WO2017001468A1

WO2017001468A1 - Two-component composition

Info

Publication number: WO2017001468A1
Application number: PCT/EP2016/065130
Authority: WO
Inventors: Per Erik Stribolt Halvorsen; Jorunn U. BRÆNDEN
Original assignee: Asamedic As
Priority date: 2015-07-02
Filing date: 2016-06-29
Publication date: 2017-01-05

Abstract

A two-component composition comprising a first and a second component, wherein the first component comprises a composition comprising aspirin and a pharmaceutically acceptable carbonate, and wherein the second component comprises a dissolution solution comprising at lest one surfactant. The two-component system is in particularly useful in the treatment of imminent myocardial infarction.

Description

Two-component composition

The present invention relates to a two-component composition, the first component comprising a composition comprising acetylsalicylic acid (ASA) and the second component comprising a dissolution solution enabling immediately dissolution of the ASA composition useful in treatment of cardiovascular diseases, e.g. in order to treat imminent myocardial infarction. The present two-component composition is in particular useful as a first aid treatment of imminent myocardial infarction.

Background of the invention

Cardiovascular diseases are one of the leading causes of mortality and morbidity in the western world. According to the World Health Organization cardiovascular diseases are the number one cause of death globally, and it is estimated that 17.5 million people die every year from cardiovascular disease, estimated to about 31% of all deaths world wide. Furthermore, 80%> of all deaths by cardiovascular diseases are caused by hearth attacks or strokes (cf.

http://www.who.int/cardiovascular__diseases/en/ and

http://www.who.int/mediacentre/factsheets/fs317/en/ ). Although numerous medicinal agents are available for the treatment of the various cardiovascular diseases, such as e.g. cholesterol reducing drugs, numerous medicines aiming at reducing blood pressure, blood thinners, etc., patients with cardiovascular diseases are still at high risk of premature death. A myocardial infarction (heart attack) is usually heralded by harbingers, i.e., warning signs occurring in advance, making it possible to take action and thus avoid or reduce the serious consequences of a myocardial infarction.

It is well known that chance of survival of patients experiencing symptoms of a myocardial infarction increase significantly if the patients receive ASA as quickly as possible, preferably immediately. Quick administration of ASA is thus crucial in order to avoid death and to reduce damage to the cardiovascular system.

Hence, in order to successfully treat an upcoming myocardial infarction, a patient needs to have ASA available in a form that may be easily and quickly taken by or administered to the patient.

As of today, effervescent tablets containing ASA are commonly used as immediate treatment of patients experiencing symptoms of a heart attack. A product commonly used for this purpose is, e.g. Dispril^®, an effervescent tablet containing 300 mg ASA. Effervescent formulations in general, as well as those containing ASA, commonly comprise effervescent agents, such as an acid source together with a type of carbonate or hydrogen carbonate, such as sodium hydrogen carbonate or calcium carbonate.

Prior to the administration of the effervescent tablets, the tablets must be dissolved in water, or dissolved in saliva in the mouth of the patient. This might take several minutes, typically 5 minutes. WO2015/061521 discloses an effervescent tablet comprising high levels of ASA and an alkaline substance (e.g. sodium hydrogen carbonate), and vitamin C.

EP1428525 discloses a pharmaceutical preparation for veterinary use containing ASA in the form of a buffered powder. Said powder still necessitates water in order to dissolve the powder, and will thus not solve the problem of needing to have a glass of water available.

US20120316140 Al describes a soluble aspirin (= ASA) composition, wherein the soluble aspirin (ASA) composition when introduced to water undergoes a reaction. This reaction triggers effervescing action and the disintegration of the ASA granules which rapidly dissolve in the water.

Multi-compartment capsules comprising different chambers for ingredients with different physical states have been described in US2005008690 Al . A successful incorporation of ASA into such a capsule has however so far not been developed and publicly disclosed.

The drawbacks with the prior art tablets are that the patients need a glass of water in order to dissolve the tablets, and the complete dissolution may take some time, often too much time.

Furthermore, a patient experiencing signs of an imminent (i.e., developing) myocardial infarction usually has reduced or deficient saliva production, resulting in a dry mouth. Reduced or deficient saliva production is hampering dissolution of an oral tablet containing ASA. It is therefore crucial that the patient has liquid readily available in order to dissolve and/or ingest ASA.

Also chewable tablets containing ASA are available as immediate treatment of patients experiencing symptoms of a heart attack. However, for the same reason as mentioned above, also the dissolution of and release of ASA from a chewable tablet is often hampered by the reduced or deficient salvia production in the patients. Taken together, even though products containing ASA for emergency use are available (see, e.g., http://dummypage2.tripod.eom/index.htm#origin), such products will be inadequate in lack of water or poor saliva production. There is therefore still a need for an ASA formulation or system suitable for quickly providing an aqueous solution comprising ASA that may be administered to patients in need for urgent treatment of an imminent myocardial infarction. In particular, there is a need for an ASA formulation that avoids the need of additional water or adequate saliva production in a given patient in order for the ASA to be

administered and taken up quickly.

Summary of the invention

It is an object of the present invention to provide a composition comprising ASA and a dissolution solution that may be used to quickly prepare a solution of ASA that may be used, e.g. as a need of urgent care situations, in the treatment imminent myocardial infarction.

Said object is solved by the providing of a two-component composition comprising or consisting of a first component comprising ASA and at least one

pharmaceutically acceptable carbonate; and a second component comprising a dissolution solution to be used for quick dissolution of the acetyl salicylic acid powder composition. In particular, the invention includes a two-component composition comprising a first and a second component, the said first component comprises a therapeutically effective amount of ASA; and optionally one or more pharmaceutically acceptable excipients; and wherein said second component comprises an aqueous dissolution solution comprising at least one surfactant.

