WO1995011030A1 - Pharmaceutical formulations of aspirin and salicylates - Google Patents
Pharmaceutical formulations of aspirin and salicylates Download PDFInfo
- Publication number
- WO1995011030A1 WO1995011030A1 PCT/EP1994/003363 EP9403363W WO9511030A1 WO 1995011030 A1 WO1995011030 A1 WO 1995011030A1 EP 9403363 W EP9403363 W EP 9403363W WO 9511030 A1 WO9511030 A1 WO 9511030A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- aspirin
- glucose
- formulation
- succinate
- mole
- Prior art date
Links
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 title claims description 128
- 229960001138 acetylsalicylic acid Drugs 0.000 title claims description 123
- 150000003873 salicylate salts Chemical class 0.000 title description 12
- 239000008194 pharmaceutical composition Substances 0.000 title description 2
- 238000009472 formulation Methods 0.000 claims abstract description 32
- 239000000203 mixture Substances 0.000 claims abstract description 32
- PBUBJNYXWIDFMU-UHFFFAOYSA-L calcium;butanedioate Chemical compound [Ca+2].[O-]C(=O)CCC([O-])=O PBUBJNYXWIDFMU-UHFFFAOYSA-L 0.000 claims abstract description 9
- 150000003872 salicylic acid derivatives Chemical class 0.000 claims abstract description 8
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000001720 carbohydrates Chemical class 0.000 claims abstract description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 40
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 15
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 claims description 10
- 229960004025 sodium salicylate Drugs 0.000 claims description 10
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 9
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 9
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- 239000002775 capsule Substances 0.000 claims description 2
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- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 14
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
Definitions
- This invention relates to the formulation of aspirin and other salicylates.
- Aspirin is an important medical product which has been in clinical use for almost TOO years. Aspirin is the generically accepted name for the chemical acetylsalicylic acid. "Salicylates" is used to denote all drugs having the 2-hydroxybenzoic acid structure and aspirin is therefore a salicylate. In the context of this patent application, however, salicylates refer more particularly to salicylic acid and its salts, for example sodium salicylate and calcium salicylate, and aspirin refers specifically to acetylsalicylic acid.
- the pharmacological effects which are common to aspirin and the salicylates include reducing the symptoms of inflammation (anti-inflammatory), reducing the elevation in body temperature during fever (antipyretic), and reducing the experience of pain without loss of consciousness (analgesia).
- Aspirin interferes with platelet aggregation through its inhibitory effect on thromboxane production, but this is not so with salicylic acid and its salts.
- SUBSTITUTESHEET(RULE2$ associated with arthritic disease Arthritis is a term meaning "inflammation of a joint". The five most common arthritic diseases are rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, and gout. Aspirin and salicylates are usually very effective in treating rheumatoid arthritis and osteoarthritis, but other more modern drugs are now very often preferred for the other arthritic diseases.
- Aspirin was the first of the so-called non-steroidal anti-inflammatory drugs (NSAIDs).
- Other NSAIDS such as indomethacin, azapropazone and diclofenac were developed when it was found that aspirin caused a high incidence of gastrointestinal side effects.
- the ingestion of aspirin may result in epigastric distress, nausea, and vomiting.
- Aspirin may also cause gastric ulceration and even haemorrhage in experimental animals and in man.
- Slight blood loss may occur in about 70% of patients with most aspirin preparations, whether buffered, soluble or plain.
- Aspirin-induced gastric bleeding is painless and frequently leads to blood loss in the stool and occasionally to an iron-deficiency anaemia. The incidence of bleeding is highest with aspirin preparations which dissolve slowly and deposit as particles in the gastric mucosal folds.
- Aspirin has a significant effect on mucosal blood flow which rises shortly after administration due to a local irritant effect, which is then followed by a fall in blood flow (ie local ischemia) as cyclooxygenase is inhibited, reducing production of vasodilatory prostaglandins.
- the result is an impairment of the ability of the tissue to adequately handle the increased flow of hydrogen ions through the gastric mucosal barrier.
- Aspirin has been solubilized to obviate the chance of particles of aspirin becoming lodged in the folds of the gastric mucosa where they can cause aggressive localized damage. Buffering of aspirin has also been tried in an attempt to overcome the local effects of acidity of the drugs on the mucosa of the stomach. Both of these approaches have provided a partial benefit in reducing the incidence and severity of gastrointestinal side effects of aspirin, but they fail to address the effect of the aspirin molecule on its local environment as it passes through the mucosa and the enterocytes during absorption. There are local biochemical deficits which are induced by aspirin during this absorption process, which are described and discussed later in this overview.
- enteric-coated pellets and tablets of aspirin are the only protective formulations; with soluble salt preparations of aspirin and buffering of aspirin being the only other "formulations" being marketed in the United States of America, where the FDA requirements are especially stringent.
