Source: https://patents.google.com/patent/US5145675
Timestamp: 2018-03-22 14:01:24
Document Index: 705259807

Matched Legal Cases: ['art 1986', 'art 1986', 'art 1986', 'art 1986', 'art 1986', 'art 1986', 'art 1986', 'art 1991', 'art 1991']

US5145675A - Two step method for preparation of controlled release formulations - Google Patents
Two step method for preparation of controlled release formulations Download PDF
US5145675A
US5145675A US07644869 US64486991A US5145675A US 5145675 A US5145675 A US 5145675A US 07644869 US07644869 US 07644869 US 64486991 A US64486991 A US 64486991A US 5145675 A US5145675 A US 5145675A
US07644869
It has been found that the therapeutic anti-inflammatory activity of fluocinonide-containing beads in a petrolatum-based delivery medium is comparable, based on final weight concentration of the fluocinonide, to that of commercially-available fluocinonide ointments such as Lidex® (Syntex). Thus, ointments formed using the delivery vehicles of the present invention may employ active ingredient concentration parallel to those of typical ointments, i.e., 0.01% to 1% by weight. It should be noted, however, that therapeutically effective anti-inflammatory compositions may include as little as 0.00001% by weight steroid active ingredient and as much as 5% by weight steroid or higher. A range of 0.01% to 0.2% is particularly useful, with 0.01% to 0.05% being preferred for the more active corticosteroids such as the fluocinonides, and 0.01% to 0.1% being preferred for less active corticosteroids such as the betnovates and the triamcinolones. When polymer beads containing active ingredient are used topically in powder form, therapeutic anti-inflammatory activity may be lower than that of commercial ointments, although activity is increased and/or provided over longer time periods if the polymer beads are rubbed occasionally to promote release of the active ingredient.
A 2000 ml four-necked reaction flask equipped with a stirrer, condenser, thermometer, and nitrogen inlet was evacuated and charged with nitrogen. 800 ml deionized water, 6.4 grams of gum arabic and 6.4 grams of a lignosulfonate available from the American Can Co. under the trademark Marasperse N-22, were charged into the reaction flask. The mixture was stirred for about 30 minutes. To this mixture was added a freshly prepared solution of 85.6 grams of styrene (99.8% purity), 102.3 grams commercial divinylbenzene (55% divinylbenzene), 5.33 grams benzoyl peroxide (70% active ingredient and 30% water), and 187.9 grams of toluene to serve as a porogen. The phase and solution were agitated by a mechanical stirrer whose stirring rate of about 900-1200 rpm was adjusted to obtain a plurality of droplets having a droplet diameter smaller than about 50 microns. The gum arabic and lignosulfonate serve to stabilize the plurality of droplets. The reaction mixture was heated to about 78° C. while maintaining a constant rate of stirring and passing a slow stream of nitrogen through the reaction vessel. After about 2 hours cross-linking became noticeable. The mixture was stirred another 22 hours at 78° C. and was then allowed to cool to room temperature. The porous polymeric beads were removed from the reaction flask by filtration and washed several times with water to remove gum arabic and lignosulfonate, followed by several washes of isopropanol/acetone mixed solvent (7:3 by volume) and were finally stirred in 400 ml of isopropanol/acetone mixed solvent (7:3) for 20 hours. The polymer was filtered and dried overnight at 65° C. in vacuo. The yield was practically quantitative. The residual monomers such as styrene, DVB and naphthalene were smaller than about 0.01%.
To obtain beads with a final active ingredient concentration of 0.05%, 7.6 g of the polymer beads described above was combined with 0.4 g of a 1% solution of fluocinonide in propylene carbonate : propylene glycol (7:3) and 14.8 g acetone. The initial slurry was stirred approximately every five minutes over a period of approximately thirty minutes, during which period the mixture became cake-like and, finally, powder-like in consistency. The resulting powder was then oven-dried for approximately three hours at 40°-60° C. and 25 mmHg, at which point the powder had reached a constant weight and the acetone has been removed. Similarly, a 0.25% formulation was prepared by mixing 4.8 g polymer beads, 3.2 g steroid solution and 6.4 g acetone, as described above.
