Composition Comprising a Therapeutic Agent and a Modulating Agent

The following examples are merely illustrative of the present invention and they should not be considered as limiting the scope of the invention in any way, as these examples and other equivalents thereof will become more apparent to those versed in the dispensing art in the light of the present disclosure and the accompanying claims.

An osmotic therapeutic device for the controlled delivery of the .beta.-adrenergic stimulant and bronchodilator salbutamol, or .alpha.-[(tertbutylamino)methyl]-4-hydroxy-m-xyene-.alpha.,.alpha.'-diol-h emisulfate, delivered at a constant rate modulated by a pulsed rate is made as follows: first, the solubility of salbutamol hemisulfate (hereafter salbutamol) and the modulating agent sodium chloride were measured in distilled water at 37.degree. C. and the measurements indicated the following solubilities: solubility of salbutamol in water is 275 mg/ml, solubility of salbutamol in saturated solution of sodium chloride is 16 mg/ml, solubility of sodium chloride in water is 321 mg/ml, solubility of sodium chloride in saturated solution of salbutamol is 320 mg/ml, and, the total solubility of salbutamol in saturated sodium chloride and sodium chloride in water is 16 plus 320 equal to 336 mg/ml.

Next, a composition is prepared containing salbutamol and sodium chloride in a ratio of 1:5 as follows: first, 14.45 mg of salbutamol, 72.30 mg of sodium chloride, 1.8 mg of cross-linked sodium carboxymethylcellulose, and 1.8 mg of poly(vinyl pyrrolidone) are passed through a 60 mesh screen and mixed in a blender for 1 hour. Then, the blended ingredients are transferred to a larger blender and 8 ml of a granulating fluid consisting of ethanol:water, 90:10, is added thereto and all the ingredients blended for about 20 minutes. The homogenously blended ingredients next are passed through a 20 mesh screen and dried in a forced air oven at 50.degree. C. for 12 hours. After drying, the granules are mixed with 0.9 mg of magnesium stearate and blended for 10 minutes. The granules are transferred to a conventional Manesty tablet press and compressed with a standard round 5/32 inch dye to a hardness of 1.5 to 2 Kp. The area of the compressed drug core measured 0.41cm.sup.2 and weighed 91.3 mg.

The compressed core is transferred to an Aeromatic.RTM. air suspension coater, and a wall consisting of cellulose acetate having an acetyl content is coated around the core. The semipermeable wall is formed from a composition comprising 42.5% (12.75 g) of cellulose acetate having an acetyl content of 39.8%, 42.5% (12.75 g) of cellulose acetate having an acetyl content of 32.0%, 15% (4.5 g) of hydroxypropyl methyl cellulose in a cosolvent consisting of methylene chloride-methanol, 80%-20% (588 ml-256 ml). After the wall is formed around the reservoir, they are transferred to a forced air oven and air dried for 48 hours at 50.degree. C. Next, an osmotic passageway having a diameter of 0.25 mm is laser drilled through the semipermeable wall. The semipermeable wall weight is 5.9 mg.

The osmotic useful agent delivery device prepared by the example is illustrated in FIGS. 5 and 6. In FIG. 5, the osmotic device 10 is seen comprising a body 11 with a passageway 12 that connects the exterior with the interior of osmotic device 10. In FIG. 6, osmotic device 10 is seen in opened section at 13 and it comprises semipermeable wall 14 that surrounds and defines internal compartment 15. Compartment 15 contains useful drug salbutamol 16, modulating agent sodium chloride 17, and other dispensing ingredients. In FIG. 7, the release rate pattern for the device is seen consisting of an essentially zero order rate of release for 7 hours, modulated by a pulsed release of useful agent from 7 to 9 hours. FIG. 8 depicts the cumulative amount of useful agent salbutamol delivered over a 12 hour delivery period. In the FIGS. 7 and 8, the bars represent the maximum and the minimum rate of release at the time of measurement.

An oral, osmotic device for the controlled codelivery of salbutamol and the bronchodilator terbutaline sulfate, 1-(3,5-dihydroxyphenyl)-2-(tert-butylamino) ethanol, at a constant rate interrupted by a pulsed rate delivery is made as follows: first, 9.64 mg of salbutamol 5 mg of terbutaline sulfate, 24 mg of sodium chloride, 0.71 mg of poly (vinyl pyrrolidone), and 0.71 mg of cross-linked sodium carboxymethyl cellulose are blended and passed through a 60 mesh screen. The ratio of the salbutamol to sodium chloride in the composition is 1 to 3. Next, 8 ml of a granulating fluid consisting of ethanol:water, 90:10, is added to the screened blend, and all the ingredients blended for about 15 to 20 minutes. The well-blended ingredients are passed through a 30 mesh screen and dried in a forced air oven for 12 to 15 hours at 50.degree. C. After drying, the granules are mixed with 0.35 mg of stearic acid and blended for 10 minutes. Then, the blend is compressed into a precompartment forming drug formulation. The compressed drug formulation is placed in an air suspension machine and coated with a microporous lamina forming composition. The microporous lamina composition comprises 49% by weight of cellulose acetate having an acetyl content of 39.8%, 28.5% by weight of hydroxypropyl methylcellulose, and 22.5% by weight of polyethylene glycol 4000. The lamina is formed from a methylene chloride-ethanol (95%) lamina solvent (80:20 wt:wt). The microporous lamina is 0.12 mm thick.