- the ability of the gastric mucosal barrier to provide protection against the gastric acidic erosion of aspirin is dependent on the physiological defense mechanisms of the mucosal cells. These include local synthesis of prostaglandins which promote mucosal vasodilation and regulate gastric acid secretion, and the energy-dependent synthesis and secretion of bicarbonate ions and gastric mucus which together constitute the natural mucosal barrier.
- the third factor which is often overlooked, is the effect of stress and compromised gastric resistance induced by underlying chronic inflammation associated with arthritic diseases, as this can affect mucosal glucose metabolism. It is this latter factor which is believed to be one of the causes of the high incidence of gastric lesions and ulceration caused by aspirin and other NSAIDs in arthritically diseased subjects when compared with the lower incidence in healthy subjects.
- Rainsford and Whitehouse US Patent 4,440,762 found that glucose (dextrose) is ineffective if formulated with aspirin alone, whereas glucose in specially formulated combinations with sodium citrate or sodium acetate reduced the gastrointestinal injury in rats and in humans.
- acetate or citrate In addition to the practical disadvantages of a large tablet or sachet if presented in granular form, the use of the acetate or citrate is not optimal for gastroprotection of aspirin.
- Acetate and citrate have been introduced into the gastroprotective formulations of aspirin, indomethacin and azapropazone due to the important function of these two carboxylates in fueling the citric acid cycle.
- Salicylates have an inhibitory effect on mitochondrial ATP production, in particular at the oxidative decarboxylation of iso-citrate.
- the succinate ion has the distinct advantage, however, of being oxidized directly by the mitochondria in the enterocytes, hence providing energy for ATP formation without requiring NAD" (the nicotinamide adenine dinucleotide ion), as it is the NAD-linked oxidations which are inhibited by salicylates.
- NAD the nicotinamide adenine dinucleotide ion
- the net result is an increase in beneficial energy-yielding catabolism within the salicylate-compromised gastric mucosa which then promotes defensive anabolism, with secretion of bicarbonate and mucus to protect the mucosa.
- succinate ion is therefore rather more effective in providing a means of achieving production of ATP, despite the inhibitory actions of salicylate on the other enzymes involved in the TCA cycle.
- succinic acid formed when gastric acid (HC1 ) mixes with succinate salts, is more lipophilic than citric acid and therefore more. likely to penetrate those cells lining the stomach which are more exposed to the NSAID "toxin".
- disodium or calcium succinate in place of sodium or calcium salts or citric acid or acetic acid, allows formulation of a tablet or granular aspirin product which is soluble in water, and which requires much lower molar quantities of succinate and D-glucose than were claimed in US Patent 4,440,762.
- the molar ratio of disodium succinate or calcium succinate to that of aspirin can be as low as 1.5:1, when the molar ratio of D-glucose to that of aspirin is as low as 1:1.
- low-level ratios may be varied within the ranges 2:1 and 1.5:1 for the succinate, and 1:1 to 1.5:1 for D-glucose, provided the total mole ratio of succinate plus D-glucose is maintained at least 2.5:1 and preferably 3:1 with respect to aspirin.
- sodium hydrogen succinate will not solubilize aspirin when used at levels as low as 1.5:1 with respect to aspirin, hence indicating the advantage of using the disodium succinate salt or calcium succinate.
- sodium succinate provides excellent solubilizing properties without the need for effervescence, such that dissolution of a tablet in water, to give a clear solution, can be achieved in a time similar to that of an effervescent tablet.
- sodium succinate it is therefore not necessary to make the tablet effervescent for ready solubility in a glass of water.
- a formulation consisting of: (a) a salicylic acid derivative, (b) a metabolisable carbohydrate and (c) disodium or calcium succinate.
- Preferred metabolizable carbohydrates are hexoses, and specially preferred examples are D-glucose for general use and D-fructose for diabetics.
- the weight ratio of nutrient to salicylic acid derivative will depend upon the salicylic acid derivative being considered, with values of 0.5:1 to 25:1 being typical, and 1:1 to 2: 1 often being used in practice.
- the preferred alkali metal or alkaline earth metal salts of succinic acid are disodium succinate and calcium succinate.
- the weight ratio of solubilizing and buffering agent to salicylic acid derivative will depend upon whether aspirin or a salicylate is being considered, with values of 1:1 to 25:1 being typical, and 1.5:1 to 2:1 often being used in practice.
- the formulation of the salicylic acid derivative may be presented as one or more of the following unit dosage forms; capsules, tablets, or sachets.
- the tablet or sachet dosage forms include the possibility of being added to a glass of water to provide a solution of the formulation which can be drunk.
- the rats are then killed by cervical disclocation. Their stomachs are removed, assessed by eye and feel for degree of swelling, everted, and washed with isotonic saline.