According to one embodiment, the pharmaceutically acceptable carbonate may be selected from the group consisting of magnesium carbonate and calcium carbonate.

The at least one surfactant includes a nonionic surfactants, such as e.g.

polysorbat80.

According to another aspect, the second component comprises EtOH and

polysorbat80. According to another aspect, the first and/or the second component comprises in addition a pH regulating agent, such as e.g. citric acid or blackcurrant juice. According to another aspect, the first component further comprises a pH regulating agent.

According to another aspect, the second component further comprises a pH regulating agent.

According to another aspect, the second component comprises in addition a preservative, such as benzoic acid. According to another aspect, the second component comprises in addition one or more sweetening agents and one or more flavoring agents.

The present invention furthermore includes a two-component composition comprising: i) a first component comprising a composition comprising ASA, a carbonate selected from the group consisting of calcium carbonate and magnesium carbonate, and optionally one or more pharmaceutically acceptable excipients; and ii) a second component comprising a dissolution solution comprising ethanol, a nonionic surfactant, a pH regulating agent, and optionally one or more sweetening agents and flavoring agents. According to one aspect the second component (ii) comprises ethanol and polysorbate80.

According to one aspect the second component (ii) comprises ethanol and/or polysorbate80citric acid, and benzoic acid.

The invention furthermore includes a two-component composition comprising a first composition comprising ASA, calcium carbonate, and optionally one or more pharmaceutically acceptable excipients; and a dissolution solution comprising polysorbate80, ethanol, citric acid, benzoic acid, saccharine sodium, and peppermint essence.

The invention furthermore includes a two-component composition comprising i) a first composition comprising 300 mg ASA, 75 mg calcium

carbonate, and optionally one or more pharmaceutically acceptable excipients; and ii) a dissolution solution comprising 10 % (v/v) ethanol, 2 % (w/v) polysorbate80, 0.1 % (w/v) citric acid, 0.1 % benzoic acid, 0.06 % (w/v) saccharine sodium, 1 % (v/v) peppermint essence. In one embodiment of the two-component composition according to the invention, the amount of ASA in the first component is in the range of 100 - 600 mg.

Further, the volume of the aqueous solution of the second component of the two- component composition of the present invention is in the range of 6 ml - 50 ml.

According to a particular embodiment of the two-component composition, the amount of ASA in the first component is in the range of 300 - 325 mg, and the volume of the second component is in the range of 8-15 ml. The present invention provides also a use of a two-component solution according the invention for treatment of myocardial infarction.

Finally, the present invention provides a capsule comprising a two-component composition according to the present invention. In particular, the capsule of the invention includes a first and a second chamber, wherein the first chamber comprises a composition comprising ASA, a carbonate selected from the group consisting of calcium carbonate and magnesium carbonate, and optionally one or more pharmaceutically acceptable excipients; and the second chamber comprising an aqueous dissolution solution comprising at least one surfactant.

According to one aspect, said capsule comprises a first chamber comprising ASA and calcium carbonate, and the second chamber comprising a dissolution solution comprising ethanol, a nonionic surfactant, pH regulating agent, and optionally one or more sweetening agents and flavoring agents.

According to another aspect, said second chamber of the capsule comprises ethanol, polysorbate80, citric acid, benzoic acid.

In yet another aspect it is provides a method for treating myocardial infarction by administering an aqueous solution of ASA comprising the steps of: a) providing a two-component composition according to any of the claims 1 - capsule according to any of the claims 12-14;

b) mixing the first component or said composition or the chamber comprising a pharmaceutically acceptable amount of acetylsalicylic acid with the dissolution solution comprised in the second component/chamber obtaining an aqueous solution of acetylsalicylic acid; c) administering to the person in need thereof mixture obtained in step b).

According to one embodiment of this method, the aqueous solution of ASA is obtained in about at least 2 minutes, such as at least one minute. In another embodiment of this method, the aqueous solution of ASA is obtained in about 15-20 sec.

Definitions The term "cardiovascular disease" as used herein refers to diseases where the patients suffering from the cardiovascular disease is in risk of having a hearth attack. In particular, "cardiovascular diseases" as used herein includes ischemic heart disease, congestive heart failure, hypertension, valvular heart disease, general atherosclerosis, hypercholesterolemia, etc.. The spectrum of ischemic heart disease comprised stable and unstable angina and acute myocardial infarction, conditions usually treated either by pharmacology or by coronary revascularization.

Revascularization procedures can be done either catheter-based, or by coronary artery bypass grafting. The product of the present invention is applicable in the treatment of imminent acute myocardial infarction, where the terms "myocardial infarction" and "heart attack" are used interchangeably herein.

The terms "treating" or "treat" as used herein refers to reduction in severity and/or elimination of symptoms, prevention of the (further) development of a heart attack, and improvement or amelioration of damage that may be caused by a heart attack.

Patients diagnosed with any of the indications listed above may risk developing a heart attack or experiencing symptoms or warnings of a heart attack being imminent. The terms "treatment", "treating" or "treat" as used herein in accordance with the present invention refers to treatment of patients diagnosed with a cardiovascular disease as defined above, and which are in need of ASA due to the occurrence of imminent acute myocardial infarction. The terms "aspirin" or "acetylsalicylic acid" or "ASA" are used interchangeably herein.

The term "two-component composition" as used herein refers to a product comprising at least two compositions which are kept apart prior to administration, and which are to be mixed in order to provide a ready to use solution to be administered to patients in need thereof. The term "surfactant" as used herein refers to a compound that lowers the surface tension (or interfacial tension) between two liquids or between a liquid and a solid. The skilled person will acknowledge that a surfactant typically may act as a detergent, a wetting agent and a dispersant.

