JPS6048484B2 - Diffusable activator dispenser - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is an improvement in a diffusible active agent dispenser;
Improvements in active agent dispensers, especially where the active agent is a drug and which operate by a diffusion mechanism in which water diffuses into the dispenser through the microporous walls and the active agent in solution form diffuses out of the dispenser through the microporous walls. It is in.

With respect to the diffusible active agent dispensers of the present invention intended for use in aqueous environments, the dispensers of the present invention are coated with a polymer that swells and becomes porous allowing water to reach the core and dissolve the active agent composition. It consists of an inner core of water-soluble active agent composition surrounded by a material or wall.

The resulting solution of active agent diffuses out of the dispenser through holes in the wall. As long as the solution is saturated with active agent, the rate of active agent release is substantially constant. As the active agent is released from the dispenser, the active agent concentration in the solution eventually drops below saturation. Once this phenomenon occurs, the release rate will change depending on the primary force (flrstorder
kinetics) and begin to decline. It is an object of the present invention to prolong the time during which the solution of active agent in the core remains saturated, thus prolonging the time during which the release rate is substantially constant. The present invention comprises an outer microporous wall defining an internal compartment and a water-soluble active agent composition contained within the compartment, the compartment also having at least one swellable material that swells in response to absorption of water. A dispersible active agent dispenser in the form of a tablet, characterized in that it contains a core of osmotic solute, a gas-generating couple or a water-swellable polymer and surrounding said core. It consists of an expandable semi-permeable membrane.

1 To operate, the dispenser is placed in an aqueous environment and water from the surroundings diffuses through the pores of the microporous wall into the internal compartment where the water dissolves the active agent composition and saturates it. Produce a solution.

The resulting solution diffuses out of the dispenser through the holes. At the same time, water within the compartment is absorbed into the swellable membrane through the semi-permeable wall of the member. The member expands in response to absorbed water under hydrostatic forces if the member core is made from an osmotic solute, and if the member core is made from a water-swellable polymer. Swells and, if the member core is made of gas-generating couples, expands due to air pressure. Absorption of water by the member reduces the amount of water available for dissolving the active agent composition, and expansion of the member reduces the volume of the compartment occupied by the solution of the active agent composition. As a result, saturation is maintained for a longer period of time. In the drawing:
) FIG. 1 is an enlarged perspective view of a tablet-shaped dispenser for oral administration of drugs to warm-blooded animals;
3 is a cross-sectional view showing the arrangement of parts during operation of the dispenser of FIG. 1; and FIG. 3 compares the theoretical release rate versus time of the dispenser of FIG. 1 with the theoretical release rate versus time of drug from a prior art dispenser. This is a graph shown as follows.

Figures 1 and 2 show a tablet-shaped dispenser, generally indicated at 10. The dispenser mouth is defined on the outside by a shape-retaining wall 12 having a plurality of holes 16 (which are depicted as circular for illustrative purposes) and encloses an interior compartment 13. Main body 11
It becomes more. Compartment 13 contains a water-soluble drug composition and an inflatable member 15. The member 15 is an osmotic solute composition, a water-swellable polymer, or an inner core 18 of a gas-generating couple.
It consists of an outer inflatable semi-permeable member 15 enclosing. Once the dispenser is inflated, it looks like this: Operate.

Water from the gastrointestinal tract diffuses into the dispenser through holes 16 in wall 12 and dissolves composition 14. Composition 14
is shown in solution form in FIG. Once in solution form, composition 14 diffuses outward through pores 16 into the gastrointestinal tract. Ma. Also, if water is present in the dispenser,
Member 15 becomes active. Water from the solution of composition 14 diffuses through semipermeable membrane 17 and reaches wick 18 . Core 18
If the solute is comprised of an osmotic solute, the water dissolves the solute and an osmotic barrier is established through the membrane 17 between the solution of composition 14 and the solute solution. As a result, more water is absorbed by the member 15 through the membrane 17. The resulting water pressure causes member 15 to expand. If the core 18 is comprised of a water-swellable polymer, the water will swell the polymer and thus the member 15 will expand. If the wick 18 is comprised of a gas-generating couple, water reacts with the couple and
Generates gas. The resulting air pressure causes member 15 to expand. As member 15 absorbs water, the water content of the solution of composition 14 decreases. As member 15 expands, the volume within compartment 13 that can be occupied by the solution of composition 14 decreases. The net result of this combined action is to maintain the saturation of the solution of composition 14, thus maintaining unit activity. FIG. 3 shows the drug release rate versus time (dotted line DEF) from the dispenser of FIG. 1 for a similar dispenser without inflatable member 15 (solid line A).
BC).

