MXPA00001517A - Compressed nitroglycerin tablet and its method of manufacture - Google Patents

Abstract

The present invention is directed to a stable nitroglycerin containing pharmaceutical composition, preferably a tablet which is prepared by direct compression technology. The formulation closely replicates the properties of nitroglycerin molded sublingual tablets (e.g. adequate disintegration and sublingual absorption), while reducing the problems experienced with compressed tablets (e.g. friability and weight variations). The stable tablets are characterized by a decreased migration of nitroglycerin, decreased potency loss, excellent content uniformity when stored. The preferred combination of components are:nitroglycerin/lactose dilution, hydrous lactose, glyceril monostearate, fumed silica, pregelatinized starch and calcium stearate. The preferred process employs direct compression technology to yield composition showing adequate disintegration, bioavailability and improved stability.

Description

COMPRESSED TABLET OF NITROGLYCERIN AND METHOD FOR ITS MANUFACTURE FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition containing nitroglycerin, preferably it is related to a compressed tablet, stabilized by the presence of glyceryl monostearate. Said formulation similarly possesses the properties of nitroglycerin in the form of sublingual tablets (for adequate disintegration and sublingual absorption), but reduces the problems experienced with compressed tablets (friability and weight variations). The stable tablets are characterized by a lower migration of nitroglycerin, less loss of potency and an excellent content of uniformity during storage. The preferred combination of the components is: dilution of nitroglycerin / lactose, hydrated lactose, glyceryl monostearate, fumed silica, pregelatinized starch and calcium stearate. The preferred process employs direct compression technology to produce a stable composition having adequate disintegration and good bioavailability.

BACKGROUND OF THE INVENTION The stabilization of nitroglycerin in solid dosage form has been a matter of scientific interest for more than twenty years. Such interest can be attributed to the discovery that nitroglycerin, being liquid at normal temperatures, easily migrates from one tablet to another tablet and / or into the container and container components. Nitroglycerin will migrate to the top of the container and to other tablets such as aspirin, if these two products are stored together in the same container. Plastics have different affinities with nitroglycerin depending on their polarity; that is the reason why the trade of the same in the form of tablets in individual dose containers has not been successful. In fact, USP notes that nitroglycerin tablets should be stored in glass containers. Several attempts have been made to improve the formulation of the molded tablet to ensure better stability. However, until now, no significant improvements have been made in the products for sale. In 1973, Parke-Davis & Co. added polyethylene glycol 3350 to its formulations for molded tablets. While this additive reduced the migration and loss of nitroglycerin to some degree, the range of uniformity content increased during storage. Therefore, after one or two years of shelf life, there was a risk that they would not comply with the USP limits. At that time, several stabilizing agents were examined and found to decrease the volatility of nitroglycerin tablets. Among them were microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP) and ß-cyclodextrin (BCD). For example, a compressed tablet was prepared using the combination of MCC and PVP and was sold by Waener Chilcott Laboratories under the NitroPRN ™ brand. The tablet was by far superior to the migration and volatility of nitroglycerin, compared to the existing molded tablets. However, the large amount of water insoluble excipient (MCC) was undesirable since the tablet provided a less acceptable sensation and less disintegration under the tongue. Many patents have been granted with respect to the stabilization of nitroglycerin in tablets. Patent No. 4, 091, 091 issued to Eli Lilly and Co., discloses the use of water soluble PVP to improve the stability of molded nitroglycerin tablets. In this application, the PVP is added from a solution and the molded tablets are manufactured by the traditional method. The patent of E.U.A. No. 4,059,686 issued to Nipón Kayaku, indicates that β-cyclodextrin is an effective stabilizing agent. The process of manufacturing sublingual nitroglycerin tablets is typically the traditional method of molded tablets. In this process, a humid mixture of nitroglycerin concentrate and other ingredients is made and still wet, compressed into cylindrical cavities. The wet tablets are ejected using punches, which are exactly aligned within the cavities and dried. The method produces a porous, fragile and rapidly dissolvable tablet. However, a high degree of weight variation occurs and this attribute, together with the migration of inter-tablet nitroglycerin, does not adequately and satisfactorily preserve the uniformity of the content during storage.