- stomachs are examined by eye, and the number and severity of lesions is recorded on the Animal Assessment Record against their colour coding.
- a suspension of aspirin in water, or solutions of formulated aspirin, of aspirin concentration 15 mg/ml were made up according to the following mole ratios: disodium succinate: glucose: aspirin
- a suspension of aspirin in water, or solutions of formulated aspirin, of aspirin concentration 15mg/ml were made up according to the following mole ratios: disodium succinate:glucose:aspirin
- a suspension of aspirin in water, or solutions of formulated aspirin, of aspirin concentration 15mg/ml were made according to the following mole ratios: disodium succinate: lucose:aspirin
- a suspension of aspirin in water, or solutions of formulated aspirin, of aspirin concentration 15mg/ml were made up according to the following mole ratios:
- results in the table show that the disodium succinate is considerably more effective than either the sodium acetate or the trisodium citrate in providing gastroprotection against aspirin-induced gastric injury, when the glucose level is 1 mole/mole aspirin.
- Results which are not shown in the table are those for the stomach swelling due to increased fluid due to aggravation by the aspirin.
- Aspirin alone with water gave an average estimate of 3.0
- aspirin with sodium acetate and glucose gave 2.5
- aspirin with disodium succinate and glucose gave 1.3
- aspirin with trisodium citrate and glucose gave 1.8.
- the severity of injury estimate with a range of 0 to 5 gave
- Aspro Clear ⁇ Nacholas Australia
- Disprin® a solution of equivalent aspirin concentration prepared by dissolving in water a tablet of Disprin .
- Each tablet of Aspro Clear® contains 300mg aspirin, 452 mg sodium bicarbonate, and 207 mg anhydrous citric acid.
- Each table of Disprin® contains 300 mg aspirin and undisclosed amounts of citric acid and calcium carbonate. The results of the rat study were as follows:
- Salicylic acid alone is very astringent and the sodium salt is normally used.
- the following formulated solutions were prepared with sodium salicylate 13.3mg/ml and salicylic acid 11.5 mg/ml (both equivalent on a mole basis to aspirin 15mg/ml), and they were compared with sodium salicylate solution and salicylic acid suspension of the same concentrations, respectively.
- disodium succ1nate glucose:sodium salicylate disodium succinate:glucose:sodium salicylate disodium succinate:glucose:sa11cy1ic acid disodium succinate:glucose:salicylic acid
- mole ratio is relative to salicylate.
- results show the relatively low toxicity of salicylic acid relative to its sodium salt, and that the gastroprotective formulation is very effective in reducing the incidence of gastric lesions with the gastro-toxic sodium salicylate.
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Abstract
A formulation comprising (a) a salicylic acid derivative, (b) a metabolisable carbohydrate, and (c) disodium or calcium succinate.
Description
PHARMACEUTICAL FORMULATIONS OF ASPIRIN AND SALICYLATES
This invention relates to the formulation of aspirin and other salicylates.
Aspirin is an important medical product which has been in clinical use for almost TOO years. Aspirin is the generically accepted name for the chemical acetylsalicylic acid. "Salicylates" is used to denote all drugs having the 2-hydroxybenzoic acid structure and aspirin is therefore a salicylate. In the context of this patent application, however, salicylates refer more particularly to salicylic acid and its salts, for example sodium salicylate and calcium salicylate, and aspirin refers specifically to acetylsalicylic acid. The pharmacological effects which are common to aspirin and the salicylates include reducing the symptoms of inflammation (anti-inflammatory), reducing the elevation in body temperature during fever (antipyretic), and reducing the experience of pain without loss of consciousness (analgesia). Aspirin interferes with platelet aggregation through its inhibitory effect on thromboxane production, but this is not so with salicylic acid and its salts.
Aspirin is used extensively to reduce occasional acute pain and headache. Aspirin and the salicylates are used chronically to reduce the inflammation and pain
SUBSTITUTESHEET(RULE2$
associated with arthritic disease. Arthritis is a term meaning "inflammation of a joint". The five most common arthritic diseases are rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, and gout. Aspirin and salicylates are usually very effective in treating rheumatoid arthritis and osteoarthritis, but other more modern drugs are now very often preferred for the other arthritic diseases.
Aspirin was the first of the so-called non-steroidal anti-inflammatory drugs (NSAIDs). Other NSAIDS such as indomethacin, azapropazone and diclofenac were developed when it was found that aspirin caused a high incidence of gastrointestinal side effects. The ingestion of aspirin may result in epigastric distress, nausea, and vomiting. Aspirin may also cause gastric ulceration and even haemorrhage in experimental animals and in man. Slight blood loss may occur in about 70% of patients with most aspirin preparations, whether buffered, soluble or plain. Aspirin-induced gastric bleeding is painless and frequently leads to blood loss in the stool and occasionally to an iron-deficiency anaemia. The incidence of bleeding is highest with aspirin preparations which dissolve slowly and deposit as particles in the gastric mucosal folds.