As shown, the constant release rate is extended from time B to time E, and the ramp from constant to empty is more rapid for the dispenser of FIG.
The microporous material forming wall 12 has a plurality of interconnected micropores or pores when the dispenser is in operation.

The pores generally occupy 5% to 95% of the volume of the material and have dimensions of 50 angstroms to 100 microns. The pores may be preformed in the material or may be formed in situ within the gastrointestinal tract. Polymers and pore formation techniques that can be used to make such materials are well known. Examples of pore pre-formation techniques include etching the polymer by atomic tracking, cooling the polymer solution to form solvent crystals in the polymer, and then curing the polymer to remove the crystals. One method is to stretch the film and then leach the soluble components from the polymer. The pores also use a polymer that swells and becomes porous or contains a water-soluble pore-forming component that is leached or leached from the polymer;
It may be formed in-situ by a method of creating holes there. Examples of polymers that can be used for wall 12 are U.S. Pat.
It is described in 6045. The semi-permeable polymer that can be used to make the membrane 17 is permeable to water so that the compartment 13
and substantially impermeable to other components of member 15. Examples of such polymers include cellulose acetate, cellulose diacetate, cellulose triacetate, dimethylcellulose acetate, cellulose acetate, ethyl carbonate, and other cellulose ethers and ethers. It may be desirable to add one or more plasticizers to the semipermeable polymer to impart flexibility and swellability to membrane 17. Examples of such plasticizers include dimethyl phthalate, dipropyl phthalate, di(2-ethylhexyl) phthalate, diisopropyl phthalate, diamyl phthalate and dicapryl phthalate; tributyl phosphate, trioctyl phosphate, tricresyl phosphate. and alkyl and aryl phosphates such as triphenyl phosphate; citric acid alkyl esters such as tributyl phenate, triethyl citrate and acetyl triethyl citrate; dioctyl adipate, diethyl adipate and di(2
- methoxyethyl); dialkyl tartrate such as diethyl tartrate and dibutyl tartrate; alkyl sebacate such as diethyl sebacate, dipropyl sebacate and dinonyl sebacate; alkyl succinate such as diethyl succinate and dibutyl succinate. ; Glycerol diacetate, glycerol triacetate, glycerol monolactate diacetate, methyl phthalylethyl glycolate,
Butylphthalyl butyl glycolate, ethylene glycol diacetate, ethylene glycol dibutyrate, triethylene glycol diacetate, triethylene glycol dibutyrate and triethylene glycol dipropionate, alkyl glycolate, alkyl glycerol, glycol There are esters and glycerol esters. Osmotic solutes that can be used in member 15 include organic and inorganic compounds that exhibit high osmotic pressures in solution.

Such solutes include magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, potassium acid phosphate, mannitol, urea,
Includes sucrose, etc. Other osmotic solutes are described in US Pat. No. 3,854,77 and US Pat. No. 4,077,407. Swellable polymers that can be used for member 15 are lightly cross-linked hydrophilic hydrogels that swell to a high degree in the presence of water without dissolving, typically exhibiting a 5-5 volume increase.

Typical hydrogels include poly(hydroxyalkyl methacrylate), poly(acrylamide), poly(methacrylamide), poly(N-vinyl-2-pyrrolidone), anionic and cationic hydrogels, polyelectrolyte complexes, and polyelectrolyte complexes. Maleic anhydride and styrene, ethylene, crosslinked with about 0.001 to about 0.5 mole of polyunsaturated crosslinker per mole of maleic anhydride in the polymer.
Water-insoluble, water-swellable copolymers produced by forming a finely divided dispersion of copolymers with propylene, butylene or isobutylene, water-swellable polymers of N-vinyl lactam, semisolid cross-linking poly(vinylpyrrolidone), diester crosslinked polyglucan hydrogels, and anionic hydrogels of heterocyclic N-vinyl monomers.

Gas-generating couples that can be used in member 15 consist of solid acid and basic compounds that dissolve in the presence of water and react to produce carbon dioxide.

Acid compounds include organic acids such as malic acid, fumaric acid, tartaric acid, methaconic acid, maleic acid, citric acid, adipic acid, succinic acid and mesaconic acid, as well as non-carboxylic acids such as sulfamic acid or phosphoric acid and magnesium citrate, acidic tartaric acid. Includes acid salts such as potassium and potassium bitartrate. Basic compounds are carbonate and bicarbonate metal salts,
Examples include alkali carbonates and bicarbonates. Representative materials include lithium carbonate and bicarbonate, sodium and potassium salts and alkaline earth compounds such as calcium carbonate and bicarbonate salts. Preferably, the pair of acids and bases are in substantially stoichiometric proportions.

Dispensers are manufactured according to standard methods.