The high content variation that occurs after tablet aging, even when stored in hermetically sealed glass containers, is attributed to inter-tablet migration. In addition, this method has certain disadvantages; among which are: the need to incorporate stabilizing agents such as PVP or nitroglycerin per se in alcohol and the subsequent removal of said solvent. It is preferable to use nitroglycerin in a non-alcoholic solution for safety purposes. Also, wet granulations may require a binder that retards and reduces the release (dissolution) of nitroglycerin from the tablet matrix. Additionally, extra handling and safety considerations related to wet granulation processing make the use of this technique less desirable. The preferred method for preparing a stabilized and improved nitroglycerin tablet appears to be the use of direct compression technology. But in it, complexity and safety considerations relative to the wet granulation process are obviated. Although much is known about the problem of nitroglycerin instability, an improved dry compression formulation that approximates the original sublingual tablet has not been produced. Such a tablet would preferably meet the requirements of the USP for molded tablets of nitroglycerin and would be comparable to molded tablets in texture, size and weight and would effectively reduce the loss of potency and inter-tablet migration of the drug. The literature reports several stabilized compositions, but none has been prepared by direct compression technology that mimics the properties of a molded tablet. Neither the technology nor the formulation techniques have been developed to prepare an improved nitroglycerin tablet, particularly one manufactured by compression. The lack of a technical improvement is related to the complexity of the formulation with respect to the selection of excipients and stabilizing agents that can be used to adequately mimic the physical and chemical attributes of molded tablets and provide significantly improved stability and similar disintegration and bioavailability .

SUMMARY OF THE INVENTION It is an object of the invention to provide new and useful sublingual nitroglycerin tablets which are not susceptible to the migration of nitroglycerin ether tablet. It is also an object of the invention to provide new and useful compressed sublingual nitroglycerin tablets that offer improved control in weight (less weight variation). It is another object of the invention to provide new and useful compressed sublingual nitroglycerin tablets having the same pharmacological activity as molded sublingual tablets. It is another object of the invention to provide new and useful compressed sublingual nitroglycerin tablets that provide a mouthfeel comparable to that of molded sublingual tablets.

It is another object of the invention to use a non-explosive crushed nitroglycerin to manufacture sublingual nitroglycerin tablets. It is another object of the invention to provide a pharmaceutical composition that is not overloaded with nitroglycerin to prolong shelf life. It is another object of the invention to provide new and useful compressed sublingual nitroglycerin tablets whose manufacture eliminates the complexity of wet granulation processes and the safety considerations involved associated with the use of a solvent. It is another object of the invention to provide new and useful compressed sublingual nitroglycerin tablets which are characterized by lower volatility of nitroglycerin and higher stability profiles. It is another object of the invention to provide new and useful compressed sublingual nitroglycerin tablets that exceed the ordinary USP requirements for uniformity testing and content. This invention achieves these objects by employing a dosage form of compressed nitroglycerin tablet that is more stable, exhibits less weight variation from tablet to tablet and uniformity content and is less prone to spray (lower friability) than compositions prepared by molding techniques. It has been found that pharmaceutical compositions, such as compressed nitroglycerin tablets containing: nitroglycerin, glyceryl monostearate, calcium stearate, silica, starch and lactose; they are stabilized against migration of the active agent from tablet to tablet, when such tablets are in contact with each other. The compositions are of the same taste and similar sensation in the mouth as the molded compositions that have hitherto been available. In addition, nitroglycerin-containing tablets exceed the specifications of the USP and are bioequivalent to molded tablets. It has further been discovered that such pharmaceutical compositions can be prepared by a direct compression method. The use of direct compression technology provides compositions that can be rapidly produced cheaply, easily, non-hazardously and environmentally safe. In the preferred embodiment of the invention nitroglycerin, glyceryl monostearate, hydrated lactose, calcium stearate, pregelatinized starch and hydrophobic fumed silica are mixed and subsequently, this mixture is compressed to form the sublingual tablet. Other benefits and advantages of the present invention will be apparent to those skilled in the art from the following description and the appended claims.

DETAILED DESCRIPTION OF THE INVENTION As indicated above, the active agent of the present invention is nitroglycerin. The novel pharmaceutical compositions of the present invention may contain from about 0.5 to about 2% by weight of nitroglycerin, said% by weight, based on the total weight of the composition. This allows a large variety of dose concentrations to be manufactured.

