CA1103161A - Oral carrier base, its preparation and dosage units made therefrom - Google Patents
Oral carrier base, its preparation and dosage units made therefromInfo
- Publication number
- CA1103161A CA1103161A CA276,537A CA276537A CA1103161A CA 1103161 A CA1103161 A CA 1103161A CA 276537 A CA276537 A CA 276537A CA 1103161 A CA1103161 A CA 1103161A
- Authority
- CA
- Canada
- Prior art keywords
- therapeutic agent
- composition according
- carrier material
- carrier
- moisture content
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
ABSTRACT OF THE DISCLOSURE
Shaped pharmaceutical tablets and other solid oral dosage unit forms which have a prolonged homogenous release pattern of active medicament over a period of hours wherein each shaped tablet or dosage unit comprises a carrier material base of hydroxypropylmethylcellulose with or without a proportion up to 20% of ethylcellulose and wherein the carrier material base is specially processed under controlled conditions of moisture, temperature and time, and then compressed at relatively low compression pressure with an incorporated active medicament. The compressed dosage units or tablets when orally administered give a continuous incremental release of the active medication without initial peaking and/or super or sub-therapeutic dosing. This provides effective blood levels free from any toxicity due to the carrier material which is chemically inert, of decreased solubility and enhanced stability, due to its processing and to the inclusion of a stabilizing agent.
Shaped pharmaceutical tablets and other solid oral dosage unit forms which have a prolonged homogenous release pattern of active medicament over a period of hours wherein each shaped tablet or dosage unit comprises a carrier material base of hydroxypropylmethylcellulose with or without a proportion up to 20% of ethylcellulose and wherein the carrier material base is specially processed under controlled conditions of moisture, temperature and time, and then compressed at relatively low compression pressure with an incorporated active medicament. The compressed dosage units or tablets when orally administered give a continuous incremental release of the active medication without initial peaking and/or super or sub-therapeutic dosing. This provides effective blood levels free from any toxicity due to the carrier material which is chemically inert, of decreased solubility and enhanced stability, due to its processing and to the inclusion of a stabilizing agent.
Description
3~6~
Hydroxypropylmethylcellulose is known and commercially available as Methocel* (Dow Chemical Co.) and a premium (pharma-ceutical) grade is known as Methocel 60 H.G.-50 viscosity.
Ethylcellulose is also well known and readily available. Metho-cel] has been used as a starting material in making buccal or sub-lingual products for transmucosally acting medicaments as de-scribed in my British Patent Nos. 1,171,691 and 1,279,214 and United States Patent No. 3,870,790. While it is thus known to produce compressed buccal lozenges or tablets from cellulose de-rivatives as carriers with medicinal agents, where steady pro-longed medication is required and a regular rate of release is needed with good absorption of medicament from an orally ingest-ible preparation subject to the action of gastric and intestinal 1uids, further ~mprovements are possible and it is to this that the present invention is directed.
According to the present invention, it has now been discovered that furthe~ and important advantages and improvements over my prior products containing Methocel as described, for example, in Unitea States Patent No. 3,870,790 and British Patent Nos. 1,171,691 and 1,279,214 can be obtained by special treatment thereof under controlled conditions of moisture, temperature and time prior to incorporation of active medicament therein and thus the inherently desirable properties of Methocel can be taken ad-vantage of in a significantly improved sustained continuous re-lease compressed stable tablet capable of providing steady thera-peutic blood levels. T~e present invention subjects hydroxy-propylmethylcellulose to special processing and stabilizing con-ditions thereby producing a modified carrier material base having greater stability, reduced water solubility, greater chemical inertness with freedom from toxicity due to the carrier material *Trademark ~' . .
111~3~61 itself, less likelihood of i~mpaction and a lowered potential of replacement or chemical changes of anhydroglucose units.
Thus, the invention provides a solid, oral-dosage-unit form of a sustained release therapeutic composition for admin-istration to a patient in need of the t~erapeutic agent thereof for the prolonged systemic treatment of a disorder susceptible to such agent, which comprises a carrier base material of 100%
hydroxypropylmetnylcellulose or a mixture of about 80% hydroxy-propylmethylcellulose witn up to about 20% ethylcellulose which carrier material has been humidified to a moisture content of at least 85% for a period of at least about 24 hours, the humidifi-cation Being there upon discontinued and then the carrier mater-~al dehumidified to a moisture content in the range of 2 to 10%, an effective amount of a therapeutic agent and about 0.1% of a stabilizer being admixed in powder form and the mixture being formulated into unit dosage form wherein it is characterized by a long-lasting, slow and regular disintergration rate upon ingest-ion to give a prolonged and regular incremental release pattern, the said carrier material having a carbonyl content of 0.92 to 1.43 grams/100 grams and a carboxyl content of 0.54 to 0.57 grams/100 grams. The moisture range is preferably 4.5-5.5% for best results and the carrier material is itself essentially of neutral pH (to litmus paper).
The hydroxypropylmethylcellulose used as the starting material for the present invention is known and commercially available as Methocel 60 H.G.-50 viscosity (Dow Chemical Co.) which is a premium grade found best for pharmaceutical products and this hydroxypropylmethylcellulose can be optionally admixed with a small proporti`.on of ethylcellulose up to about 20% of the 3a weight of the mixture, in which case the hydroxypropylmethyl-cellulose amounts to 100-80%. The hydroxypropylmethylcellulose h d~ ~ ;
lla3l6l alone or a mixture of these two materials in powder form is pro-cessed. The processing is carried out in suitable equipment hereinafter described under the conditions set forth and after the materials are processed as described, an active ingredient in suitable amount to provide an effective unit dose per tablet is incorporated therein and wh;`ch can be of any type of medica-tion which acts systemically and can be administered orally to transmit the active medicament into the gastrointestinal tract and into the blood stream to therapeutically effective levels without early excessive peak concentrations, without being in-activated by physiological fluids and without passing unchanged through the body of the patient or subject ~y being excreted unabsorbed.