The term "pH regulating agent" or "acidity regulating agents" as used herein refers to a compound added to the first or the second component of the present composition in order to change or maintain the pH of the composition. The term "preservative" as used herein refers to a substance or a chemical commonly added to pharmaceutical composition in order to prevent microbial growth or decomposition or undesired chemical changes to a product.

The term "sweetening agent" as used herein refers to compounds commonly added to pharmaceutical composition in order to sweeten or mask an unpleasant taste caused by the active ingredient or any of the excipients used in the composition.

The term "flavoring agent" as used herein refers to compounds commonly added to pharmaceutical composition in order to provide a pleasant taste and/or mask an unpleasant taste caused by the active ingredient or any of the excipients used in the composition.

Detailed description of the invention For patients having a heart attack or experiencing symptoms or warnings of a heart attack being imminent, it is shown that administration of ASA taken as soon as possible increases the chances of survival and reduces the risks of developing damage to the cardiovascular system and the heart. The appropriate dosage of ASA for such use is found to be 300 mg, which correspond to the amount of active ingredient in the effervescent tablet Dispril^®, cf. Elwood et al, 2001 , The

Pharmaceutical Journal, 266:315. The Dispril^® tablets comprise calcium carbonate, corn starch, citric acid, talk, saccharine and sodium laurylsulphate

(http://slv.no/_layouts/Preparatomtaler/Spc/0000-02602.pdf ). The problem with the standard prior art tablets containing ASA, such as e.g.

Dispril®, is that they firstly must be dissolved in water, and thus necessitates that a glass of water is available whenever needed. In addition, the lack of saliva in the mouth in patients suffering from an imminent heart attack, for reasons of acute fear and adrenergic reactions, results in the patients having trouble to dissolve tablets in their mouth. In both scenarios this results in the need of water, which is a drawback for swift administration. In addition, the time taken for the prior art tablets to be dissolved, results in the fact that the patients in need of immediate administration of ASA are not provided with said medication quickly enough.

The present invention solves this problem by providing a product that ensure rapid dissolution of ASA and provides a solution that can be quickly administered to the patient, independent of whether a glass of water is available or not and independent of the saliva production of the patient.

Acetylsalicylic acid (ASA) is commonly known as aspirin, having the following structure:

assigned the CAS Registry number 50-78-2. Aspirin is used in the treatment of numerous conditions, e.g. as analgesic, in treatment of inflammatory disorder, cardiovascular disorder etc. In particular, it is used in order to reduce the risk of death from heart attack. ASA however has poor water solubility, and the low solubility of ASA renders it difficult to provide quickly a solution to be

administered when patients is at immediate risk of having a heart attack. In standard pharmaceutical compositions, ASA is rearranged to a soluble salt upon dissolution of the composition in order to improve solubility. Both ASA and the salt of ASA are unstable in aqueous solutions and will quickly hydrolyse forming salicylic acid and acetic acid.

The present invention provides a two-component composition comprising separately i) a first component composition comprising ASA, a pharmaceutically acceptable carbonate such as e.g. calcium carbonate and/or magnesium carbonate, and optionally one or more pharmaceutically acceptable excipients; and ii) second component comprising a dissolution solution comprising at least one surfactant.

The two-component composition according to the present invention represents an improvement of emergency treatment of patients having a heart attack, or being in the process of developing a heart attack, in that it provides for:

Rapid providing of a ready to use solution comprising ASA,

Immediate treatment of myocardial infarction without the need of a glass of water,

Immediate treatment of myocardial infarction independent upon the saliva production of the patient, a ready to use emergency medicinal product that can be easily carried by a broad population, including patients in risk of developing heart attack as well as their relatives, or being available in first aid kits in private houses or public places as well as emergency rooms at medical practices and hospitals.

Although the present two-component composition is in particular useful as an emergency care product for the treatment of heart attack, the skilled person will acknowledge that the two-component composition may have other useful applications. E.g., aspirin is well known as a painkiller and an antipyretic agent. Thus, the two-component composition of the present invention may also be used for the treatment of any other medical condition where administration of aspirin to a patient is desired.

According to the present invention, the first component comprises a

pharmaceutically acceptable amount of ASA. Said first component may comprise from 50 mg to 2000 mg ASA, such as from 100 mg to 600 mg. For the purpose of treating myocardial infarction or reducing the damages thereof, the first

compartment typically comprises from 300 - 325 mg ASA. The volume of the aqueous solution of the second component of the present two- component composition depends upon the specific medical indication as well as the size of the device comprising separately the two-components of the composition. Typically, the volume of the second aqueous dissolution solution is within the range 6 - 50 ml, such as from 6-40 ml, such as from 8-30 ml, such as from 8-20 ml, or any number in-between said ranges. According to one embodiment of the present invention, the volume of the aqueous solution of the second component is in the range of 8-15 ml.

According to one embodiment, the first component comprises from 100 - 600 mg ASA, which is to be dissolved in the 6 - 50 ml of the aqueous dissolution solution of the second component of the present two-component composition.

According to another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises from 8-15 ml of the aqueous solution.

According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises about 8 ml of the aqueous solution. According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises about 10 ml of the aqueous solution. According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises about 1 1 ml of the aqueous solution.

According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises from 12 ml of the aqueous solution.

According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises from 15 ml of the aqueous solution.

