Stabilized Molded Sublingual Nitroglycerin Tablets

Abstract

Pharmaceutical compositions containing minor proportions of nitroglycerin and a non-volatile, water-soluble solvent in combination with a major proportion of a solid, water-soluble pharmaceutical carrier. Those compositions, in the form of tablets suitable for sublingual administration, can be produced by wetting a substantially dry mixture of the nitroglycerin and the solid, water-soluble pharmaceutical carrier with a solvent mixture containing a non-volatile, water-soluble solvent and a volatile solvent, forming the wetted mixture into tablets, and removing the volatile solvent.

Description

SUMMARY AND DETAILED DESCRIPTION

The present invention relates to new and improved pharmaceutical compositions of nitroglycerin, and to methods for producing those compositions.

Nitroglycerin (glyceryl trinitrate) is widely used in medical practice as a coronary vasodilator. It is normally used in the form of tablets for sublingual administration containing approximately 0.2 to 0.65 mg. of nitroglycerin per tablet. Nitroglycerin tablets are administered for the purpose of producing a rapid coronary vasodilator effect relieving acute attacks of angina pectoris, and thus it is important that they retain the correct potency in terms of the active ingredient and that the active ingredient be promptly released for absorption upon sublingual administration.

It is known that nitroglycerin tablets that meet accepted standards of potency and uniformity at the time of manufacture may fail to meet those standards of potency and uniformity following storage over a period of only a few months or less.

In accordance with the present invention, it has been found that the failure of nitroglycerin tablets to maintain satisfactory potency and uniformity upon storage can be attributed to a migration of nitroglycerin from tablet to tablet and from the tablets to the environment. It has been found that the migration of nitroglycerin from the tablets to the environment is especially significant when the container is not tightly sealed so that the nitroglycerin can volatilize from the tablets through the loose seal into the atmosphere. It has also been found that the migration of nitroglycerin from the tablets to the environment is especially significant when the container has rayon or cotton stuffing material whereby nitroglycerin is volatilized from the tablets and absorbed on the stuffing material. However, in accordance with the invention, migration of nitroglycerin from tablet to tablet with resulting loss of uniformity has been found to occur even in sealed glass containers without rayon or cotton stuffing material. The lack of uniformity can be demonstrated by the fact that after storage some tablets have abnormally high potency and some tablets have abnormally low potency, even though the average potency may remain within acceptable limits.

It is an object of the present invention to provide pharmaceutical formulations of nitroglycerin that retain an acceptable level of potency even in an imperfectly sealed container and in the presence of rayon, cotton, or other material capable of absorbing nitroglycerin.

Another object of the invention is to provide pharmaceutical formulations of nitroglycerin in the form of sublingual tablets which do not undergo a significant degree of migration of nitroglycerin from tablet to tablet within the same container.

A further object of the invention is to provide pharmaceutical formulations of nitroglycerin in the form of sublingual tablets which retain their original potency without significant deviation over a long period of storage.

Still a further object of the invention is to provide pharmaceutical formulations of nitroglycerin in the form of sublingual tablets having the improved potency retention mentioned above and having in addition the characteristic of giving rapid release of nitroglycerin upon sublingual administration.

Yet another object of the invention is to provide methods for producing the above-mentioned pharmaceutical compositions.

These as well as other objects which will appear hereinafter are achieved by the new pharmaceutical compositions and methods for producing them as described below.