Representative active medicaments include anti-inflam-matory substances, coronary dilator preparations, cerebral dil-ators, vasodilators, antibacterials, psychotropics, anti-manicsr stimulants, etc. However, it is to be understood that the invention is especially applicable to compressed tablets which are intended to be swallowed in unit dosage form and which upon 2a ingestion according to a prescribed regimen give slow and regular release of active medicament without an initial dumping of a fixed percentage in the intestinal tract while being protected against normally inactivating gastric fluids.
' : :
1~'3~
The processed hydroxypropylmethylcellulose alone or with up to 20~ of ethyl-cellulose, by weight, forms what is herein called a long-acting slow dissolv-ing oral carrier independent of pH and of such nature that it has a protective, demulcent and buffering effect in the body and causes the active medicament to exert its optimum therapeutic action immediately and incrementally for up to several hours so that full therapeutic advantage can be taken of the entire or substantially the entire amount of active medicament administered. This un-expectedly high degree of efficiency is a particular advantage of the invention and minimizes side effects of the medication.
The procedure is carried out in my above patents by introducing the hydroxypropylmethylcellulose ora mixture of the hydroxypropylmethylcellulose with ethylcellulose into a heating chamber provided with an exhaust which is at that time in closed or shut position and which chamber is provided with a heating unit and a forced air blower which is inoperative at this stage of the procedure in that the heat and forced air are only applied at a subsequent stage. The carrier material to be processed is placed in thin layers (not more than 1/4~ thick) on trays of the chamber which are lined with heat-resistant parchment paper and the trays are placed on racks in the oven chamber using only alternate shelves thereby providing adequate spacing between the layers of carrier material being treated. There is then placed within the oven chamber a humidifier equipped withahumidistat which is preset to maintain humidity in the oven chamber at about 85%, the humidifier being filled with sufficient distilled or deionized water to last for 24 to 36 hours. The humidifier is now activated and the heating chamber is closed and the process is allowed to proceed under the high humidity conditions for a period of time sufficient to ensure reaching a humidity of the carrier material of at least 85% and maintaining the same for up to 24 hours or even longer if desired, although there is no special advantage in exceeding 24 hours and unduly ex-tended times are apt to be uneconomical. Subsequent to the 24-hour minimum 1~3~6~1 period just referred to, the humidifier is removed from the heating chamber, the exhaust aperture opened by manipulation of the usual valve or closure thereof and the forced air blower is activated thereby applying heat at a controlled temperature in the range of 110 - 120 F (43 - 49 C) and at the end of 12 hours the moisture content of the treated material is checked by removing and testing a sample. The moisture content must not be less then the range of 2 - 2~o in terms of added weight of the carrier material under-going processing. This added moisture content is equivalent to about 4 - 4.5%
as determined by a standard moisture determination apparatus. The 12-hour period just referred to is, however, approximate in that the duration of the period may vary somewhat above or below 12 hours, but it has been found in practice that the period should best be approximately 12 hours. The attain-ment of the specified additional moisture percentage is important and consid-ered critical to the success of the invention.
When the required added moisture content is achieved, and referring now to the processing of hydroxypropylmethylcellulose alone, the treated material is removed from the oven and passed through a No. 2 stainless steel screen employing a Fitzpatrick Comminuter having its knives directed forwardly and operating at medium speed. In the case of the treatment of 100 - 80%
hydroxypropylmethylcellulose and 0 - 20% ethylcellulose, the comminution step may be omitted and the heat applied until the moisture content is reduced to about not less than 2.0% as determined by the usual moisture determination apparatus. Since the material is free-flowing and powdery, no further opera-tion is required thereon.
By way of example, in making up tablets containing an orally adminis-trable systemically absorbable active component such as one of the heretofore mentioned medicaments, the treated oral carrier material is thoroughly inter-mixed with the medicament which is also in powdered or granular form and any other needed ingredients which are conventional in tablet making such as 11~3~61 magnesium stearate, lactose, starch and, in general, binders, fillers, disin-tegrating agents, and the like. The complete mixture, in an amount sufficient to make a uniform batch of tablets, such as 50,000, of which each contains an effective amount of active medicament, is then subjected to tableting in con-ventional tableting machines but at, for example, compression pressures of 7 to 13 kg/in. and because of the use of the specially processed carrier material in the production of the tablets, a product is obtained which has a desired set of properties such as predetermined prolonged action and a regular delayed release pattern so that the medicinal agent or active ingredient is available over a period of 1 - 12 hours depending on the precise tablet size and hardness and the particular carrier mixture. In this way it is possible to produce sustained or slow continuous release tablets in relatively simple and economi-cal manner on a commercial scale as contrasted with the more elaborate and more complex materials and procedures heretofore employed or proposed.