Pure nitroglycerin has a vapor pressure of approximately 0.00026 mm at 20 ° C and is a violent explosive that must be handled with great care. For this reason, nitroglycerin is commercially available in a diluted form in a solution at a concentration of 10% by weight, before processing to manufacture the chemical compound. This concentration of nitroglycerin was previously considered flammable, but the new regulations of the Department of Transportation have reclassified nitroglycerin concentrations above 2% as explosives. For safety reasons, the nitroglycerin is diluted to a concentration below 2% by weight. In practice, it is advisable to have a dilution of nitroglycerin in a range that is adequate to produce several tablets of the dose that is prescribed. A common dilution of a given percentage of nitroglycerin is easily compounded with additional excipients that produce tablets with various doses. While the doses can be easily compounded using a 10% dilution according to established regulations, in the compounds developed and exemplified herein, a 1.95% dilution was used. In the preferred embodiment, the diluent is comprised of the main ingredient, lactose. Lactose greatly influences the flow path, compressibility and taste of the compositions. It has been found that the presence of lactose amounts greater than 90%, preferably from about 95 to about 98% by weight, said% by weight based on the weight of the diluent, is surprisingly advantageous. In terms of% by weight based on the total weight of the tablet, the% lactose is preferably present from about 85 to about 95, optimally from about 88 to about 93% by weight. Many lactose known to those skilled in the art are included in the scope of this invention. As an example thereof, but not limited to, there is a wide variety of commercially available lactoses such as anhydrous lactose and hydrated lactose, monohydrated forms (such as TABLETTOSE sold by Meggle Co. of Germany), fine hydrated lactose. , hydrated lactose with fast flow and hydrated lactose G-200. Different grades of anhydrous and hydrated lactose can be used to facilitate the preparation of tablets with good compressibility, low friability and rapid disintegration, as well as protection against flammability. In the alternative embodiments of the present invention, the additional excipients are included in the diluent together with the lactose. One of these additional excipients is an anti-adhesion agent. During the investigation of the additional excipients that can be introduced into the compositions of the present invention, it has been found that the presence of from about 0.1 to about 1, optimally from about 0.1 to about 0.5, preferably from about 0.3 to about 0.5% by weight of silica (a silica preferably belonging to the finely divided silica class), said% by weight based on the total weight of the tablet, is surprisingly advantageous. The use of silica in conjunction with other specified ingredients such as lactose, aids in the flow of the powder mixture and prevents adhesion of the tablets in the form of conglomerates. Despite the hydrophobic nature of some silicas, the optimized level used in the formulation does not affect the development of the tablet. There are various silicas known to those skilled in the art and the present invention is intended to encompass all of them. The silicas can be precipitated (for example, the SYLOID ™ sold by Davison Division, W. R. Grace Company) or smoked, they can be amorphous, colloidal or crystalline and be in anhydrous or hydrated form. Smoked silica or silicon dioxide (SiO2) is an amorphous, colorless, insatiable and insoluble powder in water and acids. The colloidal silica particles are agglutinated in chain-like formations and have surface areas of 50 to 400 M2 / g, depending on the degree. Smoked hydrophobic silicas are perfectly known and constitute commercially available materials, for example; the AER-O-SIL ™ R-972 sold by Degussa, Inc. of Teterboro, NJ, the CAB-O-SIL ™ N70-TS sold by Cabot Corp. of Tuscola, III., the TULLANOX ™ 500 sold by Tulco, Inc., (the use of all of which is preferred in the present invention), of the general class of amorphous precipitated silicas, but of the pyrogenic (smoked) type it provides, according to Kirk-Othmer's Encyclopedia of Chemical Technology ( Third Edition) Vol. 20 on pages 768 and 778-779, a final particle size of 1-100 nm and an aggregate particle size of 2-3 μm. Hydrophobic silicas are described in the Chemical Technology Encyclopedia of Kirk-Othmer (Third Edition), Vol. 7 on pages 440-441. The compositions of the present invention also include the presence of starch. There are many different starches known to those skilled in the art and the present invention includes, without being limited to, those listed in the Grant & Chemistry Dictionary. Hackh, Fifth Edition. A preferred starch in the present invention is pregelatinized starch. The starch is present in an amount of from about 5 to about 15% by weight, preferably from about 5 to about 10% by weight, based on the total weight of the tablet. An important ingredient that is included in the compositions of the present invention is a stabilizer. As indicated above, nitroglycerin is a volatile compound that exhibits poor physical stability when formulated without a stabilizer. The presence of the stabilizer decreases the loss of potency of the nitroglycerin in the tablets and, therefore, its addition is important. The preferred stabilizer in the present invention is glyceryl monostearate. During the investigation of the stabilizers that can be added to the compositions of the present invention, the presence of from about 0.05 to about 10, preferably from about 1 to about 5, optimally from about 1.5 to about 4% by weight of glyceryl monostearate was found. , said% by weight of glyceryl monostearate based on the total weight of the tablet; It is surprisingly advantageous. The use of glyceryl monostearate in the amounts specified above, in conjunction with the other specified ingredients, results in a compressed sublingual tablet having greater stability.