In accordance with the invention, new pharmaceutical compositions of nitroglycerin are prepared to contain in finished form (a) one part by weight of nitroglycerin, in combination with (b) 0.1 to 4 parts by weight of a non-volatile, water-soluble solvent, and (c) 20 to 200 parts by weight of a solid, water-soluble pharmaceutical carrier. The term "non-volatile" is used herein in a relative sense to designate a solvent that when incorporated in the finished formulation volatilizes to no more than a minor extent over a period of several months at ordinary temperatures and under ordinary conditions of storage. That solvent can be a high boiling liquid or a high boiling, low melting solid that exhibits the required solvent characteristics under the conditions of use. It should have a relatively high solubility for nitroglycerin. Some examples of such solvents are polyethylene glycols, tetramethylene glycol, and pentamethylene glycol. Preferred solvents are polyethylene glycols having an average molecular weight in the range of 300 to 7,500, especially 300 to 1,000. A preferred ratio of ingredients is one part by weight of nitroglycerin to 0.5 to 0.9 parts by weight of the non-volatile, water-soluble solvent. The solid, water-soluble pharmaceutical carrier is a sugar or a sugar derivative such as lactose, glucose, sucrose, mannitol, or sorbitol. The solid, water-soluble pharmaceutical carrier is used in an amount, within the proportions indicated above, to impart to the finished formulation the desired solid state under normal as well as extreme temperature conditions of storage and use. The new pharmaceutical formulations of nitroglycerin, as described above, are desirably provided as tablets suitable for sublingual administration and containing 0.1 to 1.0 mg., preferably 0.2 to 0.65 mg., of nitroglycerin per tablet. However, if desired, they can also be provided in other conventional pharmaceutical forms such as granules.

Also in accordance with the invention, pharmaceutical compositions of nitroglycerin in the form of tablets for sublingual administration are produced by the process which comprises (a) preparing a substantially dry mixture of one part by weight of nitroglycerin and 20 to 200 parts by weight of a solid, water-soluble pharmaceutical carrier, (b) wetting that substantially dry mixture with a solvent mixture containing 0.1 to 4 parts by weight of a non-volatile, water-soluble solvent and a sufficient quantity of a volatile solvent to permit an even wetting of the substantially dry mixture by the solvent mixture, (c) forming the wetted mixture into tablets, and (d) drying the tablets whereby substantially all of the volatile solvent is volatilized while substantially all of the non-volatile solvent remains unvolatilized. The term "non-volatile" is used herein in a relative sense to designate a solvent that when incorporated in the finished formulation volatilizes to no more than a minor extent over a period of several months at ordinary temperatures and under ordinary conditions of storage. That solvent can be a high boiling liquid or a high boiling, low melting solid that exhibits the required solvent characteristics under the conditions of use. It should have a relatively high solubility for nitroglycerin. Some examples of such solvents are polyethylene glycols, tetramethylene glycol, and pentamethylene glycol. Preferred solvents are polyethylene glycols having an average molecular weight in the range of 300 to 7,500, especially 300 to 1,000. A preferred ratio of ingredients is one part by weight of nitroglycerin to 0.5 to 0.9 parts by weight of the non-volatile, water-soluble solvent. The term "volatile" is used herein in a relative sense to designate a solvent that readily volatilizes under the conditions normally used in drying pharmaceutical tablets, for example drying in air at room temperature for 12 to 48 hours. Such solvents most suitably have a boiling point of about 100.degree. C. or lower and a preferred solvent for this purpose is aqueous ethanol or water. The solid, water-soluble pharmaceutical carrier is a sugar or a sugar derivative such as lactose, glucose, sucrose, mannitol, or sorbitol. The solid, water-soluble pharmaceutical carrier is used in an amount, within the proportions indicated above, to impart to the finished tablets the desired solid state under normal as well as extreme temperature conditions of storage and use. The tablets, as prepared above, are desirably constituted to contain 0.1 to 1.0 mg., preferably 0.2 to 0.65 mg. of nitroglycerin per tablet.

The pharmaceutical compositions described above can, if desired, also be formulated to contain other ingredients useful in pharmaceutical compounding.

The pharmaceutical compositions of the invention exhibit the well-known activity of nitroglycerin in medical practice but show improved behavior on storage. For example, the sublingual tablets give a rapid coronary vasodilator effect when dissolved under the tongue. Additionally, they show improved retention of potency and uniformity when stored in either glass or plastic containers, with or without stuffing materials, at temperatures from room temperature to 45.degree. C., when compared with the behavior of tablets prepared similarly but without the inclusion of a non-volatile, water-soluble solvent.