The mechanism by which salicylates injure gastric mucosal
cells are complex. Deleterious effects result from local actions, which cause injury to the submucosal capillaries with subsequent necrosis and bleeding, and from effects on the secretion of acid and mucus, which in the case of aspirin are partly attributed to systemic inhibition of the formation of prostaglandins. There may also be an increased bleeding tendency, secondary to impaired platelet aggregation. Aspirin has a significant effect on mucosal blood flow which rises shortly after administration due to a local irritant effect, which is then followed by a fall in blood flow (ie local ischemia) as cyclooxygenase is inhibited, reducing production of vasodilatory prostaglandins. The result is an impairment of the ability of the tissue to adequately handle the increased flow of hydrogen ions through the gastric mucosal barrier.
There have been many and varied attempts to overcome the gastrointestinal side effects associated with aspirin. This prior art is summarized as follows.
Aspirin has been solubilized to obviate the chance of particles of aspirin becoming lodged in the folds of the gastric mucosa where they can cause aggressive localized damage. Buffering of aspirin has also been tried in an attempt to overcome the local effects of acidity of the drugs on the mucosa of the stomach. Both of these
approaches have provided a partial benefit in reducing the incidence and severity of gastrointestinal side effects of aspirin, but they fail to address the effect of the aspirin molecule on its local environment as it passes through the mucosa and the enterocytes during absorption. There are local biochemical deficits which are induced by aspirin during this absorption process, which are described and discussed later in this overview.
Enteric coating of aspirin tablets and pellets has been partially successful as it provides a protective coating around the drug as it passes through the stomach. The enteric coating is removed when it passes through the pylorus into the duodenum, and the aspirin then has to dissolve before being absorbed. Again there remains the problem of biochemical deficits as the aspirin molecules pass through the intestinal mucosa and enterocytes during absorption.
It is evident that the above approaches have only proved to be partly successful: enteric-coated pellets and tablets of aspirin are the only protective formulations; with soluble salt preparations of aspirin and buffering of aspirin being the only other "formulations" being marketed in the United States of America, where the FDA requirements are especially stringent. Despite these attempts to protect the gastrointestinal tract from
aspirin-induced insult and injury, there is continued accumulation of evidence that a large proportion of patients who should be using aspirin are unable to do so due to gastrointestinal side effects.
The ability of the gastric mucosal barrier to provide protection against the gastric acidic erosion of aspirin is dependent on the physiological defense mechanisms of the mucosal cells. These include local synthesis of prostaglandins which promote mucosal vasodilation and regulate gastric acid secretion, and the energy-dependent synthesis and secretion of bicarbonate ions and gastric mucus which together constitute the natural mucosal barrier.
A novel approach to providing nutrients to overcome or replace the natural deficits in mucosal resistance, caused by ischaemia and attendant malnutrition of the drug-intoxicated mucosa induced by aspirin, indomethacin and azapropazone, has been discovered by K. D. Rainsford and M. W. Whitehouse (Patents: US Patent 4,440,762 (1984); US Patent 4,885,279 (1989), and US Patent 5,034,379 (1991). The gastric mucosa is normally dependent for its energy production upon either the metabolic reserves in liver and muscle or on intestinally absorbed nutrients, both being provided by the blood. Local ischaemia therefore deprives the gastric mucosa of
these supplies of metabolic fuel. However, any nutrients absorbed directly from the gastric lumen may fortify the blood-borne supply of metabolic fuel.
Adequate supply of nutrients is necessary for mitochondrial production of adenosine triphosphate (ATP), which is vital for the maintenance of mucosal protective functions, There are three interrelated factors to be considered in understanding the gastroprotective actions of nutrients. Firstly there is considerable anoxia following mucosal ischaemia produced by aspirin and other NSAIDs as a consequence of their profound effects on local prostaglandins synthesis, prostaglandins having potent effects on blood flow and vasodilatation in the gastric mucosa. The second factor is the effects of the drugs on glucose metabolism and the tricarboxylic acid (or citric acid) cycle. The third factor, which is often overlooked, is the effect of stress and compromised gastric resistance induced by underlying chronic inflammation associated with arthritic diseases, as this can affect mucosal glucose metabolism. It is this latter factor which is believed to be one of the causes of the high incidence of gastric lesions and ulceration caused by aspirin and other NSAIDs in arthritically diseased subjects when compared with the lower incidence in healthy subjects.