The efficacy of the polymer bead delivery vehicle of the present invention was demonstrated for both the powder and ointment forms of the beads using a vasoconstriction assay. This method is based on the Stoughton-McKenzie vasocontriction assay for corticosteroid formulations (McKenzie, A. W., and Stoughton, R. B., "Method for Comparing Percutaneous Absorption of Steroids," Arch. Dermatol., 86, 608-10 (1962)). All test preparations were placed in identical containers, coded and assigned by random tables to individual test sites. The test subjects were normal adult male and female volunteers not receiving any steroids and who had not participated in any studies using steroids for at least four weeks prior to testing. The forearms of the subjects were prepared by gentle washing and drying. Strips of double-adhesive coated Blenderm® tape with 7×7 mm prepunched squares (3M) are applied to each forearm to isolate the application sites. An appropriate dose of the test formulation (either 2 mg or 3 mg) was then applied to the skin in each square and was spread and rubbed with consistent pressure using a clean HPLC vial at each application site. In cases where powder-form polymer beads containing fluocinonide was used, the forearm was inverted after application and each individual site was gently brushed with a clean square of gauze to remove excess polymer beads. A protective cage was applied over the sites on the forearm designated for "open" application. On the other arm ("occluded") the sites were covered with Saran Wrap®, the margins sealed with tape and a protective cage placed over the sites. After six hours of exposure of the skin to the corticosteroid preparations, all the tapes were removed and the forearms were washed.
As evidenced in Table 1, the powder form polymer bead formulations of the present invention achieved significant vasoconstriction as compared to commercially-supplied Lidex® fluocinonide ointment (Syntex) not using a polymer bead delivery vehicle. Although vasoconstriction due to the powder form polymer beads was somewhat less than that observed with the Lidex® ointment, this difference might have been due to the fact that excess powder formulation was brushed off after application to the forearms. Table 1.1 demonstrates that intermittent rubbing of the powder-form formulations acted to promote and prolong vasoconstriction activity. Table 1.2 demonstrates that the polymer bead delivery vehicle of the present invention, when applied in an ointment form comparable to that of commercially-supplied fluocinonide ointment, achieved a level of vasoconstriction approximately equal to that of the commercially-supplied product. This effect is achieved independent of any rubbing of the polymer bead ointment subsequent to application. It may be expected that such rubbing will further enhance vasoconstriction activity attributable to the delivery vehicle of the present invention.
TABLE 1______________________________________Vasoconstriction Assay Readings-Polymer Powder FormulationsFLUOCINONIDE   Hours After ApplicationFORMULATION    8       24       32    Total %______________________________________Polymer Beads (0.4%)Occluded Application:Sites Responding (%):          50.0    62.5     50.0  162.5Intensity of Response (%):          22.9    22.9     16.7   62.5Polymer Beads (0.4%)Open Application:Sites Responding (%):          62.5    56.3     25.0  143.8Intensity of Response (%):          25.0    18.8      8.3   52.1Ointment (0.05%)Occluded Application:Sites Responding (%):          100.0   87.5     75.0  262.5Intensity of Response (%):          72.9    33.3     27.1  133.3Ointment (0.05%)Open Application:Sites Responding (%):          93.8    100.0    93.8  287.6Intensity of Response (%):          68.8    39.6     31.3  139.7______________________________________ NOTE: Dosage was 2 mg of polymer powder, with entrapped fluocinonide (0.4%), or 2 mg Lidex ® 0.05% fluocinonide ointment. Test sites were rubbed at time zero, washed at time 6 hours, and read at the times indicated.
TABLE 1.2______________________________________Vasoconstriction Assay Readings-Polymer-in-Ointment Formulations            Hours AfterFLUOCINONIDE     ApplicationFORMULATION      8       24     32    Total %______________________________________Polymer Beads(0.05% in Ointment-Occluded)Sites Responding (%)            87.5    68.8   81.3  237.6Intensity of Response (%)            75.0    29.2   29.2  133.4Polymer Beads(0.05% in Ointment-Open)Sites Responding (%)            87.5    62.5   68.8  218.8Intensity of Response (%)            72.9    20.8   25.0  118.7Polymer Beads(0.1% in Ointment-Occluded)Sites Responding (%)            87.5    62.5   68.8  218.8Intensity of Response (%)            66.7    25.0   22.9  114.6Polymer Beads(0.1% in Ointment-Open)Sites Responding (%)            93.8    75.0   81.3  250.1Intensity of Response (%)            72.9    27.1   29.2  129.2Polymer Beads(0.2% in Ointment-Occluded)Sites Responding (%)            75.0    81.3   81.3  237.6Intensity of Response (%)            58.3    29.2   29.2  116.7Polymer Beads(0.2% in Ointment-Open)Sites Responding (%)            93.8    62.5   37.5  193.8Intensity of Response (%)            68.8    25.0   12.5  106.3Commercial Ointment(0.05%-Occluded)Sites Responding (%)            93.8    68.8   68.8  231.4Intensity of Response (%)            79.2    27.1   22.9  129.2Commercial Ointment(0.05%-Open)Sites Responding (%)            87.5    75.0   87.5  250.0Intensity of Response (%)            77.1    27.1   33.3  137.5______________________________________ NOTE: Dosage was 3 mg of petrolatumbased ointment containing polymer powder, with entrapped fluocinonide at indicated proportion, or 3 mg Lide ® 0.05% fluocinonide ointment. Test sites were rubbed at time zero, washed at time 6 hours, and read at the times indicated.