According to the present invention, the first component comprises ASA, preferably in a dosage of 100-600 mg ASA, more preferably 300-325 mg ASA, such as 300 mg ASA, and a carbonate, such as magnesium carbonate, and calcium carbonate. The carbonate is used as an effervescent agent in order to facilitate and improve water solubility of the ASA when dissolution solution (second component) is added to or mixed with the first component.

Carbonates may however result in undesired foaming and too much gas formation, resulting inter alia in overflow, so that all the amount of the second component of the composition cannot be mixed with the first component in one step only. The second component of the present composition comprises at least one surfactant in order to reduce problems with foaming, gas production and overflow. In one embodiment of the invention, the first component comprises ASA and calcium carbonate.

In particular, the invention includes a two-component composition wherein the first component comprises 300 mg ASA and 75 mg calcium carbonate.

The second component of the present invention comprises at least one surfactant facilitating the dissolution of the first component, and at the same time reducing the interfacial tension and/or facilitate the wetting of the first component. A non-limiting example of surfactants that may be used in the second component of the present invention is nonionic surfactants, such as surfactants derived from polyethoxylated sorbitan and oleic acid. In particular, the invention includes a two- component composition, wherein the nonionic surfactant polysorbate80 is used in the second component of the composition. Polysorbate80 is also known as polyoxy ethylene (2) sorbitan monooleate (CAS Registry Number 9005-65-6). The polysorbat80 may be added in amounts corresponding to about 0.1 - 0.2 % (w/v) of the total amount of the second component. In one aspect, polysorbat80 is used in the amount of about 0.2% of the total amount of the second component.

According to one embodiment, the second component comprises yet another surfactant. The second surfactant comprised in the second component may e.g. be ethanol. Ethanol acts as a co solvent and a surfactant, and also improves the wetting of the first component. In the amount of 15% (v/v), ethanol also acts as a

preservative. The amount of ethanol in the second component of the invention is in the amount of about 7.5 - 15 % (v/v) of the total amount of the second component. According to one aspect, the invention includes a two-component system wherein the first component comprises ASA and calcium carbonate, and the second component comprises an aqueous dissolution solution comprising polysorbat80.

According to one aspect, the invention includes a two-component system wherein the first component comprises ASA and calcium carbonate, and the second component comprises an aqueous dissolution solution comprising polysorbat80 and ethanol.

According to one aspect, the invention includes a two-component system wherein the first component comprises ASA and magnesium carbonate, and the second component is an aqueous dissolution solution comprising ethanol and polysorbat80.

According to one aspect, the invention includes a two-component system wherein the first component comprises ASA and calcium carbonate, and the second component is an aqueous dissolution solution comprises polysorbat80 and a pH regulating agent.

The pH regulating agent may be added in order to further facilitate the dissolution of the first component, and may be added to the first component and/or the second component. The pH regulating agent may also be added to the first and/or the second component in order to improve the taste of the composition achieved when dissolving the first component in the second component of the present two- component composition. The skilled person will be well known with various pharmaceutically acceptable pH regulating agents that may be used, such as e.g. citric acid, acetic acid and lactic acid, or juice of fruit or berries. According to one aspect, the invention includes a two-component system wherein the first component comprises ASA and calcium carbonate, and the second component is an aqueous dissolution solution comprises polysorbat80, ethanol and a pH regulating agent.

According to another aspect of this embodiment, the pH regulating agent is selected from the group consisting of citric acid or blackcurrant juice.

According to one aspect, the invention includes a two-component system wherein the first component comprises ASA and calcium carbonate, and the second component comprises polysorbat80 and ethanol and pH regulating selected from the group consisting of citric acid or blackcurrant juice.

According to one aspect, the first and/or the second component of the present invention may further comprise citric acid. Citric acid is a pH regulating agent.

Citric acid may also prevent unpleasant taste. When added to the first component, citric acid may be added in the amounts of about 0 - 25 mg as dry matter. When added to the second component, it is typically added in the amounts of about 0.1 % (w/v) of the total amount of the second component.

The two-component composition according to the present invention furthermore includes a composition where a preservative is added, in particular wherein a preservative is added to the second component. The skilled person will be well known with pharmaceutically acceptable preservatives that may be used. In particular, the present invention includes a composition wherein the second component comprises a preservative, in particular benzoic acid. Benzoic acid may be added in the amounts of about 0.1 % (w/v) of the total amount of dissolution solution. The present two-component composition may furthermore include sweetening agents in order to improve taste or mask unpleasant taste of the other ingredients in the composition. The skilled person is well known with various sweetening agents commonly used as sweetening agents in pharmaceutical composition. A non- limiting example of a sweetening agent that may be used in respect of the present invention is saccharine sodium. Saccharine sodium may be added to the second component of the present composition, such as e.g. in the amounts of about 0.03 - 0.06 % (w/v) of the amount of second component.

The present two-component composition may also include flavoring agent added in order to improve the taste and/or mask unpleasant taste of the other ingredients. The skilled person is well known with various flavoring agents commonly to improve the taste or mask unpleasant taste of e.g. the active ingredient or excipients in pharmaceutical composition. A non-limiting example of a flavoring agent that may be used in respect of the present invention is e.g. peppermint essence or

blackcurrant juice. Peppermint essence may be added to the second component of the present composition, such as e.g. in the amounts of about 1% (v/v) of the amount of the second component. Blackcurrant juice may be added to the second component of the present composition, such as e.g. in the amount of 20% (v/v) of the amount of the second component. Blackcurrant juice may also act as a pH regulating agent. The two-component composition included in the present invention may be administered to the patient in need thereof using a device or capsule comprising said first component and the second component in separate departments or chambers of a device or capsule. A predetermined amount of the first component and predetermined amount the second component, will upon operation of the device or capsule be mixed and immediately form a ready to use solution of dissolved ASA to be taken by or administered to the patient in need thereof.