The humidifier employed is Arvin Model 50 H 42 (Sears Roebuck) - 10 gallon capacity having low and high air speeds and the humidistat is provided with nine settings for moisture control. In the present invention the humid-istat is set to position 7 which maintains 85 - 90~ humidity in the oven chamber per 250 cubic feet of airflow and a temperature of approximately 75 F
(24 C). It is understood that the invention is not limited to the use of this particular humidifier or equipment and that other equipment may be substituted.
The invention is further illustrated by the following non-limitative examples:
Example No. 1 Vasodilator (per 50,000 dosage units) a. Nitroglycerin 325 g.
b. Beta Lactose 2,975 g.
c. Syloid No 244 50 g.
r~JemdrKs ~:, ~ ~ .
11~}3~
d. Cherry flavor 100 g.
. e. Synchron Oral-Carrier 23,750 g.
Example No. 2 Anti-inflammatory (per 50,000 dosage units) a. Prednisolone 250 g.
b. Synchron Oral-Carrier 9,465 g.
c. Syloid No. 244 50 g.
d. Cherry flavor 100 g.
Example No. 3 Anti-Manic depressive (per 50,000 dosage units) a. ~ithium Carbonate 15,000 g.
b. Synchron Oral-Carrier 19,880 g.
c. Syloid No. 244 10 g.
d. Cherry flavor 15 g.
Example No. 4 Antacid (per 50~000 dosage units) a. Aluminum Hydroxide Gel 12,500 g.
b. Magnesium Glycinate 12,500 g.
c. Gastric Mucin 5,000 g.
d. Carbowax 6000 ~ 34.5 g.
e. Synchron Oral-Carrier 12,000 g.
f. Syloid No. 244 250 g.
g. Cherry flavor 500 g.
Example No. 5 Antibiotic (per 50,000 dosage units) a. Ampicillin 12,500 g.
b. Synchron Oral-Carrier 2,500 g.
c. Syloid No. 244 30 g.
d. Cherry flavor 25 g.
* TraJ~ncr~s - 6 -- .
11(}3~6~
The release pattern of active medicament from the new long-lasting oral carrier can be controlled according to the particular medication and its intended therapeutic effect. The release pattern varies from about 1 hour to 8 hours or as long as 12 hours and this is at least in part governed by the tablet si3e and degree of compression (hardness) since larger tablets last longer and higher compressions give a slower rate of release. For orally administered tablets, the rate of release is usually 4 - 8 hoursand this has been confirmed by X-rays with barium sulfate to show the motility and disin-tegration in the intestinal tract. For vaginal and rectal suppositories the release pattern ranges from 12 - 36 hours although it can of course be less where indicated. By predetermining the size of the tablet or suppository and the amount of compression or molding force employed in shaping it from the powder form and by keeping the end product moisture content not less than 2.0%
highly desirable release patterns of unusually reliable and regular character-istics can be secured. This is often very important medically, especially when treating patients having coronary diseases, as with nitroglycerin, or related problems of circulatory disorders such as angina pectoris or abnormal blood pressure conditions or psychotropic/manic-depressive schizophrenia. The invention is therefore of unusually versatile and adaptable nature giving it a wide scope of application and use.
The foregoing is exemplary of compositions and products responding to the present invention, but it is to be understood that they are illustrative and not limitative since many active ingredients of various types can be em-ployed in the new long-lasting oral carrier so long as they are absorbable in serum or tissue, the general intestinal tract, etc. The invention is also intended to cover other dosage forms or forms for application of sustained release ingredients such as vaginal and rectal suppositories. The total dosage is governed by usual medical considerations or physicians' directions and sufficiently large total doses of active medicament are administered in unit . . .
11C~3~61 dosage tablet form containin~ from 10-500 milligrams to overcome or control the pathological condition or disorder being treated. The presence of a stabilizing agent tends to prevent unwanted change in moisture content by avoiding pick-up or loss of moisture due to climactic conditions of high or low humidity in tropical or arid geographical locations or shipping or stor-age variations. It is therefore a particular part of this invention to add a stabilizer to the carrier material such as ascorbyl stearate or pal~itate or an initiator such as sodium metabisulfite. The stabilizer is usually added after the carrier material is otherwise processed and in a small amount of the order of 0.1 - 1.0% of the weight of the carrier, preferably about 0.2%.
The sodium metabisulfite (Na2S205), a Redox Initiator for the copolymer, per-mits copolymerization to be carried out rapidly during humidification. The sodium metabisulfite is employed for this purpose in a concentration of 0.1%
of the total weight of the polymer (hydroxypropylmethylcellulose) used.
In evaluating drugs incorporated in the oral carrier system or base of the present invention, it is important to understand the factors influenc-ing the absorption and therapeutic effectiveness of drug products in composi-tions responding hereto. Under usual circumstances, disintegration of a tab-let into small particles in the gastrointestinal fluids speeds dissolution because of much increased surface area of the drug. Consequently, absorption is more rapid and the duration of therapeutic action depends primarily upon the rate of absorption. The rate and extent of drug absorption thus can in-fluence both the duration of action and the efficacy of drug therapy. It follows that the faster the absorption, the earlier peak level of drug is reached but if absorption is too slow, the concentration of drug in blood and tissues may never reach therapeutic levels. Subsequent to absorption, there is a drop in concentration that depends in large part upon elimination and/or metabolization.