A 2000 ml four-necked reaction flask equipped with a motorized stirrer, reflux condenser, thermometer, and nitrogen inlet were evacuated and purged with nitrogen. 800 parts of deionized water, 6.4 parts of gum arabic and 6.4 parts of a lignosulfonate available from Reed Lignins, Inc., under the trademark Marasperse N-22, were charged to the reaction flask. The mixture was stirred for about 30 minutes at about 50° C. until the dispersants (gum arabic and lignosulfate) dissolved to form an aqueous phase.
To this mixture was added a freshly prepared solution of 85.6 parts of styrene (99.8% purity), 102.3 parts of commercial divinylbenzene (55.6% divinyl benzene, 42.3% ethylvinylbenzene), 5.3 parts of benzoyl peroxide (70% active ingredient and 30% water), and 187.9 parts of toluene to serve as a porogen. The aqueous phase and organic solution were agitated by stirring at a rate adjusted to give a plurality of droplets having an average droplet diameter of about 10-60 microns, as determined by visual observation of a sample of the droplets with an optical microscope (400X) with the droplets being stabilized by the dispersants. This rate was approximately 1200 rpm. The reaction mixture was heated to about 78° C. and constantly stirred while a slow stream of nitrogen is passed through the reaction vessel, thus forming porous beads of cross-linked styrene/divinylbenzene copolymer having heptane entrapped within the network of pores. The mixture was stirred another 22 hours at 78° C. and allowed to cool to room temperature. The mixture was then diluted with 200 parts of water, and the porous polymeric beads were removed from the reaction flask by filtration. The filtered beads were washed initially three times with one liter portions of deionized water to remove the dispersants, followed by several washes of isopropanol/acetone mixture (7:3, respectively, by weight) to remove any residual, unreacted monomer and the heptane used as the porogen during polymerization. The beads were filtered and then dried at 65° C. in vacuo.
In a first example of preparation of polymeric beads having a solution of an active ingredient useful for promoting hair growth dissolved in a percutaneous absorption enhancer held within a network of pores of the polymeric beads, 10.6 mg of the white Minoxidil solid CH 215M was dissolved in 2 grams of a 50:50 solution of propylene carbonate/ethanol. 1.5 grams of the polymeric beads CH 215 was then mixed into the solution until the product is homogeneous. The Minoxidil content in the resulting product, which shall be referred to as CH 215 A-3, was 3 mg/g. In a second example, 1.2 parts of the white Minoxidil solid CH 2l5M, was added to 32.1 parts of propylene glycol and stirred in a flask at 45° C. until the white Minoxidil solid CH 215M was completely dissolved. Thereafter, 61.7 parts of polymeric beads (CH 215) were added to the solution which was mixed until the product is homogeneous. The Minoxidil content in the resulting product was is 12 mg/g.
To this mixture there was then added a freshly prepared solution of 143.3 parts of styrene (99.8% purity), 44.6 parts of commercial divinylbenzene (55.6% divinyl benzene, 42.3% ethylvinylbenzene), 7.7 parts of benzoyl peroxide (70% active ingredient and 30% water), and 144 parts of toluene (porogen). The aqueous phase and organic solution were agitated by stirring at a rate adjusted to give a plurality of droplets having an average droplet diameter of about 10-60 microns, as determined by visual observation of a sample of the droplets with an optical microscope (400X) with the droplets being stabilized by the dispersants. The reaction mixture was then heated to about 95° C. and maintained at that temperature for about 20 hours, at the previously adjusted stirring rate, to form porous beads of cross-linked styrene/divinylbenzene copolymer having toluene entrapped within the network of pores. The mixture was then cooled and the porous polymeric beads were removed from the reaction flask by filtration. The filtered beads were washed initially three times with one liter portions of deionized water to remove the dispersants, followed by three washes with one liter portions of isopropanol to remove any residual, unreacted monomer and the toluene used as the porogen during polymerization. The beads were then dried in an oven at 70° C. for six hours. The average particle diameter of these beads was 10 microns, as measured by optical microscopy.
The suspensions were then filtered and the filtrates washed three times with an aqueous detergent solution (Triton), then three times with deionized water. The washed beads were then oven-dried at 70° C. for 6 hours, and their diethyl-m-toluamide contents were determined by acetone extraction (Sohxlet) to be 45%.