Glyceryl monostearate is a substance with a consistency similar to that of paraffin, which decreases the disintegration time of nitroglycerin tablets. To overcome this adverse effect, the use of a disintegrant is preferably used in the present invention. The experts in the field of pharmaceutical development know perfectly well that glyceryl monostearate is a disintegrant and also know the amounts that should be used in pharmaceutical compositions. Non-limiting examples of common disintegrants include one or more cellulose derivatives, which are dispersed in water, such as microcrystalline cellulose, croscarmellose sodium, starch and starch derivatives such as carboxylmethyl sodium starch. Initially, diluted nitroglycerin is mixed with a pre-mix of stabilizer (glyceryl monostearate) and diluent (lactose). Subsequently, the anti-adhesion agent (silica), more diluent and the disintegrant are added to the mixture. The conventional method for making compact materials requires the addition of a lubricant to the mixture before compression. Compression is carried out by holding the dry mix under pressure by means of mobile punches that operate inside a die, where the mixture is imprisoned. The lubricants are necessary because they allow the rapid expulsion of the formed compact and prevent the agglutination of the material in the die. Lubrication is only required at the tablet-die interface to prevent adhesion to the walls of the newly formed compact die. However, there are practical approaches to the lubrication of the tablet that require a homogeneous distribution of the lubricant in the complete formulation of the lubricant.

Although there are several commercially available lubricants for the manufacture of tablets, it has been determined that the use of a hydrophobic lubricant is preferable. And even, a lubricant that is a salt of an alkali metal and not a fatty acid is more preferable. In the most preferred embodiment of the present invention, the choice of calcium stearate was determined as a lubricant (calcium stearate is a well-known commercially available material, for example, calcium stearate NF powder, sold by Mallinckrodt of St. Louis, MO). During the investigation of other excipients that can be introduced into the compositions of the present invention, it has been found that the presence of from about 0.1 to about 1, optimally from about 0.1 to about 0.5, preferably from about 0.3 to about 0.5 wt.% Of stearate of calcium, said% by weight of calcium stearate based on the total weight of the tablet, is surprisingly advantageous. The use of calcium stearate in the amounts specified above, in conjunction with the other specified ingredients, results in a decrease in the weight variation of the tablet. Another aspect of this invention relates to the process for the preparation of the novel stabilized nitroglycerin tablets having the compositions described throughout this document. The process by which the stabilized nitroglycerin tablets are prepared comprises the steps of: (a) mixing the nitroglycerin with the lactose to produce a nitroglycerin dilution (ordinary regulations require that the content of the active agent be approximately 2%); (b) adding and mixing the dilution of nitroglycerin with an excipient or combination of excipients selected from the group already described to produce a mixture; (c) compressing the mixture under a force of about 200 to 800 kg and (d) recovering the mixture as a compressed product having a hardness of about 1-4kp. One embodiment of the present invention provides for the preparation of the formulation by grinding the glyceryl monostearate together with a small portion of hydrated lactose. Similarly, the hydrophobic smoked silica is ground together with a small portion of hydrated lactose. For 5 minutes and using a mixer, the diluted nitroglycerin is mixed with the glyceryl monostearate / lactose hydrate combination. More preferably, during the mixing an intensifying bar is rotated.The mixture of hydrophobic milled smoked silica / lactose hydrate and a disintegrant, such as the pregelatinized starch are added and mixed for about 5 minutes. Subsequently, a lubricant is added, such as calcium stearate. The mixture of the present invention is carried out using a mixer V. However, it should be understood that several of the mixing techniques known to those skilled in the art can be used to obtain similar results. In order to obtain uniformity in the mixture, variations of mixing time of + 50% are allowed in the present invention. Once the ingredients are perfectly blended, the composition is preferably subject to compression, because it is preferred that the compositions of the present invention are tablets. Therefore, conventional tabletting equipment and corresponding standard procedures are used to prepare compact sublingual nitroglycerin tablets with improved stability. The compression is effected by holding the mixture at high pressures by means of mobile punches that operate in a die, where the tablet is imprisoned. To prepare a tablet, the mixture is compressed directly to form the tablets in a tabletting machine. Although to compress the mixture and form a tablet, any tabletting machine known to those skilled in the art may be used, in a preferred embodiment, the tablets are pressed into any rotary press without weight control with a force of about 200 to about 800 kg at an average speed of approximately 75 RPM (65-85 RPM). More preferably, an instrumented tablet press is used for better weight control thereof. In one embodiment, the tablets are packaged and / or stored for a time. The tablets can be packed in amber glass jars (25-100 tablets per bottle).