For example, a capsule for segregated storage of two-component miscible substances as disclosed in WO00/66456 or a package device as described in

WO98/38104 and as provided by Bormioli Rocco S.p.A., Italy (e.g. the 3 phase kit with PET bottle) may be used in connection with the present invention for the treatment of myocardial infarction.

The skilled person will understand that a device or capsule for segregated storage of two-component miscible substances, such as a first component comprising a dry powder comprising ASA and optionally one or more pharmaceutically acceptable excipients and a second component comprising a dissolution solution according to the present invention, may be designed in various ways. It is to be understood that the two-component composition according to the present invention may be placed in any capsule or device that will provide immediate dissolution of the ASA in the first component composition upon mixing with the dissolution solution of the second component composition irrespective of the exact design of the capsule, package or device the two-components may be placed in as long as the two -components are separated during storage and prior to use.

The volume of the chamber of the capsule or storage device to be used with the present second component of the two-component composition is in size suitable for storage of the aqueous dissolution solution enabling the dissolution of the desired amount of ASA in accordance with the present invention. Similarly, the size of the chamber of the capsule or storage device to be used for storage of the first component of the two-component composition of the present invention is in size suitable for storage of the desired amount of the said first component. Examples

Material and Methods

The ingredients used to prepare the first and the second composition of the two- component composition of the present invention was purchased from Norsk

Medisinaldepot (NMD) (all fulfilling the requirements of the European

Pharmacopoeia (Ph. Eur (6)):

Acetylsalicylic acid 0.15 mM

Sodium hydrogen carbonate (NaHC0₃),

Magnesium carbonate (light) (MgC0₃),

Calcium carbonate (heavy) (CaC0₃),

Citric acid (anhydrous)

Talk

Benzoic acid

Saccharine sodium

Blackcurrant juice (unsweetened)

In addition, rectified alcohol (EtOH) was purchased from Arcus AS, Oslo, peppermint essence was provided by Stroms Chem. Laboratorium AS, Voyenenga.

Granules prepared for Dispril® tablets were provided by Reckitt Coleman Ltd, England. Water (water for injection) was provided from Rikshospitalets Apotek.

The ingredients used in preparation of ASA powder were weighed using an analysis weight, transferred to a 10 ml sample tube and mixed manually. The sample tubes used is transparent and of the same dimensions as the capsule to be used in the device described in example 1.

For analysis of the dissolution characteristics of the obtained ASA powder blending, the dissolution solution tested was added, and wetting, development of gas and foaming was registered. Furthermore, the dissolution characteristic of the ASA powders were observed in respect of whether the tested powders dissolved easily simply by turning the test tubes.

The amount of ASA in all powder compositions tested was 300 mg, except for the first powder tested which comprised 150 mg ASA. The carbonate used in each test powder was added as dry powder to the ASA. The type and amount of excipients used is the tested powder compositions are shown in table 1.

Table 1 : Type and amounts of excipients tested

The compositions of the tested powders and the dissolution solution used and the results obtained is shown in the below examples.

Example 1 Dissolution characteristics of powder comprising 150 mg ASA

In this experiment, the dissolution characteristics of ASA powder comprising various amounts of sodium carbonate dissolved in 4.5 ml water was tested. The various composition and their dissolution characteristics are outlined in table 2 below.

Table 2: Screening powders of 150 mg ASA and NaHC0₃.

ASA NaHC0₃ Observations

(mg) (mg)

150 50 (3 : 1) Poor wetting, foaming and effervescence, not

dissolved after shaking

150 100 (2: 1) Poor wetting, foaming and effervescence, dissolved after shaking

150 150 (1 : 1) Poor wetting, a lot of foaming and effervescence, is dissolved after shaking, dissolved after shaking but in the expense of production of significant amounts gas Increasing the amount of powder to 300 mg ASA and 140 - 165mg NaHC0₃, the production of gas (effervescence) resulted in production of increasing amounts of foam. The results confirmed that the use of water as dissolution solvent provides poor wetting of the powder. Solid matter was seen on the surface of the solution after dissolution, and the shaking of the liquid was necessary in order to provide dissolution of the powder. In order to avoid the need of shaking, e.g. due to limitation of the two chambered device or capsule used, appropriate wetting of the powder is important.

The use of sodium carbonate as effervescent agent resulted in both undesired formation of foam and gas, both in the higher as well as the lower amount of NaC0₃ tested.

Example 2: The effect of reduced amounts of sodium carbonate and addition of further excipients

In this experiment, the effect of reducing the amount of NaHC0₃ and adding further excipients on dissolution characteristics of the ASA powder was tested in order to reduce the problem with foaming and gas production when using NaHC0₃ as effervescent.

The aim of the experiment was to identify agents that allowed for the reduction of the amount of sodium hydrogen carbonate by adding excipients in the water phase that might reduce the interfacial tension and improve the wetting of the powder and dissolution of ASA (i.e. excipients falling within the group commonly named surfactants). Various dissolution solutions were tested comprising ethanol and/or polysorbat80.

The dissolution characteristics of the ASA powders upon adding 8 ml of various dissolution solutions is shown in table 3 below. The powder comprised ASA and NaHC0₃, whereas the dissolution solution used to dissolve the powder comprised water, or water added various amounts of EtOH and/or Polysorbat80. The various compositions tested and the results obtained are summarized in table 3. Table 3: Effect of reduced amounts of NaHC0₃ and addition of excipients.