A 0.5 part sample of the diethyl-m-toluamide containing beads of Example 3.3, on a sheet of filter paper, and a sheet of filter paper impregnated with an equivalent amount of diethyl-m-toluamide, were heated under a vacuum of 25 inches of mercury at 100° C. for 10 hours, during which time the percentage weight loss of diethyl-m-toluamide was determined each hour by weighing the bead and filter paper samples. The results of these weight loss determinations are shown graphically in FIG. 1, and demonstrate that a high degree of sustained release can be achieved using the polymeric delivery systems of this invention.
A 2000 ml four-necked reaction flask equipped with a motorized stirrer, reflux condenser, thermometer, and nitrogen inlet was evacuated and purged with nitrogen. 800 parts of deionized water, 6.4 parts of gum arabic and 6.4 parts of a sodium-based lignosulfonate available from Reed Lignins, Inc., under the trademark Marasperse N-22, were charged to the reaction flask. The mixture was heated, with stirring, in an oil bath at about 50° C. until the dispersants (gum arabic and lignosulfate) dissolved to form an aqueous phase.
To this mixture there was then added a freshly prepared solution of 102.3 parts of styrene (99.8% purity), 85.6 parts of commercial divinylbenzene (55.6% divinyl benzene, 42.3% ethylvinylbenzene), 5.3 parts of benzoyl peroxide (70% active ingredient and 30% water), and 130 parts of heptane. The aqueous phase and organic solution were agitated by stirring at a rate adjusted to give a plurality of droplets having an average droplet diameter of about 10-60 microns, as determined by visual observation of a sample of the droplets with an optical microscope (400X) with the droplets being stabilized by the dispersants. This rate is approximately 1200 rpm. The reaction mixture was then heated to about 80° C. and maintained at that temperature for about 20 hours, at the previously adjusted stirring rate, to form porous beads of cross-linked styrene/divinylbenzene copolymer having heptane entrapped within the network of pores. The mixture was then cooled, diluted with 200 parts of water, and the porous polymeric beads were removed from the reaction flask by filtration. The filtered beads were washed initially three times with one liter portions of deionized water to remove the dispersants, followed by three washes with 0.6 liter portions of isopropanol: acetone mixture (7:3, respectively, by weight) to remove any residual, unreacted monomer and the heptane used as the porogen during polymerization. The beads were then dried in an oven at 80°-100° C. for eight hours.
TABLE 4.1__________________________________________________________________________Ratio Of Parts         Calculated               Avg.  Surface                          PoreStyrene/Divinyl-         Crosslnkng               Particle                     Area VolumeExampleBenzene/Porogen         Density, %               Diam, μm                     m.sup.2 /g                          ml/g__________________________________________________________________________2    89/100/180         29    25    75   1.36(porogen =mineral oil)3    85.6/102.3/188         30    25    1.8  0.04(porogen =toluene)__________________________________________________________________________
A 2000 ml four-necked reaction flask equipped with a motorized stirrer, reflux condenser, thermometer, and nitrogen inlet was evacuated and purged with nitrogen. 800 part of deionized water, 6.4 parts of gum arabic and 6.4 parts of sodium-based lignosulfonate (Reed lignin) available from the American Can Co. under the trademark Marasperse N-22, were charged to the reaction flask. The mixture was heated, with stirring, in an oil bath at about 50° C. until the dispersants (gum arabic and lignosulfate) dissolved to form an aqueous phase.
To this mixture there was then added a freshly prepared solution of 85.6 parts of styrene (99.8% purity), 102.3 parts of commercial divinylbenzene (55.6% divinyl benzene, 42.3% ethylvinylbenzene), 5.3 parts of benzoyl peroxide (70% active ingredient and 30% water), and 188 parts of toluene (porogen). The aqueous phase and organic solution were agitated by stirring at a rate adjusted to give a plurality of droplets having an average droplet diameter of below about 60 microns, as determined by visual observation of a sample of the droplets with an optical microscope (400X) with the droplets being stabilized by the dispersants. This rate was approximately 1000 rpm. The reaction mixture was then heated to about 78° C. and maintained at that temperature for about 20 hours, at the previously adjusted stirring rate, to form porous beads of cross-linked styrene/divinylbenzene copolymer having toluene entrapped within the network of pores. The mixture was then cooled, diluted with 1000 parts of water, and the porous polymeric beads removed from the reaction flask by filtration. The filtered beads were washed initially three times with one liter portions of water to remove the dispersants, followed by three washes with one liter portions of acetone to remove any residual, unreacted monomer and the toluene used as the porogen during polymerization. The beads were then dried in an oven at 70° C. for 10 hours. These beads were white and opaque in appearance, indicating the microporosity, and had an average particle diameter of less than 50 microns. They had a pore volume of 0.04 ml/g as measured by a mercury intrusion porosimeter.
