active ingredient. The dry sample is mixed with a solvent in which the active ingredient can be dissolved to form a wet sample. When the dry sample consists of the delivery excipient according to the present invention, the wet sample is again stirred for a sufficient time to wet the beads.

The amount of active ingredient demolded into the solvent is measured again. The amount of active ingredient demolded into the solvent is actually equal to the initial amount of active ingredient when the dry sample consists mainly of the delivery excipient, whereas the demolded amount is initially determined if the dry sample contains the actual amount of gel or microencapsulated product. Is actually less than the amount of.

The process of the present invention can be done without the use of expensive and environmentally toxic solvents such as chloroform or other chlorinated solvents often used in interfacial polymerization. Furthermore, since it is desirable to retain the porogen retained in the porous network, no additional washing step is required to dissolve the porogen to be removed from the porous network. Thus, the process of the present invention is very economical and minimizes possible environmental pollution when suitable initiators and phases or solvents are selected.

In order to use the delivery excipient according to the method of the present invention, the delivery excipient is mixed with the medium to form a mixture applied to the surface.

The active ingredient is again demolished from the porous network by energy or force. Control time release is done by diffusion or volatilization, and both methods are prone to change in kinetic energy.

The active ingredient is also demolded by a force such as pressure. Pressure release proceeds gradually and steadily. Pressure demoulding is also initiated by intermittent pressure that will change the concentration of demolded active ingredient from the porous network.

The delivery excipient of the present invention is mechanically subtracted due to the polymer structure of the beads and the degree of crosslinking or copolymerization. The beads can be shaped like a rigid sponge, that is, a network formed by three-dimensional crosslinking or copolymerization, leaving random spaces or holes forming collectively porous networks.

The polymer structure or beads are physically porous because the active ingredient diffuses into the polymer network formed during the polymerization of the beads and the external forces or energy are retained until demolding the porogen from the porous network in the polymerization beads. Retains active ingredients in the network

However, in contrast to the removal or demolding of the gel, which causes the polymer network to collapse when the material is retained in the network, the delivery excipient according to the invention disintegrates or actually collapses the beads when the porogen is removed from the porous network. A minimum calculated cross-linking degree should be retained to give sufficient strength to the entire structure or bead at a given active ingredient concentration to prevent total shrinkage.

The invention further illustrates an embodiment in which the delivery excipient is copolymerized from styrene and divinylbenzene, which are particularly preferred comonomer pairs due to the chemical stability of styrene divinylbenzene. As will be apparent to one of ordinary skill in the art, the term "divinylbenzene" as used herein includes pure divinylbenzene as well as commercial divinylbenzene, which is actually a mixture of divinylbenzene and ethylvinylbenzene. . Other preferred comonomer pairs are vinyl stearate and divinylbenzene, and methyl methacrylate and ethylene glycol dimethyl methacrylate, the active ingredients and porogens in the following examples are mineral oils which are particularly preferred wetting agents in many cosmetic additives. Other similar wetting agents include vegetable oil or sunflower seed oil.

Example 1

Empty the 2,000 ml 4-L flask with a stirrer, condenser, thermometer and nitrogen inlet and fill with nitrogen.

The reaction flask is filled with 900 ml deionized water, 7.2 g of Arabian rubber and 7.2 g of lignosulfonate from the American cans company of the brand Marsperse N-22. The mixture is stirred and heated in an oil barrel at about 60 ° C. until the dispersant dissolves to form one phase. In this mixture, 90.8 g of styrene (purity 99.8%), 45.2 g of commercial divinylbenzene (55.6% divinylbenzene, 42.3% ethylvinylbenzene), 2.5 g of benzoyl peroxide (70% active ingredient and 30% water), and mineral oil 146.0 g of freshly prepared solution are added.

Mineral oil is not easily dissolved in benzoyl peroxide unless the benzoyl peroxide is dissolved in one multimer, so the benzoyl peroxide, which is an initiator, is dissolved in the monomer before adding the mineral oil. The phase and solution are stirred by a mechanical stirrer and the stirring speed is adjusted to obtain a plurality of droplets having a droplet diameter in the range of 5 to 80 microns. Arabian rubber and lignosulfonate serve to stabilize a plurality of droplets.

The reaction mixture is again heated to 95 ° C. and maintained at that temperature for about 18-20 hours at a controlled stirring rate to form porous beads of styrene divinylbenzene having a porous network with mineral oil retained in the porous network. The mixture was again cooled, the porous polymer beads were filtered off from the reaction flask, washed initially with 1 liter of water three times to remove arabic rubber and lignosulfonate, followed by 1 liter of methanol. Washing removes residue and unreacted monomers.

The purified product is dried again to remove methanol and as a result the polymer delivery excipients are white and opaque, exhibiting their macroporosity.

The calculated or theoretical crosslink density of the purified beads is 18.5%. This density is calculated by multiplying the weight of divinylbenzene (45.2 g) by the purity of divinylbenzene (0.556) to obtain the actual weight of pure divinylbenzene divided by the total weight of monomers (45.2 g + 90.8 g).

The surface area of the sample of the purified beads is measured by the BET method to be 7.25 m ² / g, while the co-volume is measured by the nitrogen isothermal adsorption method to be 0.1028 ml / g.

The B.E.T.laws are described in Brunauer, S. Emmet, P.H., and J. Am. Chem. Soc., 60, 309-16 (1938). Nitrogen isotherm adsorption methods include Barrett, E. P., Joyner, L. G. and Helenda, P. P., J. Am. Chem. Soc., 73. 373-80 (1951).