Physical Characteristics of Compressed Sublingual Compositions It is a desirable feature of the compact pharmaceutical tablets of the present invention to be bioequivalent to molded nitroglycerin tablets. In this invention, the bioavailability of the active ingredient is not impeded by the process or excipients added to manufacture a sublingual tablet of stable nitroglycerin. The present invention is surprisingly advantageous by the inclusion of the excipients necessary to impart essential physical characteristics of manufacture with the existing compaction equipment, but without having adverse effects with respect to the availability of nitroglycerin. The initial disintegration time of the compositions of the present invention is about 25 seconds. Preferably, the disintegration of the compositions of the present invention is in the order of about 10 to about 40 seconds. More preferably, the disintegration of the compositions of the present invention is of the order of from about 20 to about 30 seconds. Free-flowing granulation is crucial for rapid filling of the die cavity during compression in a high-speed press. The poor or irregular flow of the granulation results in an erratic filling of the die cavity and consequently, a variation in weight. Small differences in weight are magnified in relative standard deviations important for a tablet with an average weight as low as 35 mg. Because diluted nitroglycerin is a non-fluid moist appearance mix, it is a major contributor to the flow problems of a spray mixture. Without the aid of the excipients, the impediment to the flow of the granulations can be predicted as the highest concentration of material (0.6 mg) where the highest amount of nitroglycerin is incorporated in the mixture. The compressed nitroglycerin compositions of the present invention show less variation in weight than the previously known molded nitroglycerin compositions. The weight variations of the compositions of the present invention are less than about 3% RSD. Preferably, the weight variations of the compositions of the present invention are of the order of 1-2% RSD. More preferably, the weight variations of the compositions of the present invention are about 1% RSD. The compressed nitroglycerin compositions of the present invention also show a better uniformity content than previously known molded nitroglycerin compositions. Variations in the uniformity content of the compositions of the present invention are less than about 4% RSD. Preferably, the uniformity content variations of the compositions of the present invention are in the order of about 1% RSD to about 3% RSD. More preferably, variations in the uniformity content of the compositions of the present invention are in the order of about 2% RSD. Additionally, the compressed nitroglycerin compositions of the present invention show significantly lower friability than the previously known molded nitroglycerin compositions, thus indicating improved structural integrity against external mechanical forces, for example, during packing, shipping or shipping. driving. The friability of the compositions of the present invention is less than about 1%. Preferably, the friability of the compositions of the present invention is less than about 5%. In addition, the compressed nitroglycerin compositions of the present invention show consistent thickness and hardness when compressed into tablets. The thickness of the compressed tablets of the compositions of the present invention is from about 1.7 to about 2.5 mm. The hardness of the compressed tablets of the compositions of the present invention is greater than about 1 kp. Preferably, the hardness of the compressed tablets of the compositions of the present invention is in the order of about 1-4 kp. The hardness of a tablet is enough to facilitate its handling without risk of breaking. It will be apparent to those skilled in the art that the compressed sublingual tablets of the present invention can be multilayer tablets and have various shapes, colors and sizes. In addition, it will be evident that shower tablets once formed, can be coded and / or coated by various methods well known to those skilled in the art. Even, the coated tablets may be subjected to a polishing process or other routine processes, which have been carried out on the compressed tablets prior to this invention. The term "tablet" used herein, includes tablets of any form and also includes caplets, which are capsule shaped tablets. If desired, a pharmaceutically acceptable coloring agent can be added to the tablets. The compressed tablets may also be coated with a pharmaceutically acceptable polymer, gelatin or sugar. The addition of the coloring agent or the coating of polymer, gelatin or sugar can be carried out by any person skilled in the art. Although several of the ingredients listed in the specification and in the claims have been designated with the suffix "USP" (United States Pharmacopia) or "NF" (National Formulary), this is only an attempt to better identify the ingredient or its purity and it does not limit the invention in any way with respect to the use of ingredients marked in that way, since identical materials are available under other designations, for example, in foreign countries. The present invention also comprises a product prepared by the manufacturing methods of the nitroglycerin-containing compressed compositions described above. The product is preferably a compressed sublingual nitroglycerin tablet prepared according to a process having the steps comprising: (a) mixing the ingredients selected from the group consisting of nitroglycerin, hydrated lactose, glyceryl monostearate, calcium stearate, starch and hydrophobic smoked silica; (b) compressing said mixture under a pressure of 200 to about 800 kg and (c) recovering said mixture as a compressed product. In one embodiment, the process further comprises the step of diluting the nitroglycerin before mixing the other ingredients. Preferred ingredients in the process are nitroglycerin, lactose monohydrate, calcium stearate, silica, starch and glyceryl monostearate in the following amounts: 0.5 to about 5% by weight of nitroglycerin; 88 to about 93% by weight of lactose; 0.3 to about 0.5% by weight of silica; 0.3 to about 0.5% by weight of calcium stearate; 5 to about 15% by weight of starch and about 0.5 to about 10% by weight of glyceryl monostearate. The products preferably compressed into tablets and manufactured by the process having the following physical properties: disintegration in the order of about 20 to about 30 seconds; weight variations of the order of about 1 to about 2% RSD; content variations in the order of less than 4% RSD approximately; friability of the order of less than approximately 1%; thickness of the order of approximately 1.7-2.5 mm and a hardness of the order of approximately 1-4 kp.