The reaction mixture was then heated to 80° C. and maintained at that temperature for 6 hours while maintaining a nitrogen flow of 1 ml/minute, to form porous beads of cross-linked methyl methacrylate/butyl methacrylate/ethylene glycol dimethacrylate terpolymer having toluene entrapped within the pores. The reaction mixture was then cooled and the beads were collected by filtration, washed three times with 1000 parts of water, and three times with 1000 parts of isopropanol, and then dried in air at room temperature.
A 1 part sample of each batch of fragrance containing beads, together with a 0.5 part sample of unabsorbed fragrance absorbed on filter paper, were held in air at room temperature (about 25° C.) and atmospheric pressure for 24 hours, during which time the percentage weight loss by weighing the bead and filter paper samples. The results of these weight loss determinations demonstrated that a high degree of sustained release over a longer period of time was achieved using the polymeric fragrance delivery systems of this invention.
The reaction mixture was then heated to about 75° C. and maintained at that temperature for 10 hours to form porous beads of cross-linked styrene/divinylbenzene copolymer having heptane entrapped within the pores. The reaction mixture was then cooled to room temperature and the resulting polymeric beads collected by filtration, washed three times with 1000 parts of deionized water, and three times with 1000 parts of acetone, then dried in a vacuum oven at 80° C. for 24 hours.
The reaction mixture was heated to 65° C. for 1 hour, then 75° C. and allowed to remain at this temperature for approximately 7 hours while maintaining a nitrogen flow of 2 ml/minute to form porous beads of cross-linked methacrylate/ethyleneglycoldimethacrylate copolymer having toluene entrapped within the pores. The reaction mixture was then cooled and the beads collected by filtration, washed three times with 1000 parts of deionized water, and three times with 1000 parts of acetone, then dried in a vacuum oven at 80° C. for about 24 hours.
A two-liter four-necked reaction flask equipped with a stirrer driven by a variable speed motor, reflux condenser, thermometer, and nitogen inlet tube was set up. A slow flow of nitrogen was maintained through the reaction flask, and an aqueous phase consisting of 4.5 g gum arabic and 4.5 g sodium lignosulfate (Marasperse N-22, available from Reed Lignin, Inc.) was added to 450 ml of deionized water in the flask. An organic solution made up of 52.0 g methyl methacrylate glycol dimethacrylate and 78.0 g ethylene glycol dimethacrylate is stirred in a separate beaker, and 150.0 g of octyl dimethyl PABA added thereto. The organic solution with octyl dimethyl PABA was then added to the reaction flask without stirring, and 2.0 g benzoyl peroxide dissolved in 20.0 g methyl methacrylate in a separate beaker. The benzoyl peroxide-methacrylate solution was then poured into the flask while continuing to purge with a slow stream of nitrogen. After addition of the benzoyl peroxide methyl methacrylate solution, the mixture was stirred at 2600 rpm for about 10 minutes. Sample of the monomer droplets were obtained and examined, and the stirring speed adjusted to obtain an average droplet size of about 45 microns. The stirring speed was reduced to 1300 rpm after the desired particle size had been obtained. The reaction mixture was then heated to 40° C. and maintained at that temperature for 30 minutes, and the temperature then increased to 60° C. for 5.5 hours. After cooling the mixture to room temperature, the polymer beads were collected on a Buchner funnel under vacuum, washed three times with one liter of water, and dried under a fume hood.
To this mixture was then added a freshly prepared solution of 90.5 parts of styrene (99.8% purity), 55 parts of commercial divinylbenzene (55.6% divinyl benzene, 42.3% ethylvinylbenzene), 2 parts benzoyl peroxide (70% active ingredient and 30% water), and 69.4 parts of heptane (porogen). The aqueous phase and organic solution were agitated by stirring at a rate adjusted to give a plurality of droplets having an average droplet diameter of about 10-60 microns, as determined by visual observation of a sample of the droplets with an optical microscope (400X) with the droplets being stabilized by the dispersants. This rate was approximately 1200 rpm. The reaction mixture was then heated to about 80° C. and maintained at that temperature for about 12 hours, at the previously adjusted stirring rate, to form porous beads of cross-linked styrene/divinylbenzene copolymer having toluene entrapped within the network of pores. The mixture was then cooled and the porous polymeric beads are removed from the reaction flask by filtration. The filtered beads were washed initially three times with one liter portions of deionized water to remove the dispersants, followed by three washes with 0.6 liter portions of isopropanol to remove any residual, unreacted monomer and the toluene used as the porogen during polymerization. The beads were then dried in an oven at 80° C. for eight hours.