Rainsford and Whitehouse (US Patent 4,440,762)) found that glucose (dextrose) is ineffective if formulated with aspirin alone, whereas glucose in specially formulated combinations with sodium citrate or sodium acetate reduced the gastrointestinal injury in rats and in humans. It was postulated that the added acetate or citrate stimulates the tricarboxylic acid (citric acid) cycle with the result that both glucose and these buffer anions can be oxidized with subsequent ATP production. In studies with rats it was found that gastroprotection was provided with co-administration of glucose and sodium acetate in molar proportions of 3:3:1 with respect to aspirin. Studies with indomethacin (US Patent 4,885,279 (1989)) and azapropazone (US Patent 5,034,379 (1991)) in rats were followed by successful studies in humans. The weight ratios of dextrose monohydrate:sodium acid citrate:NSAID were found to be optimally 15:15:1 for indomethacin and 1:1:1 for azapropazone.
The above approach of Rainsford and Whitehouse used either citrate or acetate as the buffer ion, and it was postulated that these ions were oxidized as part of the citric acid cycle to provide mitochondrial ATP. The patents (US Patent 4,440,762 (1984); US Patent 4,885, 279 (1989); and US Patent 5,034,379 (1991) of K. D. Rainsford and M. W. Whitehouse exemplify and claim formulations including various NSAIDs specifically aspirin,
salicylates, indomethacin, and azapropazone, together with D-glucose and a citrate, or a hydrogen succinate, or an acetate citrate.
In particular, in US Patent 4,440,762 there is mention only of tri-sodium citrate and sodium acetate used in molar proportions of citrate or acetate:D-glucose:aspirin of 3:3:1. Also in US Patent 4,885,279 it is claimed that citrate or succinate are effective, with examples of use of the citrate, the weight ratios of carboxylic acid salt and D-glucose to indomethacin being a minimum of 3:1 with one of these components being at least 10:1. In US Patent 5,034,379 for azapropazone, the use of a monohydrogen or dihydrogen citrate, a hydrogen succinate, or an acetate are claimed as metabolic carboxylates, with molar ratios of 1:1:1 being required for carboxylic acid:D-glycose:azapropazone. In this latter patent, only monosodium and disodium citrate are exemplified.
One of the advantages of a formulation such as that suggested in US Patent 4,440,762 is that it provides a soluble aspirin, which can be readily dissolved in water. There are disadvantages in the formulation, however, which have made it less than practical for manufacture and for subsequent use. The size of the total does required for use under US Patent 4,440,762 is very high, requiring for each 300mg of aspirin: 900mg of D-Glucose
and 1470mg sodium citrate or 680mg sodium acetate. The total weight of a tablet containing 300mg aspirin (the standard industry dose) and using sodium citrate would therefore be at least 2.69g, or if using sodium acetate, at least 1.88g. This problem has tended to make the formulation unfeasible commercially.
In addition to the practical disadvantages of a large tablet or sachet if presented in granular form, the use of the acetate or citrate is not optimal for gastroprotection of aspirin. Acetate and citrate have been introduced into the gastroprotective formulations of aspirin, indomethacin and azapropazone due to the important function of these two carboxylates in fueling the citric acid cycle. Salicylates have an inhibitory effect on mitochondrial ATP production, in particular at the oxidative decarboxylation of iso-citrate. The succinate ion has the distinct advantage, however, of being oxidized directly by the mitochondria in the enterocytes, hence providing energy for ATP formation without requiring NAD" (the nicotinamide adenine dinucleotide ion), as it is the NAD-linked oxidations which are inhibited by salicylates. The net result is an increase in beneficial energy-yielding catabolism within the salicylate-compromised gastric mucosa which then promotes defensive anabolism, with secretion of bicarbonate and mucus to protect the mucosa. The use of
the succinate ion is therefore rather more effective in providing a means of achieving production of ATP, despite the inhibitory actions of salicylate on the other enzymes involved in the TCA cycle. Furthermore, succinic acid, formed when gastric acid (HC1 ) mixes with succinate salts, is more lipophilic than citric acid and therefore more. likely to penetrate those cells lining the stomach which are more exposed to the NSAID "toxin".
It has been surprisingly discovered that the use of disodium or calcium succinate, in place of sodium or calcium salts or citric acid or acetic acid, allows formulation of a tablet or granular aspirin product which is soluble in water, and which requires much lower molar quantities of succinate and D-glucose than were claimed in US Patent 4,440,762. In fact the molar ratio of disodium succinate or calcium succinate to that of aspirin can be as low as 1.5:1, when the molar ratio of D-glucose to that of aspirin is as low as 1:1. These low-level ratios may be varied within the ranges 2:1 and 1.5:1 for the succinate, and 1:1 to 1.5:1 for D-glucose, provided the total mole ratio of succinate plus D-glucose is maintained at least 2.5:1 and preferably 3:1 with respect to aspirin. In addition, it has been found that sodium hydrogen succinate will not solubilize aspirin when used at levels as low as 1.5:1 with respect to aspirin, hence indicating the advantage of using the
disodium succinate salt or calcium succinate.