Next, an exterior semipermeable lamina is laminated onto the microporous lamina in the conventional air suspension machine. The semipermeable lamina forming composition comprises 90% by weight of cellulose acetate having an acetyl content of 39.8% and 10% cellulose acetate having an acetyl content of 32%. The semipermeable lamina is applied in laminar arrangement from a solvent mixture comprising methylene chloride and ethanol (80:20 wt:wt). The osmotic devices are dried and a passageway having a diameter of 0.26 mm is drilled with a laser through the laminated wall. In FIG. 9, osmotic device 10 is seen comprising body 11, passageway 12, opened section 13, outside semipermeable wall 14, inside compartment 15, salbutamol 16, sodium chloride 17, inside microporous wall 18 and terbutaline 19.

An oral, osmotic device for the controlled and continuous delivery of oxprenolol-HCl modulated by a pulsed release of oxprenolol-HCl is made by following the general procedure described about. In the osmotic device of this example, the compartment houses a drug formulation comprising a nonequilibrium formulation of 1 part of oxprenolol-HCl to 6 parts of potassium chloride:sodium chloride (50:50) mixture. The compartment contains also 2 mg of dextrose, 2 mg of potato starch and 3 mg of magnesium stearate. The formulation after compressing has a diameter of 9 mm. The device has a laminated wall consisting essentially of 60% by weight of cellulose acetate having an acetyl content of 43.5% and a degree of substitution of 3 and 40% by weight of cellulose acetate having an acetyl content of 39.8 and a degree of substitution of 2.4. The semipermeable lamina is applied from a solvent consisting essentially of methylene chloride and methanol, 80:20 by weight. The device has an exterior microporous lamina consisting essentially of 55% by weight of cellulose acetate having an acetyl content of 39.8%, 35% by weight of sorbitol, and 10% by weight of polyethylene glycol 400. The lamina is applied from a solvent comprising methylene chloride-methanol, 90:10 by weight. The semipermeable lamina is 0.12 mm thick, and the microporous lamina is 0.13 mm thick. The device has a 0.25 mm passageway.

The procedure of Example 1 is repeated to yield an osmotic device wherein the ratio of salbutamol to sodium chloride is 1 to 7, and the compartment of the osmotic device contained a drug formulation consisting essentially of 9.6 mg of salbutamol hemisulfate, 56 mg of sodium chloride, 1.4 mg of poly(vinyl pyrrolidone), 1.4 mg of cross-linked sodium carboxymethyl cellulose and 0.6 mg of magnesium stearate. The device delivers salbutamol for 12 hours and has a terminal pulsed release of salbutamol as seen in FIG. 10. The osmotic device has a semipermeable wall 4.9 mils thick (0.13 mm), comprising the semipermeable wall composition of Example 1.

The procedure of Example 1 is followed to yield an osmotic device wherein the ratio of salbutamol to the modulating agent sodium chloride is 1 to 9. The compartment of the osmotic device contains a drug formulation consisting essentially of 28.9 mg of salbutamol hemisulfate, 216 mg of sodium chloride, 5.2 mg of poly(vinylpyrrolidone), 5.2 mg of cross-linked sodium carboxymethyl cellulose, and 2.6 mg of magnesium stearate. The osmotic device has a semipermeable wall weighing 20.1 mg comprising the composition of Example 1. The device has a zero order rate of release of salbutamol for 16 hours followed by an increased pulsed salbutamol for 8 hours. The 24 hour release pattern for the osmotic device is illustrated in FIG. 11.

An oral osmotic device that delivers acebutolol, a .beta.-adrenergic blocker, is sized, shaped and manufactured for administration into the gastrointestional tract as follows: 10 parts of acebutolol hydrochloride and 90 parts of potassium carbonate, 8.75 mg of noncross-linked poly(vinylpyrrolidone) are mixed and passed through a 60 mesh stainless steel screen and blended for 1 hour at room temperature. Next, the blended ingredients are transferred to a larger blender and 40 ml of a granulating fluid consisting of ethanol:water, 90:10 by volume, is added to the blender, and the ingredients blended for 20 minutes. The thoroughly blended ingredients are passed through a 30 mesh screen and dried in a forced air oven at 50.degree. C. for 16 to 17 hours.