Drugs embedded in the present "Synchron" Carrier System, as I term il~3161 the carrier base, are intended to attain and maintain a steady concentration of drug in blood or tissues. One objective in using these preparations is to reduce the dosage frequency, to make therapy simple and convenient, and to improve compliance by the patient. In addition, by maintaining a reasonably constant plasma concentration of drug, excessive or premature peaking is avoided and side effects, which may be associated with peak concentrations of drug, would be lessened. In addition, a more uniform concentration of drug in blood and tissues is much more likely to be paralleled by a more uniform pharmacologic effect and response. With dissolution being the main rate-limiting step in drug absorption, the rate of solution of the drug from the dosage form into the surrounding fluids at the absorption site is controlled by the physical technique employed in the production of the "Synchron" Carrier System. With the "Synchron" Carrier System the drug can further be released to a specific site at a uniform rate independently of the pH environment, resulting in steady concentrations of the drug in tissues. Drugs incorporated into the "Synchron" Carrier System vehicle are prone to be absorbed completely, but more slowly, and are formulated to maintain the therapeutic effective level of the particular drug and to produce a prolonged response and a diminished rate of unassimilated drug elimination.
The absorption data may be determined and expressed as the cumulative percentage of the dose absorbed plotted against time, or analyzed further to derive information as to the kinetics of the absorption process. Usually the total body clearance of a drug is fixed. Then the total area under the plasma concentration-time curve is proportional to the dose absorbed and independent of the rate of absorption. Area analysis forms the basis for estimation and ; comparison of the extent of absorption when the same dose is given in different dosage forms or by different routes of administration, or in different carrier systems. The "Synchron" Carrier System has the added advantage compared to other available prolonged-release vehicles employed in dosage forms insofar as .: ,., . :.
1~316~
it will not release the drug in a d~ping action and prevents the potential haæard of over-dosage if all the drug is released at one time and is rapidly absorbed. The potency for determining sustaining dose with the present car-rier system may be expressed by the formula:
D x 0.693 x SV/~/2 ,wherein D is the normal therapeutic dose, SV is the number of hours desired to extend the duration of action, and Ll/2 is the drug's half-life. The primary difference between the use of my t'Synchron" Carrier System and other sustained-release vehicles is that the hydrolysis or digestion of the vehicle is not dependent upon the pH or the enzymatic activity of the intestinal fluids.
Via the concentration of the vehicle in the dosage form site action predeter-mination is possible.
_ 10 --
Hydroxypropylmethylcellulose is known and commercially available as Methocel* (Dow Chemical Co.) and a premium (pharma-ceutical) grade is known as Methocel 60 H.G.-50 viscosity.
Ethylcellulose is also well known and readily available. Metho-cel] has been used as a starting material in making buccal or sub-lingual products for transmucosally acting medicaments as de-scribed in my British Patent Nos. 1,171,691 and 1,279,214 and United States Patent No. 3,870,790. While it is thus known to produce compressed buccal lozenges or tablets from cellulose de-rivatives as carriers with medicinal agents, where steady pro-longed medication is required and a regular rate of release is needed with good absorption of medicament from an orally ingest-ible preparation subject to the action of gastric and intestinal 1uids, further ~mprovements are possible and it is to this that the present invention is directed.
According to the present invention, it has now been discovered that furthe~ and important advantages and improvements over my prior products containing Methocel as described, for example, in Unitea States Patent No. 3,870,790 and British Patent Nos. 1,171,691 and 1,279,214 can be obtained by special treatment thereof under controlled conditions of moisture, temperature and time prior to incorporation of active medicament therein and thus the inherently desirable properties of Methocel can be taken ad-vantage of in a significantly improved sustained continuous re-lease compressed stable tablet capable of providing steady thera-peutic blood levels. T~e present invention subjects hydroxy-propylmethylcellulose to special processing and stabilizing con-ditions thereby producing a modified carrier material base having greater stability, reduced water solubility, greater chemical inertness with freedom from toxicity due to the carrier material *Trademark ~' . .
111~3~61 itself, less likelihood of i~mpaction and a lowered potential of replacement or chemical changes of anhydroglucose units.
Thus, the invention provides a solid, oral-dosage-unit form of a sustained release therapeutic composition for admin-istration to a patient in need of the t~erapeutic agent thereof for the prolonged systemic treatment of a disorder susceptible to such agent, which comprises a carrier base material of 100%
hydroxypropylmetnylcellulose or a mixture of about 80% hydroxy-propylmethylcellulose witn up to about 20% ethylcellulose which carrier material has been humidified to a moisture content of at least 85% for a period of at least about 24 hours, the humidifi-cation Being there upon discontinued and then the carrier mater-~al dehumidified to a moisture content in the range of 2 to 10%, an effective amount of a therapeutic agent and about 0.1% of a stabilizer being admixed in powder form and the mixture being formulated into unit dosage form wherein it is characterized by a long-lasting, slow and regular disintergration rate upon ingest-ion to give a prolonged and regular incremental release pattern, the said carrier material having a carbonyl content of 0.92 to 1.43 grams/100 grams and a carboxyl content of 0.54 to 0.57 grams/100 grams. The moisture range is preferably 4.5-5.5% for best results and the carrier material is itself essentially of neutral pH (to litmus paper).