This unexpected discovery of a reduction of dosage size through use of disodium or calcium succinate in place of the corresponding citrate or acetate, has allowed formulation of tablets with total weights below 1.2- 1.3g, which is the maximum which could be tolerated for a tablet which is to be swallowed. This provides a distinct advantage over a product which has to be dissolved in water prior to administration due to its size, and which normally requires effervescence to achieve rapid dissolution.
Thus, for the first time we can provide a swallowable tablet containing a standard 300mg dose of aspirin, taking advantage of the gastroprotectant effect provided by formulation with a metabolizable carbohydrate and a carboxylic acid salt.
Effervescence can be distinctly annoying for patients who do not enjoy bubbly or gaseous drinks. In fact, sodium succinate provides excellent solubilizing properties without the need for effervescence, such that dissolution of a tablet in water, to give a clear solution, can be achieved in a time similar to that of an effervescent tablet. By using sodium succinate, it is therefore not necessary to make the tablet effervescent for ready
solubility in a glass of water.
Thus, according to a first aspect of the invention, there is provided a formulation consisting of: (a) a salicylic acid derivative, (b) a metabolisable carbohydrate and (c) disodium or calcium succinate.
Examples of salicylic acid derivatives are aspirin and salicylates, e.g. alkali metal or alkaline earth metal salicylates, especially sodium and calcium salicylates.
Preferred metabolizable carbohydrates are hexoses, and specially preferred examples are D-glucose for general use and D-fructose for diabetics. The weight ratio of nutrient to salicylic acid derivative will depend upon the salicylic acid derivative being considered, with values of 0.5:1 to 25:1 being typical, and 1:1 to 2: 1 often being used in practice.
The preferred alkali metal or alkaline earth metal salts of succinic acid are disodium succinate and calcium succinate. The weight ratio of solubilizing and buffering agent to salicylic acid derivative will depend upon whether aspirin or a salicylate is being considered, with values of 1:1 to 25:1 being typical, and 1.5:1 to 2:1 often being used in practice.
The formulation of the salicylic acid derivative may be presented as one or more of the following unit dosage forms; capsules, tablets, or sachets. The tablet or sachet dosage forms include the possibility of being added to a glass of water to provide a solution of the formulation which can be drunk.
Several non-limiting examples of the invention will now be given:
EXAMPLES
Studies in rats
A number of studies have been performed with rats, of two species (Dark Agouti and Hooded Wistar) and both sexes.
The general protocol for the studies was as follows:
Four days prior to study, pretreat rat with 0.1ml oleyl alcohol injected into the tail. Fast rats for at least 16 hours prior to dosing. Make up solutions or suspensions (aspirin is essentially insoluble in water, unless formulated) according to pre-prepared Formulation Manufacturing Records; the aspirin dosage is 150mg/kg, the positive control being aspirin suspended in water. Colour code the tails of the rats and record the weight and tail thickness on an Animal Colour Code and Dosing Record. Administer the doses by gavage, recording the dose
against the colour code on the Animal Colour Code and Dosing Record.
Place the rats in cages, generally not more than 6 per cage, and place the cages in a -20°C cold room for 15 minutes.
Allow the animals to incubate for 2 hours at room -temperature.
The rats are then killed by cervical disclocation. Their stomachs are removed, assessed by eye and feel for degree of swelling, everted, and washed with isotonic saline.
The everted stomachs are examined by eye, and the number and severity of lesions is recorded on the Animal Assessment Record against their colour coding.
The results are then collected on a Study Summary, where the breaking of the code occurs.
The following examples include tables where the column "mole ratio" gives mole ratio relative to aspirin, HW refers to Hooded Wistar, DA refers to Dark Agouti, and in the 4th column the top line of each row gives the change from the average of the number of lesions with the aspirin control (suspension in water) to the average of the number of lesions with the formulated aspirin. The individual rat data is presented below these averages.
Example 1 :
A suspension of aspirin in water, or solutions of formulated aspirin, of aspirin concentration 15 mg/ml were made up according to the following mole ratios: disodium succinate: glucose: aspirin
1.5:3:1 solution
1.0:3:1 solution
0.5:3:1 solution
0:0:1 control suspension This study showed the effect of reducing disodium succinate mole ratio at constant 1 mole glucose/mole aspirin. The results were as follows:
It can be seen that the formulated aspirin solutions were very effective in providing gastroprotection against aspirin gastric injury. There was a loss of gastroprotection when the sodium succinate level dropped to 0.5 mole/mole aspirin, even when the level of glucose is as high as 3 mole/mole aspirin.