The following non-limiting examples illustrate the best mode contemplated by the inventors to carry out the present invention.

EXAMPLES SUMMARY Two active batches (0.3 and 0.6 mg) were manufactured and the manufacturing processes (grinding, mixing and compression) were successfully designed and the tablets satisfactorily met the physical and chemical stability requirements for a period of twelve months.

II. PROCESS DESCRIPTION A. Materials / Formulations The examples presented below illustrate particular embodiments of the invention and are not intended to limit the scope of the specifications or claims in any way.

Material Example 1 Example 2 Mixture of 1.95% nitroglycerin 15,385 30,769 Glyceryl monostearate 0.615 1,231 Lactose Monohydrate 16,730 3,880 Silicon dioxide 0.065 N / A Pregelatinized 2,100 4,000 Calcium stearate 0.105 0.120 Note: No excess Nitroglycerin was used B. Manufacturing Equipment and Process (Active Lots) The amount of heavy USP Nitroglycerin was calculated based on the results of the tests. The total amount of Lactose Monohydrate needed was adjusted based on the amount of nitroglycerin used. Glyceryl monostearate, NF (Myvaplex 600P) and Lactose Monohydrate, NF were ground together and collected in a drum.

The silicon dioxide and the Lactose Monohydrate were ground together and collected in another drum. The diluted USP nitroglycerin and the milled mixture of glyceryl monostearate / lactose monohydrate were directed to a mixer equipped with an intensifier bar. The ingredients were mixed for ten minutes with the intensifier bar in the ON position. Subsequently, the milled mixture of Silicon Dioxide / Lactose Monohydrate and the Pregelatinized Starch were added to the PK mixer and mixed for five minutes with the intensifier bar in the ON position. The calcium stearate was added to the mixer and the materials mixed for five minutes. The pulverized mixtures were compressed into tablets using a suitable press for tabletting. In those formulations lactose was used as the diluent, pregelatinized starch as the disintegrant, glyceryl monostearate as the stabilizer, silicon dioxide as the auxiliary flow agent and calcium stearate as the lubricant.