The hydroxypropylmethylcellulose used as the starting material for the present invention is known and commercially available as Methocel 60 H.G.-50 viscosity (Dow Chemical Co.) which is a premium grade found best for pharmaceutical products and this hydroxypropylmethylcellulose can be optionally admixed with a small proporti`.on of ethylcellulose up to about 20% of the 3a weight of the mixture, in which case the hydroxypropylmethyl-cellulose amounts to 100-80%. The hydroxypropylmethylcellulose h d~ ~ ;
lla3l6l alone or a mixture of these two materials in powder form is pro-cessed. The processing is carried out in suitable equipment hereinafter described under the conditions set forth and after the materials are processed as described, an active ingredient in suitable amount to provide an effective unit dose per tablet is incorporated therein and wh;`ch can be of any type of medica-tion which acts systemically and can be administered orally to transmit the active medicament into the gastrointestinal tract and into the blood stream to therapeutically effective levels without early excessive peak concentrations, without being in-activated by physiological fluids and without passing unchanged through the body of the patient or subject ~y being excreted unabsorbed.
Representative active medicaments include anti-inflam-matory substances, coronary dilator preparations, cerebral dil-ators, vasodilators, antibacterials, psychotropics, anti-manicsr stimulants, etc. However, it is to be understood that the invention is especially applicable to compressed tablets which are intended to be swallowed in unit dosage form and which upon 2a ingestion according to a prescribed regimen give slow and regular release of active medicament without an initial dumping of a fixed percentage in the intestinal tract while being protected against normally inactivating gastric fluids.
' : :
1~'3~
The processed hydroxypropylmethylcellulose alone or with up to 20~ of ethyl-cellulose, by weight, forms what is herein called a long-acting slow dissolv-ing oral carrier independent of pH and of such nature that it has a protective, demulcent and buffering effect in the body and causes the active medicament to exert its optimum therapeutic action immediately and incrementally for up to several hours so that full therapeutic advantage can be taken of the entire or substantially the entire amount of active medicament administered. This un-expectedly high degree of efficiency is a particular advantage of the invention and minimizes side effects of the medication.
The procedure is carried out in my above patents by introducing the hydroxypropylmethylcellulose ora mixture of the hydroxypropylmethylcellulose with ethylcellulose into a heating chamber provided with an exhaust which is at that time in closed or shut position and which chamber is provided with a heating unit and a forced air blower which is inoperative at this stage of the procedure in that the heat and forced air are only applied at a subsequent stage. The carrier material to be processed is placed in thin layers (not more than 1/4~ thick) on trays of the chamber which are lined with heat-resistant parchment paper and the trays are placed on racks in the oven chamber using only alternate shelves thereby providing adequate spacing between the layers of carrier material being treated. There is then placed within the oven chamber a humidifier equipped withahumidistat which is preset to maintain humidity in the oven chamber at about 85%, the humidifier being filled with sufficient distilled or deionized water to last for 24 to 36 hours. The humidifier is now activated and the heating chamber is closed and the process is allowed to proceed under the high humidity conditions for a period of time sufficient to ensure reaching a humidity of the carrier material of at least 85% and maintaining the same for up to 24 hours or even longer if desired, although there is no special advantage in exceeding 24 hours and unduly ex-tended times are apt to be uneconomical. Subsequent to the 24-hour minimum 1~3~6~1 period just referred to, the humidifier is removed from the heating chamber, the exhaust aperture opened by manipulation of the usual valve or closure thereof and the forced air blower is activated thereby applying heat at a controlled temperature in the range of 110 - 120 F (43 - 49 C) and at the end of 12 hours the moisture content of the treated material is checked by removing and testing a sample. The moisture content must not be less then the range of 2 - 2~o in terms of added weight of the carrier material under-going processing. This added moisture content is equivalent to about 4 - 4.5%
as determined by a standard moisture determination apparatus. The 12-hour period just referred to is, however, approximate in that the duration of the period may vary somewhat above or below 12 hours, but it has been found in practice that the period should best be approximately 12 hours. The attain-ment of the specified additional moisture percentage is important and consid-ered critical to the success of the invention.
When the required added moisture content is achieved, and referring now to the processing of hydroxypropylmethylcellulose alone, the treated material is removed from the oven and passed through a No. 2 stainless steel screen employing a Fitzpatrick Comminuter having its knives directed forwardly and operating at medium speed. In the case of the treatment of 100 - 80%
hydroxypropylmethylcellulose and 0 - 20% ethylcellulose, the comminution step may be omitted and the heat applied until the moisture content is reduced to about not less than 2.0% as determined by the usual moisture determination apparatus. Since the material is free-flowing and powdery, no further opera-tion is required thereon.
By way of example, in making up tablets containing an orally adminis-trable systemically absorbable active component such as one of the heretofore mentioned medicaments, the treated oral carrier material is thoroughly inter-mixed with the medicament which is also in powdered or granular form and any other needed ingredients which are conventional in tablet making such as 11~3~61 magnesium stearate, lactose, starch and, in general, binders, fillers, disin-tegrating agents, and the like. The complete mixture, in an amount sufficient to make a uniform batch of tablets, such as 50,000, of which each contains an effective amount of active medicament, is then subjected to tableting in con-ventional tableting machines but at, for example, compression pressures of 7 to 13 kg/in. and because of the use of the specially processed carrier material in the production of the tablets, a product is obtained which has a desired set of properties such as predetermined prolonged action and a regular delayed release pattern so that the medicinal agent or active ingredient is available over a period of 1 - 12 hours depending on the precise tablet size and hardness and the particular carrier mixture. In this way it is possible to produce sustained or slow continuous release tablets in relatively simple and economi-cal manner on a commercial scale as contrasted with the more elaborate and more complex materials and procedures heretofore employed or proposed.