Example 2 :
A suspension of aspirin in water, or solutions of formulated aspirin, of aspirin concentration 15mg/ml were made up according to the following mole ratios: disodium succinate:glucose:aspirin
2:2:1 solution
2:1.67: 1 solution
2:1.33: 1 solution
0:0:1 control suspension
This study showed the effect of reducing the glucose mole ratio with constant 2 mole disodium succinate/mole aspirin. The result were as follows:
The results showed that glucose could be reduced to 1 mole/mole aspirin, without reducing the effectiveness of the succinate in providing gastroprotection.
Example 3
A suspension of aspirin in water, or solutions of formulated aspirin, of aspirin concentration 15mg/ml were made according to the following mole ratios: disodium succinate: lucose:aspirin
2:0.75:1 solution 1.75:1 :1 solution 1.5:1.25:1 solution 1.25:1.5:1 solution 0:0:1 control solution
This study showed the effect of varying the proportions of glucose and disodium succinate for constant glucose- plus-disodiu -succinate mole ratio of 2.75 mole/mole aspirin. The results were as follows:
These results show that the effectiveness of the formulation drops off when the disodium succinate level (mole disodium succinate/mole aspirin) drops to 1.5 or
lower. The level of 1.5 mole disodium succinate/mole aspirin was taken as being on a threshold, below which the formulation starts to lose its effectiveness.
Example 4:
A suspension of aspirin in water, or solutions of formulated aspirin, of aspirin concentration 15mg/ml were made up according to the following mole ratios:
disodium succinate:glucose:aspirin 1.75: 1 : 1 solution 1.5:1:1 solution 0:0:1 control suspension
This study showed the effect of reducing the mole ratio of sodium succinate at a constant mole ratio of glucose of 1 mole glucose/mole aspirin. The results were as follows:
The mole ratio of 1.5 mole disodium succinate/mole aspirin was found to be effective but probably on the threshold level below which effectiveness falls off. On this basis 1.5 mole disodium succinate/mole aspirin was selected as a lower limit for the ratio of disodium succinate to aspirin.
Example 5 :
The following formulated solutions were prepared with aspirin 15mg/ml, and they were compared with aspirin suspension of the same concentration:
mole ratio sodium acetate: glucose: spirin 3:1:1 solution disodium succinate: glucose:aspirin 1.5:1:1 solution trisodium citrate: glucose: aspirin 1:1:1 solution carboxylic acid:glucose:aspirin 0:0:1 control suspension
The mole ratios were such that there were 3 sodium atoms per molecule of aspirin, and 3 carboxylic acid groups per molecule of aspirin. Thus the neutralizing capacities of each formulation were equivalent. The results from the rat study were as follows :
The results in the table show that the disodium succinate is considerably more effective than either the sodium acetate or the trisodium citrate in providing gastroprotection against aspirin-induced gastric injury, when the glucose level is 1 mole/mole aspirin. Results which are not shown in the table are those for the stomach swelling due to increased fluid due to aggravation by the aspirin. On a scale of 1 (minimum) to 5 (maximum) for stomach swelling, aspirin alone with water gave an average estimate of 3.0, aspirin with sodium acetate and glucose gave 2.5, aspirin with disodium succinate and glucose gave 1.3 and aspirin with trisodium citrate and glucose gave 1.8. In addition, the severity of injury estimate with a range of 0 to 5 gave
» the following average estimates: aspirin alone 2.5, acetate 1.2, succinate 0.5, and citrate 1.0. Thus with all three means of assessment, the disodium succinate was found to be a much more effective gastroprotectant than the sodium acetate or trisodium citrate.
Example 6 :
A solution with mole ratio disodium succinate:glucose: aspirin equal to 2:2:1, with the aspirin at 15 mg/ml, was compared with a solution of equivalent aspirin concentration prepared by dissolving in water a tablet of
Aspro Clear^ (Nicholas Australia), and another solution of equivalent aspirin concentration prepared by dissolving in water a tablet of Disprin . Each tablet of Aspro Clear® contains 300mg aspirin, 452 mg sodium bicarbonate, and 207 mg anhydrous citric acid. Each table of Disprin® contains 300 mg aspirin and undisclosed amounts of citric acid and calcium carbonate. The results of the rat study were as follows:
It can be seen from these results that Aspro Clear and Disprinfc caused substantial gastric injury, and that in comparison, the gastroprotectant formulation with disodium succinate and glucose was very effective in
22 reducing aspirin-induced gastric injury to very low levels.