The invention is illustrated by the following examples.

EXAMPLE 1

Ingredient Quantity Nitroglycerin mixture soluble, 6.93 kg. 10% nitroglycerin Diluent (lactose + sucrose, 44.07 kg. 95:5) Solvent mixture containing: Ethanol, 95% 3381 ml. Polyethylene glycol 400 520 ml. Purified water 1302 ml.

The nitroglycerin mixture soluble is a product containing 10% nitroglycerin on .beta.-lactose and the quantity used is seven percent in excess of the calculated amount.

The diluent contains 95% by weight of the usual lactose of pharmacy (.alpha.-lactose monohydrate) and 5% by weight of sucrose.

The polyethylene glycol 400 is a polymer of ethylene oxide and water, represented by the formula H(OCH.sub.2 CH.sub.2).sub.n OH, in which the average value of n lies between 8.2 and 9.1.

The nitroglycerin mixture soluble is blended with a sufficient quantity of diluent to produce a siftable mixture. With care, the siftable mixture is passed through a number 80 mesh silk sieve. Approximately one-half of the diluent, then the sifted nitroglycerin and diluent mixture, and then the remainder of the diluent are added to a blender and thoroughly mixed. While the blender is operating the solvent mixture is then added and the ingredients are again blended. The wetted mixture is then formed into tablets, each weighing approximately 34 mg. after air drying, on a tablet molding machine. Optimum temperature and humidity conditions for this operation are a dry bulb temperature of 22.degree. to 26.degree. C. and a dew point temperature of 6.degree. to 9.degree. C. The molded tablets are collected into trays and air dried at room temperature. Yield equals 1,400,000 to 1,500,000 tablets, each weighing approximately 34 mg. and labeled to contain 1/150 grain (approximately 0.43 mg.) of nitroglycerin per tablet; the acceptable variation is an average assay of 90 percent to 11 percent of the indicated potency.

The tablets prepared as described above are suitable for sublingual administration and exhibit improved behavior on storage when compared with tablets prepared similarly but without the use of polyethylene glycol. They maintain acceptable standards of potency and uniformity upon prolonged storage at room temperature, at 37.degree. C., and at 45.degree. C. The improved behavior on storage is observed in closed containers as well as in containers that are opened periodically to simulate conditions of use.

EXAMPLE 2

Ingredient Quantity Nitroglycerin mixture soluble, 10.2 kg. 10% nitroglycerin Diluent (lactose + sucrose, 40.8 kg. 95:5) Solvent mixture containing: Ethanol, 95% 3135 ml. Polyethylene glycol 400 765 ml. Purified water 1302 ml.

The nitroglycerin mixture soluble is a product con-taining 10% nitroglycerin on .beta.-lactose and the quantity used is five percent in excess of the calculated amount.

The diluent contains 95% by weight of the usual lactose of pharmacy (.alpha.-lactose monohydrate) and 5% by weight of sucrose.

The polyethylene glycol 400 is a polymer of ethylene oxide and water, represented by the formula H(OCH.sub.2 CH.sub.2).sub.n OH, in which the average value of n lies between 8.2 and 9.1.

The nitroglycerin mixture soluble is blended with a sufficient quantity of diluent to produce a siftable mixture. With care, the siftable mixture is passed through a number 80 mesh silk sieve. Approximately one-half of the diluent, then the sifted nitroglycerin and diluent mixture, and then the remainder of the diluent are added to a blender and thoroughly mixed. While the blender is operating the solvent mixture is then added and the ingredients are again blended. The wetted mixture is then formed into tablets, each weighing approximately 34 mg. after air drying, on a tablet molding machine. Optimum temperature and humidity conditions for this operation are a dry bulb temperature of 22.degree. to 26.degree. C. and a dew point temperature of 6.degree. to 9.degree. C. The molded tablets are collected into trays and air dried at room temperature. Yield equals 1,400,000 to 1,500,000 tablets, each weighing approximately 34 mg. and labeled to contain 1/100 grain (approximately 0.65 mg.) of nitroglycerin per tablet; the acceptable variation is an average assay of 90 percent to 110 percent of the indicated potency.