The humidifier employed is Arvin Model 50 H 42 (Sears Roebuck) - 10 gallon capacity having low and high air speeds and the humidistat is provided with nine settings for moisture control. In the present invention the humid-istat is set to position 7 which maintains 85 - 90~ humidity in the oven chamber per 250 cubic feet of airflow and a temperature of approximately 75 F
(24 C). It is understood that the invention is not limited to the use of this particular humidifier or equipment and that other equipment may be substituted.
The invention is further illustrated by the following non-limitative examples:
Example No. 1 Vasodilator (per 50,000 dosage units) a. Nitroglycerin 325 g.
b. Beta Lactose 2,975 g.
c. Syloid No 244 50 g.
r~JemdrKs ~:, ~ ~ .
11~}3~
d. Cherry flavor 100 g.
. e. Synchron Oral-Carrier 23,750 g.
Example No. 2 Anti-inflammatory (per 50,000 dosage units) a. Prednisolone 250 g.
b. Synchron Oral-Carrier 9,465 g.
c. Syloid No. 244 50 g.
d. Cherry flavor 100 g.
Example No. 3 Anti-Manic depressive (per 50,000 dosage units) a. ~ithium Carbonate 15,000 g.
b. Synchron Oral-Carrier 19,880 g.
c. Syloid No. 244 10 g.
d. Cherry flavor 15 g.
Example No. 4 Antacid (per 50~000 dosage units) a. Aluminum Hydroxide Gel 12,500 g.
b. Magnesium Glycinate 12,500 g.
c. Gastric Mucin 5,000 g.
d. Carbowax 6000 ~ 34.5 g.
e. Synchron Oral-Carrier 12,000 g.
f. Syloid No. 244 250 g.
g. Cherry flavor 500 g.
Example No. 5 Antibiotic (per 50,000 dosage units) a. Ampicillin 12,500 g.
b. Synchron Oral-Carrier 2,500 g.
c. Syloid No. 244 30 g.
d. Cherry flavor 25 g.
* TraJ~ncr~s - 6 -- .
11(}3~6~
The release pattern of active medicament from the new long-lasting oral carrier can be controlled according to the particular medication and its intended therapeutic effect. The release pattern varies from about 1 hour to 8 hours or as long as 12 hours and this is at least in part governed by the tablet si3e and degree of compression (hardness) since larger tablets last longer and higher compressions give a slower rate of release. For orally administered tablets, the rate of release is usually 4 - 8 hoursand this has been confirmed by X-rays with barium sulfate to show the motility and disin-tegration in the intestinal tract. For vaginal and rectal suppositories the release pattern ranges from 12 - 36 hours although it can of course be less where indicated. By predetermining the size of the tablet or suppository and the amount of compression or molding force employed in shaping it from the powder form and by keeping the end product moisture content not less than 2.0%
highly desirable release patterns of unusually reliable and regular character-istics can be secured. This is often very important medically, especially when treating patients having coronary diseases, as with nitroglycerin, or related problems of circulatory disorders such as angina pectoris or abnormal blood pressure conditions or psychotropic/manic-depressive schizophrenia. The invention is therefore of unusually versatile and adaptable nature giving it a wide scope of application and use.
The foregoing is exemplary of compositions and products responding to the present invention, but it is to be understood that they are illustrative and not limitative since many active ingredients of various types can be em-ployed in the new long-lasting oral carrier so long as they are absorbable in serum or tissue, the general intestinal tract, etc. The invention is also intended to cover other dosage forms or forms for application of sustained release ingredients such as vaginal and rectal suppositories. The total dosage is governed by usual medical considerations or physicians' directions and sufficiently large total doses of active medicament are administered in unit . . .
11C~3~61 dosage tablet form containin~ from 10-500 milligrams to overcome or control the pathological condition or disorder being treated. The presence of a stabilizing agent tends to prevent unwanted change in moisture content by avoiding pick-up or loss of moisture due to climactic conditions of high or low humidity in tropical or arid geographical locations or shipping or stor-age variations. It is therefore a particular part of this invention to add a stabilizer to the carrier material such as ascorbyl stearate or pal~itate or an initiator such as sodium metabisulfite. The stabilizer is usually added after the carrier material is otherwise processed and in a small amount of the order of 0.1 - 1.0% of the weight of the carrier, preferably about 0.2%.
The sodium metabisulfite (Na2S205), a Redox Initiator for the copolymer, per-mits copolymerization to be carried out rapidly during humidification. The sodium metabisulfite is employed for this purpose in a concentration of 0.1%
of the total weight of the polymer (hydroxypropylmethylcellulose) used.
In evaluating drugs incorporated in the oral carrier system or base of the present invention, it is important to understand the factors influenc-ing the absorption and therapeutic effectiveness of drug products in composi-tions responding hereto. Under usual circumstances, disintegration of a tab-let into small particles in the gastrointestinal fluids speeds dissolution because of much increased surface area of the drug. Consequently, absorption is more rapid and the duration of therapeutic action depends primarily upon the rate of absorption. The rate and extent of drug absorption thus can in-fluence both the duration of action and the efficacy of drug therapy. It follows that the faster the absorption, the earlier peak level of drug is reached but if absorption is too slow, the concentration of drug in blood and tissues may never reach therapeutic levels. Subsequent to absorption, there is a drop in concentration that depends in large part upon elimination and/or metabolization.