C. Stability results Physical Stability The following table shows the results of physical stability at 12 months (hardness and disintegration time) for Examples 1 and 2 stored in bottles of 25 and 100 tablets at conditions of ° C / 60% RH and 40 ° C / 75% RH. All results met the intended hardness parameters used during the in-process tests and also met the acceptable decay criteria of < 2 minutes. However, during storage there was a small increase in tablet hardness and disintegration times.

Content of Uniformity The tablet samples were tested with respect to the uniformity content of the nitroglycerin (CU) initially and after twelve months of storage at 25 ° C / 60% RH. The results show low variation (RSD < 2%) and the USP specification of 75.0-135.0% of the Claim on the Label was met.

Test and Degradation of the Products. The following table shows the results of chemical stability at 12 months (test and degradation of the products) for the two examples stored in bottles of 25 and 100 tablets at 25 ° C / 60% RH and 40 ° c / 75% RH.

All the results met the USP specification of 90.0 -115.0% LC and no significant change in the degradation of the products was observed.

The present invention can be developed in other specific forms without departing from its spirit or essential characteristics. The described modalities are considered in all their aspects only as illustrative and not as restrictions. The scope of the invention is therefore indicated in the appended claims and not by the foregoing description. Changes in the meaning and equivalence range of the claims are contemplated in the scope of the present invention.

Claims (19)

1. CLAIMS A stable composition comprising effective amounts of nitroglycerin, lactose, silica, starch, glyceryl monostearate and lubricant, wherein nitroglycerin is the only pharmacologically active agent.
2. The composition according to claim 1, wherein the composition is available as a sublingual tablet.
3. The composition according to claim 1, wherein the starch is pregelatinized starch used as a disintegrant.
4. The composition according to claim 1, wherein the silica is fumed silica.
5. The composition according to claim 1, wherein the lubricant is a salt of an alkali metal.
6. The composition according to claim 1, wherein the lactose is lactose hydrated.
7. The composition according to claim 1, wherein the stabilizer is glyceryl monostearate in an amount from about 0.5 to about 10% by weight.
8. The composition according to claim 1 comprising the following amounts: 0.5 to about 5% by weight of nitroglycerin, diluent at a concentration greater than about 90% by weight of lactose, 0.1 to about 1% by weight of silica; 0.1 to about 1% by weight of calcium stearate; 5 to about 15% by weight of starch and about 0.5 to about 10% by weight of glyceryl monostearate.
9. The composition according to claim 1, wherein the composition disintegrates in the order from about 20 to about 30 seconds.
10. The composition according to claim 1, wherein the variation in weight of the composition is from about 1 to about 2% RSD.
11. The composition according to claim 1, wherein the composition has the following properties: disintegration of the order of about 20 at about 30 seconds; weight variations of the order of about 1 to about 2% RSD; content variations in the order of less than approximately 4% RSD; friability of the order of less than about 1%; thickness of the order of approximately 1.7-2.5 mm and hardness of the order of approximately 1-4 kp.
12. The composition according to claim 1, wherein the composition is a compressed tablet.
13. A stable compressed tablet consisting essentially of effective amounts of nitroglycerin, lactose, silica, pregelatinized starch, glyceryl monostearate and lubricant, wherein nitroglycerin is the only pharmacologically active agent.
14. The composition according to claim 13, wherein the silica is fumed silica.
15. 15. The composition according to claim 14, wherein the lubricant is calcium stearate.
16. 16. The composition according to claim 15, wherein the lactose is lactose hydrated.
17. 17. A dry, compressed nitroglycerin-containing product produced by the steps comprising: (a) mixing nitroglycerin with lactose to produce a nitroglycerin dilution in which the content of the active agent is about 2 percent or less; (b) adding and mixing the nitroglycerin dilution with the silica, the lubricant, the glyceryl monostearate, the starch and optionally additional lactose to produce a mixture; (c) compressing the mixture and (d) recovering the mixture as a compressed product.
18. 18. The product according to claim 17, wherein the starch is pregelatinized starch.
19. 19. A process for preparing a dry, compressed nitroglycerin-containing product produced by the steps comprising: (a) mixing nitroglycerin with lactose to produce a nitroglycerin dilution in which the content of active ingredient is about 2 percent or less; (b) adding and mixing the nitroglycerin dilution with the silica, the lubricant, the glyceryl monostearate, the starch and optionally additional lactose to produce a mixture; (c) compressing the mixture and (d) recovering the mixture as a compressed product.