The inventors observed that when using 300 mg ASA and 140 - 165 mg sodium hydrogen carbonate, the formation of gas and foam was to large, resulting in that amount of dissolution solution had to be added during a period of 2 min, and overflow was a problem. This is not when the two-components, placed in e.g. two chambers of a capsule, are to be mixed immediately and when overflow have to be avoided to ensure administration of a correct amount of the active ingredient.

Reduction of the amount of NaHC0₃ (70 mg) still resulted in to much foaming and effervescence. Ethanol and/or polysorbat80 were added in order to see whether this would result in less foaming and gas formation. Both the use of 15% EtOH and 0.2 polysorbat80 alone resulted in improved wetting, less foaming and less gas production. However, at the same time, the powder did not dissolve properly.

The use of sodium carbonate results in to much foaming and to much gas development. The reduction of the amount of sodium carbonate and adding of excipients reducing the interfacial tension reduce the problem of foaming and gas production, but not without negatively compromise the solubility of the ASA powder. The reduction in solubility could not be adequately remedied by improving the wetting by the addition of excipient acting as surfactant and optionally also acting as a co-solvent. Example 3: Effect of MgC0₃ on gas production and foaming

ASA powder was prepared as described in example 1 with the difference that NaHC0₃ was replaced by MgC0₃. Optionally, citric acid was also added as a wetting agent. The dissolution solution was prepared by adding EtOH and/or polysorbate80 to 8 ml water (WFI).

The dissolution characteristics of powders upon adding dissolution solutions were then tested in respect of development of foaming and production of gas, and whether an even dispersion was obtained upon turning.

Table 4 below shows the results of the tested samples. The observations were scaled from 1 (poor) to 3 (best). God wetting, little gas production, thin layer of foam and even dispersion upon turning of the test tube resulted in high score. The addition of water to Dispril® granulate was used as reference.

Table 4: Test of compositions comprising MgC0₃.

Composition Results

ASA MgC0₃ Citric acid EtOH Polysorbate80 Wetting Effervescence Foam Even dispersion Measured pH

(mg) (mg) (mg) (%v/v) (% (w/v) (upon turning)

300 75 0 15 0 1 3 3 2 5.5

300 140 0 15 0 1 3 3 2 6.5

300 75 20 15 0 1 3 3 1 5.4

300 140 20 15 0 1 3 3 1 6.0

300 75 0 0 0.2 2 3 3 3 6.0

300 140 0 0 0.2 3 3 2 1 6.5

300 75 20 0 0.2 2 2 2 2 5.2

300 140 20 0 0.2 3 3 1 2 5.2

300 100 10 7.5 0.1 1 2 2 1 6

300 75 0 15 0.2 3 3 3 3 5.2

300 140 0 15 0.2 2 3 3 2 ND

Reference: Dispril granulate 500 mg + 8 ml WFI 3 2 1 2 4.9

The results show that both 140 and 75 mg magnesium carbonate provides acceptable foaming and gas product, and overflow was not a significant problem. The best results were obtained when adding both EtOH and polysorbate80, in particular when using 75 mg MgC03, 15 % EtOH and 0.2 % polysorbat80, which was as easily wetted as the reference granulate, but which showed less foaming and less gas production as well as providing a more even dispersion.

Example 4: Use of CaC0₃ as effervescent agent. As shown above, sodium carbonate provided unsuitable as an effervescent agent. Magnesium carbonate, when used together with a dissolution solution comprising polysorbat80 and ethanol, on the other hand provided acceptable scores in respect of wetting, effervescence, foaming, and even dispersion. However, due to the presence of water in magnesium carbonate (about 1% humidity) it is a risk of hydrolysis of ASA during storage. The use of calcium carbonate was in stead of magnesium carbonate was therefore tested.

Calcium carbonate is used as effervescent agent in Dispril ® tablets in an amount of 90 mg to 300 mg ASA, cf. "Felleskatalogen over farmasoytiske spesialpreparater markedsfort i Norge", Oslo, 2002 (Corporate Directory of pharmaceutical compositions on the market in Norway, Oslo, 2002).

Powders comprising ASA and various amounts of calcium carbonate were prepared by mixing ASA and calcium carbonate. In order to test the dissolution

characteristics, 8 ml dissolution solution was added. The results of the test are shown in table 5.

Table 5: testing of various amounts of calcium carbonate on the dissolution characteristics of ASA powder

Composition Dissolution solution Results

ASA 300 mg Polysorbat80 0.2 % (w/v) Inadequate wetting, weak CaC0₃ 50 mg WFI to 8 ml effervescence and little foaming

ASA 300 mg Polysorbat80 0.2 % (w/v) Inadequate wetting, weak CaC0₃ 100 mg WFI to 8 ml effervescence and little foaming, powder in the bottom and solid matter on the top of the solution in the test tube after 1 ½ min Two different amounts (50 and 100 mg) have been tested together with 300 mg ASA. Polysorbat80 was added to the dissolution solution. The results show that the samples comprising 100 mg calcium carbonate did not provide complete dissolution of the dry matter and solid matter was shown on the surface.

Based on the results, further experiments were performed, using 50 and 75 mg calcium carbonate. The addition of ethanol alone to the dissolution solution was found not to provide acceptable wetting. Polysorbat80 was therefore added to the dissolution solution. In addition, citric acid was added as pH regulating agent in order to obtain the same pH as the reference product (Dispril® granulate). The citric acid was added as dry matter to the ASA powder.

Also blackcurrant juice (unsweetened) was added. As blackcurrant is acidic, it acts both as pH regulating agents as well as a flavoring agent.