Drugs embedded in the present "Synchron" Carrier System, as I term il~3161 the carrier base, are intended to attain and maintain a steady concentration of drug in blood or tissues. One objective in using these preparations is to reduce the dosage frequency, to make therapy simple and convenient, and to improve compliance by the patient. In addition, by maintaining a reasonably constant plasma concentration of drug, excessive or premature peaking is avoided and side effects, which may be associated with peak concentrations of drug, would be lessened. In addition, a more uniform concentration of drug in blood and tissues is much more likely to be paralleled by a more uniform pharmacologic effect and response. With dissolution being the main rate-limiting step in drug absorption, the rate of solution of the drug from the dosage form into the surrounding fluids at the absorption site is controlled by the physical technique employed in the production of the "Synchron" Carrier System. With the "Synchron" Carrier System the drug can further be released to a specific site at a uniform rate independently of the pH environment, resulting in steady concentrations of the drug in tissues. Drugs incorporated into the "Synchron" Carrier System vehicle are prone to be absorbed completely, but more slowly, and are formulated to maintain the therapeutic effective level of the particular drug and to produce a prolonged response and a diminished rate of unassimilated drug elimination.
The absorption data may be determined and expressed as the cumulative percentage of the dose absorbed plotted against time, or analyzed further to derive information as to the kinetics of the absorption process. Usually the total body clearance of a drug is fixed. Then the total area under the plasma concentration-time curve is proportional to the dose absorbed and independent of the rate of absorption. Area analysis forms the basis for estimation and ; comparison of the extent of absorption when the same dose is given in different dosage forms or by different routes of administration, or in different carrier systems. The "Synchron" Carrier System has the added advantage compared to other available prolonged-release vehicles employed in dosage forms insofar as .: ,., . :.
1~316~
it will not release the drug in a d~ping action and prevents the potential haæard of over-dosage if all the drug is released at one time and is rapidly absorbed. The potency for determining sustaining dose with the present car-rier system may be expressed by the formula:
D x 0.693 x SV/~/2 ,wherein D is the normal therapeutic dose, SV is the number of hours desired to extend the duration of action, and Ll/2 is the drug's half-life. The primary difference between the use of my t'Synchron" Carrier System and other sustained-release vehicles is that the hydrolysis or digestion of the vehicle is not dependent upon the pH or the enzymatic activity of the intestinal fluids.
Via the concentration of the vehicle in the dosage form site action predeter-mination is possible.
_ 10 --
Claims (15)
1. A solid, oral-dosage-unit form of a sustained re-lease therapeutic composition for administration to a patient in need of the therapeutic agent thereof for the prolonged systemic treatment of a disorder susceptible to such agent, which comprises a carrier base material of 100% hydroxypropylmethylcellulose or a mixture of about 80% hydroxypropylmethylcellulose with up to about 20% ethylcellulose which carrier material has been humidified to a moisture content of at least 85% for a period of at least about 24 hours, the humidification being there upon discontinued and then the carrier material dehumidified to a moisture content in the range of 2 to 10%, an effective amount of a therapeutic agent and about 0.1% of a stabilizer being admixed in powder form and the mixture being formulated into unit dosage form wherein it is characterized by a long-lasting, slow and regular disintergration rate upon ingestion to give a prolonged and regular incremental release pattern, the said carrier material having a carbonyl con-tent of 0.92 to 1.43 grams/100 grams and a carboxyl content of 0.54 to 0.57 grams/100 grams.
2. A composition according to claim 1, wherein the stabilizer is ascorby palmitate or stearate in an amount of about 0.1 to 1.0% of the carrier, by weight.
3. A composition according to claim 1, wherein the stabilizer is ascorbyl stearate or palmitate in an amount of about 0.2% of the carrier, by weight.
4. A composition according to claim 1, in which the therapeutic agent is nitroglycerin or amyl nitrite.
5. A composition according to claim 1 in which the therapeutic agent is prednisolone.
6. A composition according to claim 1 in which the therapeutic agent is ampicillin.
7. A composition according to claim l in which the therapeutic agent is amoxycillin.
8. A composition according to claim 1 in which the therapeutic agent is cephalothin, cephalexin or cephaloglycine.
9. A composition according to claim 1 in which the therapeutic agent is lithium carbonate.
10. A composition according to claim 1 in which the therapeutic agent is a tetracycline.
11. A composition according to claim 1 in compressed tablet form with an effective amount of a therapeutic agent per dosage unit and which therapeutic agent is released after inges-tion over a period of time and at a rate related to the size of the tablet and the degree of its compression.
12. A method of producing a therapeutic composition of claim 1 which comprises humidifying a carrier material of about 100% hydroxypropylmethylcellulose or a mixture of about 80% hy-droxypropylmethylcellulose with up to 20% ethylcellulose for about 24 hours until the moisture content of the carrier material reaches about 85% while still remaining in powder form, discontinuing the humidification and subsequently dehumidifying the resulting car-rier material at elevated temperature until its moisture content is in the range of 2 to 10%, by weight, prior to incorporation therein of a therapeutic agent and a stabilizer and admixing the same and unitizing the mixture into dosage unit form.
13. A method according to claim 12, wherein the moisture content is about 4.5 to 5.5%.
14. A method according to claim 12, wherein the stabil-izing agent is about 0.1%, wherein the stabilizing agent is as-corbyl palmitate stearate.