The tablets prepared as described above are suitable for sublingual administration and exhibit improved behavior on storage as described in Example 1.

Example 3

Ingredient Quantity Nitroglycerin mixture soluble, 5.31 kg. 10% nitroglycerin Diluent (lactose + sucrose, 45.69 kg. 95:5) Solvent mixture containing: Ethanol, 95% 3502 ml. Polyethylene glycol 400 398 ml. Purified water 1302 ml.

The nitroglycerin mixture soluble is a product containing 10% nitroglycerin on .beta.-lactose and the quantity used is nine percent in excess of the calculated amount.

The diluent contains 95% by weight of the usual lactose of pharmacy (.alpha.-lactose monohydrate) and 5% by weight of sucrose.

The polyethylene glycol 400 is a polymer of ethylene oxide and water, represented by the formula H(OCH.sub.2 CH.sub.2).sub.n OH, in which the average value of n lies between 8.2 and 9.1.

The nitroglycerin mixture soluble is blended with a sufficient quantity of diluent to produce a siftable mixture. With care, the siftable mixture is passed through a number 80 mesh silk sieve. Approximately one-half of the diluent, then the sifted nitroglycerin and diluent mixture, and then the remainder of the diluent are added to a blender and thoroughly mixed. While the blender is operating the solvent mixture is then added and the ingredients are again blended. The wetted mixture is then formed into tablets, each weighing approximately 34 mg. after air drying, on a tablet molding machine. Optimum temperature and humidity conditions for this operation are a dry bulb temperature of 22.degree. to 26.degree. C. and a dew point temperature of 6.degree. to 9.degree. C. The molded tablets are collected into trays and air dried at room temperature. Yield equals 1,400,000 to 1,500,000 tablets, each weighing approximately 34 mg. and labeled to contain 1/200 grain (approximately 0.32 mg.) of nitroglycerin per tablet; the acceptable variation is an average assay of 90 percent to 110 percent of the indicated potency.

The tablets prepared as described above are suitable for sublingual administration and exhibit improved behavior on storage as described in Example 1.

Claims

We claim:

1. A pharmaceutical molded tablet composition for sublingual administration consisting essentially of

a. one part by weight of nitroglycerin,

b. 0.5 to 0.9 parts by weight of a non-volatile, water-soluble solvent selected from the group consisting of polyethylene glycols having an average molecular weight in the range of 300 to 7,500, tetramethylene glycol, and pentamethylene glycol, and

c. 20 to 200 parts by weight of a solid, water-soluble pharmaceutical carrier of the class consisting of lactose, glucose, sucrose, mannitol, and sorbitol,

said molded sublingual tablet composition being capable of giving a rapid release of nitroglycerin upon sublingual administration, and being thereby stabilized against the tendency of nitroglycerin to otherwise migrate significantly from tablet to tablet, from tablet to environment, and from tablet to container stuffing capable of absorbing nitroglycerin in sealed or imperfectly sealed containers with resulting loss of original potency during storage.

2. A pharmaceutical composition according to claim 1 wherein the non-volatile, water-soluble solvent is a polyethylene glycol having an average molecular weight of 300 to 1,000.

3. A pharmaceutical composition according to claim 1 wherein the solid, water-soluble pharmaceutical carrier is substantially a mixture of lactose and sucrose.

4. A pharmaceutical composition according to claim 1 in the form of tablets containing 0.1 to 1.0 mg. of nitroglycerin per tablet.