Powder compositions consisting of ASA, calcium carbonate and optionally citric acid was prepared as in example 3 above. The dissolution solution tested was prepared by adding to 8 ml water (WFI) polysorbat80 and optionally blackcurrant juice and/or EtOH. The dissolution characteristics were scored, the worst score being 1 and the best score being 5. God wetting, little gas production, thin layer of foam and even dispersion when turning the test tube resulted in high score. The addition of water to Dispril® granulate was used as reference. The results are shown in table 6.

Table 6: Test of compositions comprising CaC0₃.

Composition Results

ASA CaC0₃ Citric Acid Blackcurrant EtOH Polysorbate80 Wetting Effervescence Foam Even dispersion Measured pH

(mg) (mg) (mg) juice (%v/v) (% (w/v) (turning)

(% v/v)

300 50 0 20 0 0.2 4 4 3 3 4.4

333 75 0 20 0 0.2 2 4 3 3 4.7

300 50 20 0 0 0.2 4 4 5 4 4.5

300 75 20 0 0 0.2 2 2 2 4 4.6

300 50 0 20 15 0.2 3 4 4 4 4.4

300 75 0 20 15 0.2 4 4 5 4 4.5

300 50 20 0 15 0.2 3 4 4 4 4.4

300 75 20 0 15 0.2 4 4 2 4 4.7

Reference: Dispril granulate 500 mg + 8 ml WFI 5 3 2 4 4.9

The results show that when using calcium carbonate, it is necessary to include a surfactant, such as polysorbat80 into the dissolution solution. Furthermore, a pH regulating agent, and/or a co-solvent (ethanol) will further facilitate the dissolution and improve the characteristics of the two-component composition.

The results furthermore show that the two-component composition achieving the highest scores consisted of a first component comprising 300 mg ASA and 75 mg calcium carbonate, and a second component forming the dissolution solution comprising 15% ethanol, 0.2 % polysorbate80 and blackcurrant juice.

Example 5 Additions of flavoring agents and sweetening agents

The results above show that addition of excipients acting as co-solvent/wetting agents and/or surfactants, such as EtOH and polysorbate80, is necessary in order to achieve optimal characteristics in respect of wetting, foaming and gas production.

The results above furthermore indicate that the presence of acidic components in the dissolution solution is advantageous to the wetting and dissolution characteristics, in particular when calcium carbonate is used as effervescent.

However, the taste of the obtained solution was could be further optimized. In order to improve the taste of the dissolved ASA solution, sweeting agents and flavoring agents was added. Saccharin sodium was tested as sweetening agent, and

peppermint essence was used as flavoring agent.

In addition, although the inventors observed that blackcurrant juice resulted in better wetting and less gas production and foaming, e.g. compared with citric acid, the addition of blackcurrant juice also showed some tendency of resulting in an unclear dissolution solution. In order to avoid an unclear dissolution solution, citric acid was used in stead of blackcurrant juice. In addition, the amount of EtOH was reduced in order to reduce any dominating taste of alcohol. Benzoic acid was furthermore selected as an optional preservative for the acidic dissolution solution used in this experiment. Peppermint essence was added in order to mask any remaining unpleasant taste.

As sweetening agent, saccharide sodium was used (0.03 % and 0.06 % (w/v)), and 0.06 % turned out to provide the most pleasant taste.

The following composition was prepared as dissolution solution:

Benzoic 100 mg

Ethanol 10 ml Polysorbat80 200 mg

Saccharine sodium 60 mg

Citric acid, anhydrous 100 mg

Peppermint essence 1 ml

Water to 100 ml

The benzoic acid was dissolved in EtOH and added to a solution comprising the other ingredients in water. Example 6 Preparation of capsules comprising a two-component composition.

A first component composition comprising a powder consisting of ASA and calcium carbonate was prepared by mixing 300 mg of the active ingredient and 75 mg of said carbonate.

A second component, a dissolution solution, was then prepared by first dissolving benzoic acid in ethanol. A second solution was then prepared by dissolving and mixing polysorbate80, citric acid (anhydrous), saccharine sodium, and peppermint essence in water. The two solutions were then mixed to form the second component composition.

375 mg of the first component was filled into a first chamber of capsules, said first chamber of the capsules comprising 300 mg ASA and 75 mg calcium carbonate. 8 ml of the second component (dissolution solution) was then filled into the second chamber of the capsule. The composition of the second component is shown in table 7 below.

Table 7: composition of dissolution solution/1 ml

The capsule used in this experiment is a device/capsule corresponding to the one disclosed in WO WO00/66456. The capsule is designed so as to comprise two separate chambers, one comprising the first compositions (ASA and calcium carbonate), and a second chamber comprising the second component, the dissolution solution. In operation, the content of the two chambers are mixed upon opening of the device, resulting in that the first component of the composition (ASA powder) is added into the chamber comprising the second component (dissolution solution). The active ingredient is thus dissolved in the chamber comprising the dissolution solution, resulting in the quick formation of a ready to be used solution of ASA. Said ASA can quickly and easily, without the need of water/glass and irrespective of the saliva production, be taken or

administered to the patient.

Stability test was performed and the results showed that the composition is stable. Example 7 Stability testing

The stability of the two-component composition according to the present invention was carried out in order to provide information about the stability of the

composition, and in particular the stability of the acetylic acid comprised in the present first component, when stored at 25 °C ± 2 °C, 60% RH ± 5%RH for six weeks.

The stability study was executed and analysis performed at Hydro Organics AS, Porsgrunn, Norway, according to ICH guideline Q 1AR.

The two-component composition according to the present invention was contained in capsules as disclosed in WO00/66456, ensuring that the inner seal of the device is free of air bubbles, and comprising two gaskets ensuring that the two parts of the device are air tightly closed in order to prevent any undesired leakage. The device is produced from PED (polyethylene High Density) and the gaskets providing sealing used in the device are made of pellethane.