For example, member 15 is made by first wrapping the permeable solute, gas-generating couple, or swellable polymer in a semi-permeable polymeric film and then coating or crimping the water-soluble active agent composition 14 onto member 15. Membrane 12 is then molded, sprayed, or air suspended onto the formed assembly.
iOn) or by dipping. In another method, wall 12 is first cast, then shaped into an open container, filled with active agent composition 14 and member 15, and then closed and sealed. The following examples further illustrate the invention.

These examples are not intended to limit the scope of the invention in any way. Percentages and proportions are by weight unless otherwise specified. Example 1 First, 125 mg of sodium chloride was compressed, and then the compressed sodium chloride was dissolved in methylene chloride-methanol (80:2 methanol ratio) with 70% cellulose acetate with an acetyl content of 32% in an air suspension machine. Molecular weight 4
00 mixed with 30% polyethylene glycol until an intumescent film is formed on the membrane and coated to form an intumescent member.

Next, 235 m9 of dry procainamide is mixed with this part and the mixture is compressed.

This compressed mixture is then mixed in an air suspension with 65 m of cellulose acetate with an acetyl content of 32%, 41 y of hexanehexol, 11.7 m of polyethylene glycol 400 and 19 ml of acetone and 375 m of water.
1 and coated with a composition consisting of a solvent. The covering is 1
75 microns thick, and when the dispenser is placed in the gastrointestinal tract, the pore-forming hexanehexol leaches from the coating wall to form pores having a diameter with an average size of 50 angstroms to 100 microns. . Example 2 First, potassium hydrogen carbonate 56.7%, citric acid 40.2%
% and 3% anhydrous magnesium silicate, the mixture was then compressed in an air suspension to obtain a molecular weight of 400
Cellulose acetate 9 with an acetyl content of 32% in which 10% by weight of polyethylene glycol is homogeneously dispersed.
Cover with a film consisting of 0%. Ru.

The recirculation operation is carried out using a solvent consisting of 80:20 (by volume) methylene chloride-methanol. The part is then surrounded by 500 m9 of potassium chloride by compression in a Manesty machine to form a pore-forming poly(vinyl chloride) microporous wall. Poly(vinyl chloride) containing poly[p-dimethylaminose styrene] as an agent
Formed by leaching a sheet of polymer consisting of:

The walls are formed by casting from a cyclohexane solution and evaporating the solvent. Next, an acidic aqueous solution of hydrochloric acid is used to leach the pore-forming agent to form a microporous wall. Leaching is carried out at room temperature and then washed with distilled water to remove acid and produce microporous walls with pores of average size from 50 angstroms to 100 microns. Example 3 A dispenser in the form of a tablet for administering procainamide hydrochloride to the gastrointestinal tract of warm-blooded animals is prepared as follows: First, 200 m9 of lightly cross-linked swellable poly(hydroxyalkyl)methacrylate are 80:20 in air suspension machine (
molecular weight 4 dissolved in methylene chloride-methanol (volume)
A composition consisting of 70% cellulose acetate with 32% acetyl content mixed with 30% polyethylene glycol 0.00 is coated to enclose the polymer.

Next, 235 m9 of procainamide hydrochloride is compressed to form a solid mass having a shape corresponding to the shape of member 15, which is encapsulated and bonded to member 15 with adhesive liquefied cellulose acetate. The resulting assembly is then described in U.S. Pat.
Following the description in No. 426754, 0.565-0.0
Surrounded by a wall of microporous polymeric polypropylene having a pore volume of 75 d/d, a density of 0.60-0.85 d/d and a pore size of 150-5000 angstroms.
Although only dispensers have been described above in which the active agent is a chemical, it will be apparent that embodiments containing other active agents such as agricultural chemicals and water treatment chemicals may also be made.

[Brief explanation of the drawing]

FIG. 1 is an enlarged perspective view of the tablet-shaped dispenser; FIG. 2 is a sectional view showing the arrangement of components of the dispenser of FIG. 1 during operation; and FIG. 3 is a comparison of the dispenser of FIG. 1 and the prior art. 2 is a graph showing a theoretical release rate curve with a dispenser.

Claims (1)

[Claims] 1 an outer microporous wall surrounding and defining an internal compartment having pores in the range of 50 angstroms to 100 microns formed by leaching pore-forming material from the wall and within the compartment; A dispersible active agent dispenser in the form of a tablet comprising a water-swellable active agent composition contained therein, the compartment comprising a core of an osmotic solute or a gas-generating couple or a water-swellable polymer and a core of the core. A diffusible active agent dispenser as described above, comprising an expansible member that expands in response to absorption of water, comprising an encasing expansible semipermeable membrane.