15. A method according to claim 12, wherein about 0.1%
of sodium metabisulfite is incorporated in the carrier material as an initiator prior to the addition of the therapeutic agent.
of sodium metabisulfite is incorporated in the carrier material as an initiator prior to the addition of the therapeutic agent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US68341076A | 1976-05-05 | 1976-05-05 | |
| US683,410 | 1976-05-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1103161A true CA1103161A (en) | 1981-06-16 |
Family
ID=24743943
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA276,537A Expired CA1103161A (en) | 1976-05-05 | 1977-04-20 | Oral carrier base, its preparation and dosage units made therefrom |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS5817445B2 (en) |
| BR (1) | BR7702882A (en) |
| CA (1) | CA1103161A (en) |
| DE (1) | DE2718260C2 (en) |
| FR (1) | FR2358895A1 (en) |
| GB (1) | GB1583801A (en) |
| IL (1) | IL50175A0 (en) |
| MX (1) | MX4545E (en) |
| SE (1) | SE7704764L (en) |
| YU (1) | YU43437B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7919116B2 (en) | 1998-03-20 | 2011-04-05 | Andrx Labs, Llc | Controlled release metformin formulations |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2042888B (en) * | 1979-03-05 | 1983-09-28 | Teijin Ltd | Preparation for administration to the mucosa of the oral or nasal cavity |
| JPS6034925B2 (en) * | 1979-07-31 | 1985-08-12 | 帝人株式会社 | Long-acting nasal preparation and its manufacturing method |
| US4259314A (en) | 1979-12-10 | 1981-03-31 | Hans Lowey | Method and composition for the preparation of controlled long-acting pharmaceuticals |
| US4369172A (en) * | 1981-12-18 | 1983-01-18 | Forest Laboratories Inc. | Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose |
| JPS59501162A (en) * | 1982-06-24 | 1984-07-05 | キイ・フア−マシユ−テイカルズ・インコ−ポレイテツド | Extended release propranolol tablets |
| JPS59193831A (en) * | 1983-04-18 | 1984-11-02 | Sankyo Co Ltd | Preparation of enteric drug |
| US4680323A (en) * | 1983-12-01 | 1987-07-14 | Hans Lowey | Method and composition for the preparation of controlled long-acting pharmaceuticals for oral administration |
| US4775535A (en) * | 1986-04-04 | 1988-10-04 | Hans Lowey | Method of preparing controlled long-acting pharmaceutical formulations in unit dosage form having uniform and comparable bioavailability characteristics |
| US4855143A (en) * | 1986-04-04 | 1989-08-08 | Hans Lowey | Method of preparing controlled long-acting pharmaceutical formulations in unit dosage form having uniform and comparable bioavailability characteristics |
| ATE130189T1 (en) * | 1989-08-25 | 1995-12-15 | Bioglan Ireland R & D Ltd | PHARMACEUTICAL COMPOSITION AND TAKING DEVICE THEREOF. |
| JPH07112934A (en) * | 1993-10-15 | 1995-05-02 | Taiyo Yakuhin Kogyo Kk | Sustained release preparation of pentoxyphylline and its production |
| US5948437A (en) * | 1996-05-23 | 1999-09-07 | Zeneca Limited | Pharmaceutical compositions using thiazepine |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3065143A (en) * | 1960-04-19 | 1962-11-20 | Richardson Merrell Inc | Sustained release tablet |
| AU452221B2 (en) * | 1971-09-20 | 1974-08-09 | Forest Laboratories, Inc. | Long-acting oral carrier |
| GB1388786A (en) * | 1972-04-03 | 1975-03-26 | Scherer Corp R P | Integral solid gel-lattice dosage form of high-moisture content |
| US3965256A (en) * | 1972-05-16 | 1976-06-22 | Synergistics | Slow release pharmaceutical compositions |
| CA1018456A (en) * | 1972-06-26 | 1977-10-04 | Hans Lowey | Prolonged release lozenges |
-
1976
- 1976-07-26 YU YU1841/76A patent/YU43437B/en unknown
- 1976-07-30 IL IL50175A patent/IL50175A0/en unknown
-
1977
- 1977-03-25 FR FR7709055A patent/FR2358895A1/en active Granted
- 1977-04-20 CA CA276,537A patent/CA1103161A/en not_active Expired
- 1977-04-25 DE DE2718260A patent/DE2718260C2/en not_active Expired
- 1977-04-26 SE SE7704764A patent/SE7704764L/en unknown
- 1977-04-28 JP JP52049778A patent/JPS5817445B2/en not_active Expired
- 1977-05-01 GB GB8515/77A patent/GB1583801A/en not_active Expired
- 1977-05-04 BR BR2882/77A patent/BR7702882A/en unknown
- 1977-05-04 MX MX775718U patent/MX4545E/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7919116B2 (en) | 1998-03-20 | 2011-04-05 | Andrx Labs, Llc | Controlled release metformin formulations |
| US8475841B2 (en) | 1998-03-20 | 2013-07-02 | Andrx Labs, Llc | Controlled release metformin formulations |
Also Published As
| Publication number | Publication date |
|---|---|
| DE2718260C2 (en) | 1983-08-11 |
| BR7702882A (en) | 1978-01-31 |
| MX4545E (en) | 1982-06-10 |
| FR2358895A1 (en) | 1978-02-17 |
| JPS5817445B2 (en) | 1983-04-07 |
| SE7704764L (en) | 1977-11-06 |
| YU184176A (en) | 1984-02-29 |
| JPS52145514A (en) | 1977-12-03 |
| GB1583801A (en) | 1981-02-04 |
| FR2358895B1 (en) | 1982-10-22 |
| IL50175A0 (en) | 1976-09-30 |
| YU43437B (en) | 1989-08-31 |
| DE2718260A1 (en) | 1977-11-17 |
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