Then, the dried granules are passed through a 20 mesh screen and 5 mg of magnesium stearate is added to the granules. The ingredients are blended for 15 minutes, and the blended granules transferred to a conventional Manesty press. The ingredients are compressed into acebutolol reservoirs having a diameter of about 6 mm.

The acebutolol precompartment forming compositions are transferred to an air suspension coater and surrounded with a semipermeable wall. The semipermeable wall is formed from a wall forming composition comprising 35 g of cellulose acetate having an acetyl content of 39.8 from an organic solvent consisting essentially of 550 ml of methylene chloride and 110 of methanol. After the semipermeable wall is formed surrounding the drug reservoir, they are dried in a forced air oven for 50 hours at 50.degree. C. Next, a 0.4 mm passageway is laser drilled through the semipermeable wall connecting the interior compartment with the exterior of the osmotic device. The semipermeable wall weighed 8.6 mg and the device delivers the drug for 12 hours time span modulated by a terminal pulsed delivery.

The procedure of Example 1 is repeated to manufacture an osmotic device wherein the ratio of useful agent salbutamol to modulating agent is 1 to 9 to produce a device wherein the pulsed delivery occurs near the middle of the release pattern. In Example 7, the osmotic device comprises 9.3% by weight of salbutamol, 1.9% by weight as the hemisulfate, 83.8% by weight of sodium chloride, 2% by weight of cross-linked sodium carboxymethyl cellulose, 2% by weight of polyvinylpyrrolidone, and 1% by weight of magensium stearate. The device has a semipermeable wall consisting of 42.5% by weight of cellulose acetate having an acetyl content of 39.8%, 42.5% by weight of cellulose acetate having an acetyl content of 32%, and 15% by weight of hydroxypropyl methylcellulose. The diameter of the passageway is 0.25 mm, the semipermeable wall weighs 4.8 mg and the wall is 0.06 mm thick. The measured release rate pattern for the osmotic device is depicted in FIG. 12 and the cumulative amount released is illustrated in FIG. 13.

The invention in one presently preferred embodiment pertains also to a method for delivering a drug at a constant rate modulated by a pulsed delivery of the drug, which method comprises the steps of: (A) admitting orally osmotic device shaped, sized and structured into the gastrointestional tract of a patient, the osmotic device comprising: (a) a wall formed of a nontoxic semipermeable composition that is permeable to the passage of an exterior fluid and substantially impermeable to the passage of drug and modulating agent, the wall surrounding and forming; (b) a compartment containing a dosage unit amount of drug and an effective amount of modulating agent which modulating agent is a means for providing a pulsed delivery of drug; and (c) a passageway in the wall for communicating the exterior of the osmotic device with the interior of the osmotic device; (B) imbibing exterior fluid through the semipermeable wall into the compartment at a rate determined by the permeability of the semipermeable wall and the osmotic pressure gradient across the semipermeable wall to form a solution comprising drug that is hydrodynamically and osmotically delivered from the osmotic device; and (C) delivering the drug in a therpeutically effective amount at a substantially constant rate accompanied by a pulsed delivery of drug in an effective amount larger than the constant rate through the passageway to the gastrointestional tract of the patient to produce the desired beneficial effect of the constant rate and the pulsed rate of drug delivery over the prolonged period of time.

The osmotic devices also can be used as an implant, or a conduct can be attached to the passageway for intravenous delivery of drug, or for subcutaneous delivery of drug. Drugs that can be delivered in a zero order rate with a pulsed rate comprise a method for the controlled and substantially constant delivery of salbutamol accompanied by a pulsed delivery of salbutamol; a method for the controlled and constant delivery of acebutolol accompanied by a time-dependent pulsed delivery of acebutolol; a method for the management of asthma which method comprises administering to a patient suffering with asthma a therapeutically effective amount of salbutamol at a constant rate interrupted by a pulsed amount of salbutamol for producing a beneficial effect in said asthmatic patient. The salbutamol and acebutolol also can be administered in a method for producing bronchodilation in a patient in need of a bronchodilator, particularly for acute and chronic patients. The beneficial agent is delivered at a controlled and continuous rate over a period of time from 15 minutes to 24 hours accompanied by an intermittent pulsed or terminal pulsed delivery of 15 minutes to 24 hours.

The invention provides an osmotic therapeutic system manufactured in the form of an osmotic device for producing an improved drug delivery program. While there has been described and pointed out the novel features of the invention as applied to presently preferred embodiments, those skilled in the art will appreciate that various modifications, changes and omissions in the invention illustrated and described can be made without departing from the spirit of the invention.