The procedure of Example 7.1 was repeated in every essential detail, except for the following: 800 parts of deionized water were used to dissolve 5.6 parts of gum arabic and 5.6 parts of Marasperse N-22 at about 23° C.; 105 parts of styrene and 9.5 parts of divinylbenzene were used; 2.8 parts of benzoyl peroxide (70% active ingredient and 30% water) and 120 parts of heptane were employed during polymerization and stirring was adjusted to give an average droplet diameter of below about 50 microns (rate approximately 800-1600 rpm); three 300 ml portions of isopropanol were used to wash the beads. The macroporous cross-linked polymer beads obtained had the following characteristics:
______________________________________Calculated Cross-linking Density, %:                  26.4Average Particle Diameter, μ:                  25Surface Area, m.sup.2 /g:                  85.9Pore Volume, ml/g:     0.44______________________________________
A two liter four-necked reaction flask equipped as described in Example 7.1 was evacuated and purged with nitrogen. An aqueous phase made up of 600 parts of deionized water, 6.0 parts of gum arabic and 6.0 parts of Marasperse N-22 was added to the flask, and an organic solution made up of 72.0 parts of methyl methacrylate, 78.0 parts of ethylene glycol dimethacrylate, 2.0 parts of benzoyl peroxide (70% active ingredient and 30% water) and 108.4 parts of toluene was dispersed in the aqueous phase with strong agitation (stirrer speed approximately 1000 rpm) to obtain a plurality of droplets having an average droplet diameter of below about 50 microns, as determined by visual observation of a sample of the droplets with an optical microscope (400 ×), with the droplets being stabilized by the dispersants.
The reaction mixture was then heated to 80° C. and maintained at that temperature for 12 hours while maintaining a nitrogen flow of 6 ml/minute, to form porous beads of cross-linked methyl methacrylate/ethylene glycol dimethacrylate copolymer having toluene entrapped within the pores. The reaction mixture was then cooled and the beads were collected by filtration, washed three times with 1000 part portions of water, then three times with 1000 part portions of isopropanol, and then dried at 80° C. for about 8 hours.
The procedure of Example 7.3 was again repeated in every essential detail except for the following: 400 parts of deionized water were used to dissolve 4.0 parts of gum arabic and 4.0 parts of Marasperse N-22; 70 parts of methyl methacrylate and 30 parts of ethylene glycol dimethacrylate were used; 1.0 part of lauroyl peroxide and 69.4 parts of toluene were employed during polymerization; the reaction was conducted at 85° C. for 12 hours. The resulting polymer beads were collected and washed with three 1000 ml portions of deionized water followed by three 1000 ml portions of isopropanol, and then dried at 80° C. for about 8 hours. The macroporous cross-linked polymer beads obtained had the following characteristics:
______________________________________Calculated Cross-linking Density, %:                  30Average Particle Diamter, μm:                  30Surface Area, M.sup.2 /g:                  12.54Pore Volume, ml/g:     0.170______________________________________
A 2000 ml four-necked reaction flask equipped with a motorized stirrer, reflux condenser, thermometer, and nitrogen inlet was evacuated and purged with nitrogen. 1200 parts of deionized water, 9.6 parts of gum arabic and 9.6 parts of a sodium-based lignosulfonate available from Reed Lignins, Inc., under the trademark Marasperse N-22, were charged to the reaction flask. The mixture was heated, with stirring, in an oil bath at about 50° C. until the dispersants (gum arabic and lignosulfate) dissolved to form an aqueous phase.
To this mixture there was then added a freshly prepared solution of 90.5 parts of styrene (99.8% purity), 55 parts of commercial divinylbenzene (55.6% divinyl benzene, 42.3% ethylvinylbenzene), 2 parts of benzoyl peroxide (70% active ingredient and 30% water), and 69.4 parts of heptane. The aqueous phase and organic solution were agitated by stirring at a rate adjusted to give a plurality of droplets having an average droplet diameter of about 10-60 microns, as determined by visual observation of a sample of the droplets with an optical microscope (400X) with the droplets being stabilized by the dispersants. This rate is approximately 1200 rpm. The reaction mixture was then heated to about 85° C. and maintained at that temperature for about 12 hours, at the previously adjusted stirring rate, to form porous beads of cross-linked styrene/divinylbenzene copolymer having heptane entrapped within the network of pores. The mixture was then cooled and the porous polymeric beads were removed from the reaction flask by filtration. The filtered beads were washed initially three times with one liter portions of deionized water to remove the dispersants, followed by three washes with one-liter portions of isopropanol to remove any residual, unreacted monomer and porogen. The beads were then dried in an oven at 80° C. for eight hours. The average particle diameter of these beads, which were white and opaque in appearance, indicating their macroporosity, was less than 35 microns, as measured by a Sedimentation Micromeritics Microsizer 5300, an instrument available from Micromeritics Instrument Company, Norcross, Ga. The particle diameter determination method is described in detail in the "Microsizer 5300 Particle Size Analyzer Instruction Manual" (1984) associated with the instrument.