The samples described in these methods are prepared by dissolving mineral oil in ethyl acetate to remove mineral oil from the porous network.

Samples of tablet delivery excipients are also subjected to a wet test. Accurately weigh 2.0 g of purified beads and place into a flask with 250 ml glass stopper. The stopper is placed back into the flask fixed to the Burrel brand mechanical stirrer set at its highest speed 10 for 5 ± 1 minutes. The liquid is immediately filtered with Whatman paper # 54.

The 20 ml sample is pipetted off and placed in a weighed glass vessel placed under a heating lamp or on a steam bath until the hexane vaporizes. The vessel is again placed in an oven maintained at a temperature of 105 ° C for 30 minutes. The vessel is cooled again and weighed.

Calculate the amount of free oil as follows.

Glass oil (%) was 50% of the total volume of the sample.

The sample or delivery excipient consists of about 50% by weight beads and about 50% by weight mineral oil, and in practice all active ingredients are demolded from the porous network of the beads into the solvent.

The particle size of the beads was 40 microns or less with an average particle size diameter in the range of about 10 to 30 microns as measured by an optical microscope.

Another dry sample of tablet delivery excipient is placed in a glass jar with a cap and stored on a shelf with glass doors for about a year. The bottle is air sealed.

After about a year, when the bottle was opened and the sample was visually observed, nothing changed. Wetting tests are performed on samples obtained from bottles.

Example 2-4

These examples are carried out in the same manner as in the reaction conditions of Example 1 except for the weight of the mineral oil and monomers used in the reaction.

These values are described in Table 1.

TABLE 1

The sample obtained in Examples 2-4 has an average particle diameter in the range of about 10 to 50 microns.

Samples from these examples were subjected to the wetting test described in Example 1 and virtually all mineral oil was demolded from the porous network of beads of each example.

The calculated pore volume surface area and crosslink density of each of Examples 2-4 were obtained according to the procedure described in Example 1 and this data is described in Table 2.

TABLE 2

Example 5

This example is carried out in the same manner as in the reaction conditions of Example 1 except for the weight of the mineral oil and monomers used in the reaction.

This example used 42.7 g of styrene, 7.3 g of divinylbenzene (DVB) and 55.0 g of mineral oil.

Theoretical crosslink density was 8.0 and the surface area was 1.93 m ² / g while the porous volume was 0.0284 ml / g.

Average particle diameters range from about 10 to 50 microns.

However, when the sample of this composition was subjected to the wetting test described in Example 1, the amount of free oil was 10% and the composition was a non-macroporous gel bead and could not be used in the controlled time release method of the present invention.

As the invention has been fully described, it will be apparent from the foregoing description that specific compositions, procedures, and processes can be modified in many ways within the scope of the invention.

Therefore, the present invention is not limited to any particular composition, procedure or method except as required by the legal scope of the following claims.

Claims (13)

Dissolving at least one monomer in an inert porogen to form a solution, suspending the solution in a phase incompatible with the solution, stirring the solution and the phase to form a plurality of droplets of the solution suspended in the bed. Activating at least one monomer in the plurality of droplets to polymerize the at least one monomer and to form a porous bead having a porous network having porogen in the porous network that is not substantially disrupted upon removal of the porogen. Separating the porous polymer beads from the phase, removing impurities from the porous polymer beads, and retaining the porogen in the porous network as an active ingredient for forming the delivery excipient. Time release, useful for delivering active ingredients by controlling demolding How to prepare a month excipients. The method of claim 1 wherein one monomer is crosslinked to form porous beads. The method of claim 1, wherein a pair of comonomers are copolymerized to form beads, and the copolymer pair is selected from the group consisting of styrene and divinylbenzene, methyl methacrylate and ethylene glycol dimethyl methacrylate. Way. The method of claim 1 wherein the porogen is a mineral oil. The method of claim 1 wherein the polymer beads have a diameter of about 10 to 100 microns. The method of claim 1 wherein the polymer beads have a calculated crosslink density of greater than about 10%. The delivery excipient is composed of porous polymeric beads of porous network having an active ingredient retained in the porous network, and the porous network does not actually collapse when removing the active ingredient, and the delivery excipient is mixed with a medium. Forming a mixture, applying the mixture to a surface, and demolding the active ingredient from the porous network, wherein the active ingredient is delivered by a controlled time release. 8. The method of claim 7, wherein the delivery excipient has a diameter of about 10 to 100 microns. 8. The method of claim 7, wherein the active ingredient is comprised in the range of about 5 to 60% of the total weight of the delivery excipient. 8. The method of claim 7, wherein the active ingredient is demolded by pressure, diffusion, or volatilization. 8. The method of claim 7, wherein the active ingredient consists of a carrier and a reagent. 8. The method of claim 7, wherein the active ingredient is demolded gradually and continuously from the porous network. The delivery excipient consists of porous polymeric beads of porous network having an active ingredient retained in the porous network, and virtually all of the activity when the beads are placed in a solvent in which the active ingredient can be dissolved for a sufficient time to wet the beads. The delivery excipient having a calculated crosslink density and active ingredient concentration so that the component can be demolded from the porous network, mixing the delivery excipient with a medium to form a mixture, applying the mixture to a surface, and And demolding the active ingredient from the porous network, wherein the active ingredient is delivered by a controlled time release.