Example 7:
Salicylic acid alone is very astringent and the sodium salt is normally used. The following formulated solutions were prepared with sodium salicylate 13.3mg/ml and salicylic acid 11.5 mg/ml (both equivalent on a mole basis to aspirin 15mg/ml), and they were compared with sodium salicylate solution and salicylic acid suspension of the same concentrations, respectively.
disodium succ1nate:glucose:sodium salicylate disodium succinate:glucose:sodium salicylate disodium succinate:glucose:sa11cy1ic acid disodium succinate:glucose:salicylic acid
The results were as follows:
Claims
1. A formulation comprising (a) a salicylic acid derivative, (b) a metabolisable carbohydrate, and (c) disodium or calcium succinate.
2. A formulation according to claim 1 wherein the salicyclic acid derivative is aspirin or sodium salicylate.
3. A formulation as claimed in claim 1 or claim 2, wherein the metabolizable carbohydrate comprises a hexose.
4. A formulation as claimed in claim 3, wherein the hexose comprises D-glucose or D-fructose.
5. A formulation according to claim 2, wherein the nutrient is D-glucose, and the molar ratio of disodium or calcium succinate to aspirin or sodium salicylate is from 2:1 to 5:1 and the molar ratio of D-glucose to aspirin or sodium salicylate is from 1:1 to 5:1 , provided that the total molar ratio of succinate plus D-glucose to aspirin or sodium salicylate is at least 2.5:1.
6. A formulation according to claim 5, wherein said total molar ratio is at least 3:1.
7. A formulation as claimed in any one of claims 1 to 6, wherein the unit dosage form comprises a capsule.
8. A formulation as claimed in any one of claims 1 to 6, wherein the unit dosage form comprises a tablet.
9. A formulation as claimed in any one of claims 1 to 6, wherein the unit dosage form comprises a sachet containing the formulation as a powder or as granules.
10. A formulation according to claim 8, wherein the tablet is a swallowable tablet weighing up to 1.3g and containing a standard 300mg dose of aspirin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU79909/94A AU7990994A (en) | 1993-10-20 | 1994-10-12 | Pharmaceutical formulations of aspirin and salicylates |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB939321655A GB9321655D0 (en) | 1993-10-20 | 1993-10-20 | Pharmaceutical formulation of aspirin and salicylates |
| GB9321655.4 | 1993-10-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1995011030A1 true WO1995011030A1 (en) | 1995-04-27 |
Family
ID=10743859
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1994/003363 WO1995011030A1 (en) | 1993-10-20 | 1994-10-12 | Pharmaceutical formulations of aspirin and salicylates |
Country Status (4)
| Country | Link |
|---|---|
| AU (1) | AU7990994A (en) |
| GB (1) | GB9321655D0 (en) |
| WO (1) | WO1995011030A1 (en) |
| ZA (1) | ZA948192B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1295601A4 (en) * | 2000-04-05 | 2007-12-12 | Veniamin Abramovich Khazanov | Pharmaceutical composition based on a non-steroid anti-inflammatory agent |
| US20190060450A1 (en) * | 2004-08-11 | 2019-02-28 | Palo Alto Investors | Methods of Treating a Subject for a Condition |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US440762A (en) * | 1890-11-18 | Island | ||
| US4885279A (en) * | 1986-03-27 | 1989-12-05 | Rainsford Kim D | Pharmaceutical formulation containing indomethacin |
| US5034379A (en) * | 1984-03-08 | 1991-07-23 | Rainsford Kim D | Pharmaceutical formulation containing azapropazone |
-
1993
- 1993-10-20 GB GB939321655A patent/GB9321655D0/en active Pending
-
1994
- 1994-10-12 WO PCT/EP1994/003363 patent/WO1995011030A1/en active Application Filing
- 1994-10-12 AU AU79909/94A patent/AU7990994A/en not_active Abandoned
- 1994-10-19 ZA ZA948192A patent/ZA948192B/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US440762A (en) * | 1890-11-18 | Island | ||
| US5034379A (en) * | 1984-03-08 | 1991-07-23 | Rainsford Kim D | Pharmaceutical formulation containing azapropazone |
| US4885279A (en) * | 1986-03-27 | 1989-12-05 | Rainsford Kim D | Pharmaceutical formulation containing indomethacin |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1295601A4 (en) * | 2000-04-05 | 2007-12-12 | Veniamin Abramovich Khazanov | Pharmaceutical composition based on a non-steroid anti-inflammatory agent |
| US20190060450A1 (en) * | 2004-08-11 | 2019-02-28 | Palo Alto Investors | Methods of Treating a Subject for a Condition |
| US11389534B2 (en) * | 2004-08-11 | 2022-07-19 | Palo Alto Investors | Methods of treating a subject for a condition |
Also Published As
| Publication number | Publication date |
|---|---|
| AU7990994A (en) | 1995-05-08 |
| ZA948192B (en) | 1995-06-08 |
| GB9321655D0 (en) | 1993-12-08 |
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