The procedure of Example 7.18 was repeated in every essential detail, except for the following: 750 parts of deionized water were used to dissolve 7.0 parts of gum arabic and 7.0 parts of Marasperse N-22 at about 23° C.; 75 grams of styrene and 75 grams of divinylbenzene were used; 1.0 part of benzoyl peroxide and 65.03 parts of heptane were employed during polymerization and stirring was adjusted to give an average droplet diameter of below about 50 microns (rate approximately 800-1600 rpm); and three 300-ml portions of isopropanol were used to wash the beads. The macroporous cross-linked polymer beads obtained had the following characteristics:
The reaction mixture was then heated to 85° C. and maintained at that temperature for 12 hours while maintaining a nitrogen flow of 2 ml/minute, to form porous beads of cross-linked methyl methacrylate/ethylene glycol dimethacrylate copolymer having toluene entrapped within the pores. The reaction mixture was then cooled and the beads collected by filtration, washed three times with 1000 part portions of water, and three times with 1000 part portions of isopropanol, then dried in air at 80° C. for about 8 hours.
To this mixture there was then added a freshly prepared solution of 102.3 parts of styrene (99.8% purity), 85.6 parts of commercial divinylbenzene (55.6% divinyl benzene, 42.3% ethylvinylbenzene), 5.3 parts of benzoyl peroxide (70% active ingredient and 30% water), and 130 parts of heptane. The aqueous phase and organic solution were agitated by stirring at a rate adjusted to give a plurality of droplets having average droplet diameter of about 10-60 microns, as determined by visual observation of a sample of the droplets with an optical microscope (400X) with the droplets being stabilized by the dispersants. This rate is approximately 1200 rpm. The reaction mixture was then heated to about 80° C. and maintained at that temperature for about 20 hours, at the previously adjusted stirring rate, to form porous beads of cross-linked styrene/divinylbenzene copolymer having heptane entrapped within the network of pores. The mixture was then cooled, diluted with 200 parts of water, and the porous polymeric beads were removed from the reaction flask by filtration. The filtered beads were washed initially three times with one liter portions of deionized water to remove the dispersants, followed by three washes with 0.6 liter portions of isopropanol: acetone mixture (7:3, respectively, by weight) to remove any residual, unreacted monomer and the heptane used as the porogen during polymerization. The beads were then dried in an oven at 80°-100° C. for eight hours. The average particle diameter of these beads was 25 microns, as measured by a Sedimentation Micromeritics Microsizer 5300, an instrument available from Micromeritics Instrument Company, Norcross, Ga. The particle diameter determination method is described in detail in the "Microsizer 5300 Particle Size Analyzer Instruction Manual" (1984) associated with the instrument.
The reaction mixture was then heated to 80° C. and maintained at that temperature for 6 hours while maintaining a nitrogen flow of 1 ml/minute, to form porous beads of cross-linked methyl methacrylate/butyl methacrylate/ethylene glycol dimethacrylate terpolymer having toluene entrapped within the pores. The reaction mixture was then cooled and the beads collected by filtration, washed three times with 1000 parts of water, and three times with 1000 parts of isopropanol, then dried in air at room temperature.
In these examples, preformed dry polymer beads from Examples 8.1 through 8.5 were impregnated with counterirritants or counterirritant solutions at specified proportions by combining the beads and counterirritant (or its solution), then mixing the resulting wet powder until it was homogeneous. In all cases except Example 8.12, the beads and counterirritant were combined and mixed at room temperature. In Example 8.12, the menthol, which is solid at room temperature, was first melted to liquid form by heating to 80° C., which temperature was maintained as the compounds were combined and mixed Counterirritant contents of the finished products in all cases including Example 8.12 were then determined by extraction and analysis according to conventional techniques. The materials, proportions, and final counterirritant contents are listed in Table 8.3. Example 8.15 is a prophetic example.
A two-liter four-necked reaction flask equipped as described in Example 8.1 was evacuated and purged with nitrogen. An aqueous solution made of 800 parts of deionized water, 8 parts of gum arabic and 8 parts of Marasperse N-22 was added to the flask, and an organic solution made up of 120 parts of methyl methacrylate, 80 parts of ethylene glycol dimethacrylate, 10 parts of butyl methacrylate, 100 parts of menthol, 100 parts of mineral oil and 2 parts of lauroyl peroxide was dispersed in the aqueous phase were agitated by stirring at a rate adjusted to give a plurality of droplets having an average droplet diameter of about 10-60 microns. The reaction mixture was then heated to about 78° C. and maintained at that temperature for about 20 hours, to form porous beads of cross-linked methyl methacrylate/butyl methacrylate/ethylene glycol dimethacrylate terpolymer having mineral oil and menthol entrapped within the pores. The mixture was then cooled, diluted with 200 parts of water, and the porous polymeric beads were removed from the reaction flask by filtration. The filtered beads were washed three times with one liter portions of deionized water to remove the dispersants. The beads were then dried in air at room temperature.
To this mixture there was then added a freshly prepared solution of 102.3 parts of styrene (99.8% purity), 85.6 parts of commercial divinylbenzene (55.6% divinyl benzene, 42.3% ethylvinylbenzene), 5.3 parts of benzoyl peroxide (70% active ingredient and 30% water), and 130 parts of heptane. The aqueous phase and organic solution were agitated by stirring at a rate adjusted to give a plurality of droplets having an average droplet diameter of about 10-60 microns, as determined by visual observation of a sample of the droplets with an optical microscope (400X) with the droplets being stabilized by the dispersants. This rate is approximately 1200 rpm. The reaction mixture was then heated to about 80° C. and maintained at that temperature for about 20 hours, at the previously adjusted stirring rate, to form porous beads of cross-linked styrene/divinylbenzene copolymer having heptane entrapped within the network of pores. The mixture was then cooled, diluted with 200 parts of water, and the porous polymeric beads were removed from the reaction flask by filtration. The filtered beads were washed initially three times with one liter portions of deionized water to remove the dispersants, followed by three washes with 0.6 liter portions of isopropanol:acetone mixture (7:3, respectively, by weight) to remove any residual, unreacted monomer and the heptane used as the porogen during polymerization. The beads were then dried in an oven at 80°-100° C. for eight hours. The average particle diameter of these beads was 25 microns, as measured by a Sedimentation Micromeritics Microsizer 5300, an instrument available from Micromeritics Instrument Company, Norcross, Ga. The particle diameter determination method is described in detail in the "Microsizer 5300 Particle Size Analyzer Instruction Manual" (1984) associated with the instrument.
The reaction mixture was then heated to 85° C. and maintained at that temperature for 12 hours while maintaining a nitrogen flow of 2 ml/minute, to form porous beads of cross-linked methyl methacrylate/ethylene glycol dimethacrylate copolymer having toluene entrapped within the pores. The reaction mixture was then cooled and the beads collected by filtration, washed three times with 1000 parts of water, and three times with 1000 parts of isopropanol, then dried in air at 80° C. for about 8 hours.
A two-liter four-necked reaction flask equipped as described in Example 9.1 was evacuated and purged with nitrogen. A mixture made up of 900 parts of deionized water, 7.2 parts of gum arabic, and 7.2 parts of Marasperse N-22 was charged to the flask. The mixture was heated with stirring in an oil bath at about 50° C. until the dispersants (the gum arabic and the lignosulfonate) dissolved, to form an aqueous phase.
To this mixture there was then added a freshly prepared solution of 71 parts styrene (99.8% purity), 84 parts of commercial divinylbenzene (55.6% divinylbenzene and 42.3% ethylvinylbenzene), 7.0 parts of benzoyl peroxide (70% active ingredient, 30% water) and 135 parts of squalane. The aqueous and organic phases were agitated by stirring at a rate adjusted to give a plurality of droplets having an average droplet diameter of about 10-60 microns, as determined by visual observation of a sample of the droplets with an optical microscope (100X), the droplets being stabilized by the dispersants. This rate was approximately 1200 rpm. The reaction mixture was then heated to about 89° C. and maintained at that temperature for about 20 hours, at the previously adjusted stirring rate, to form porous beads of cross-linked styrene/divinylbenzene copolymer having squalane retained within the network of pores.
1. A method for preparing a delivery system for an active substance, said method comprising:
polymerizing monomers suspended in an immiscible phase in the presence of a porogen to form a plurality of rigid cross-linked polymer beads each defining a substantially non-collapsible internal pore network having residual porogen therein, wherein the beads have a cross-linking density in the range from 20% to 80% and the pore network is open to the exterior of the beads;
extracting substantially all residual porogen from the internal pore network; and
introducing the active substance into the internal pore network after the porogen has been substantially completely extracted, whereby the porogen and polymerization conditions may be selected to provide pore dimensions which result in desired release characteristics for an active substance from the beads.
2. A method as in claim 1, further comprising removing unbound organic species from the internal pore network by washing the beads in a solvent after the residual porogen has been extracted and drying the solvent prior to introducing the active substance.
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