The storage conditions were continuously monitored electronically. As a control, a device only comprising the first component according to the present invention, and thus no second component comprising an aqueous dissolution solution, was also tested as control. The control was included in order to see whether optional hydrolysis of the acetyl salicylic acid might be due to moisture ingression from outside the capsule. The capsules were stored in a horizontal position to reflect the expected ordinary use. In addition, the stability of ASA powder mixture used to prepare the first

component of the invention (manufactured by Apotekproduksjon AS, Oslo (Ph. Eur. 4^th Ed., 4.0) was measured at start.

The testing program was performed as shown in the below table 8 on samples taken from different devices at each time point. The window to define the time point was the calendar date plus minus 5 days.

Table 8: Storage program

x = Testing of ASA powder mixture

¹ = testing performed on composition from three individual devices

² = testing performed on composition from one devices

³ = testing performed on composition from three individual devices

The initial time point (study start) was the same as the packaging date.

The following tests were performed at each time point according to the above table:

Appearance

Appearance of ASA powder mixture was determined by visual inspection and comparison with a color chart according to HRW-ANA-A105.

At initiation of the stability storage test, the appearance was observed to be within specification for all three capsules comprising the two-component composition according to the invention. After three weeks of storage, the appearance was still within the specification for all the tested compositions concerning the color of the powder. The powder in the first device comprised some lumps and was not finely divided.

After six weeks storage, the appearance of the first component was within the specification for all the three tested compositions.

No notable changes were observed for the control capsule not comprising the second component curing the test period (up to and including six weeks). Assay by HPLC

The test material was analyzed according to the analytical method HYO-QC-A08. ASA was quantified as %w/w. The test material was furthermore analyzed in order to quantify impurities (salicylic acid as % w/w and unknown impurities as % area) by the same method.

The results showed that all assay results, including content of salicylic acid, was within specification at the initial time point. After three weeks storage, the assay results in the second and third device comprising the two-component composition according to the invention were within the specification. For all three capsules, the assay result was lower than the assay content achieved at the initial time point. However, the amount of salicylic acid was within the specification in all three devises tested although it was significantly decreased in the first device. This is in agreement with the appearance assay, indicating some degradation of ASA in this capsule (probably due to leakage between the two compartments).

Three major unspecified impurities was detected in the assay analysis at retention time (about) 5.1 , 6.0 and 15.1 min. All three impurity peaks were also found in the standard.

After six weeks storage, the content of salicylic acid was still within specification in all three capsules, although the content is increased in all three devices compared with the initial time point. The impurity peaks were furthermore seen to be nearly unchanged throughout the study compared with the initial time point.

No notable change in assay results was observed for the control not comprising the second component at any time point (up to an including 6 weeks).

Based on the results after six weeks storage, it was found that the product fulfilled the stability requirements. The difference in respect of stability of the first device comprising the two-component composition according to the invention was found to be caused by a leakage between the compartments of the device. Although the ASA was slightly degraded during the stability study storage period, the level of salicylic acid is still within the specification. Analysis of the control capsule shows that the device provides protection against potential moisture ingress from environment during the stability time.

The results are shown in the table 9 below: Table 9: Results of stability testing

Test Method Specification Device Nr. Storage time (weeks)

IP 001 , Rev 1

0 3 6

Appearance Visual inpection With to slightly I white, finely White to off- White, finely and comparison yellowish finely devided powder white powder devided powder with a colour divided powder with some lumps chart II White, finely White, finely White, finely devided powder devided powder devided powder

III White, finely White, finely White, finely devided powder devided powder devided powder**

Content of ASA HYO-QC-A08 72-78 % of dry I 85.7 67.7 78.3

(% w/w) powder weight II 86.5 84.7 80.2

III 86.1 86.2 76.9

Content of HYO-QC-A08 < 6% of dry I 0.06 2.85 3.41 salicylic acid powder weight II 0.07 0.58 3.25

(% w/w) III 0.09 0.66 4.36

Total unspecified HYO-QC-A08 Not developed I 0.37 NQ^B NQ^C impurities II 0.53 NQ^B NQ^C (% area) III NQ^A NQ^B NQ^C

Claims

1. A two-component composition comprising a first and a second component, the said first component comprises a therapeutically effective amount of

acetylsalicylic acid, and a pharmaceutically acceptable carbonate, and optionally one or more pharmaceutically acceptable excipients; and wherein said second component comprises an aqueous dissolution solution comprising at least one surfactant.

2. A two-component composition according to claim 1 , wherein the at least one surfactant is a nonionic surfactants.

3. A two-component composition according to any of the above claims, wherein the at least one surfactant is polysorbat80.

4. A two-component composition according to any of the above claims, wherein the second component comprises both EtOH and polysorbat80.

5. A two-component composition according to any of the above claims, wherein said second composition further comprises pH regulating agent.

6. A two-component composition according to any of the above claims, wherein said second composition further comprises a preservative.

7. A two-component composition according to any of the above claims, comprising: iii) a first component comprising a composition comprising

acetylsalicylic acid, a carbonate selected from the group consisting of calcium carbonate and magnesium carbonate, and one or more pharmaceutically acceptable excipients; and iv) a second component comprising a dissolution solution comprising ethanol, a nonionic surfactant, pH regulating agent, and optionally one or more sweetening agents and flavoring agents.

8. A two-component composition according to any of the above claims, wherein the amount of acetylsalicylic acid in the first component is in the range of 100 - 600 mg.

9. A two-component composition according to any of the above claims, wherein the volume of the aqueous solution of the second component is in the range of 6 ml - 50 ml.

10. A two-component composition according to any of the above claims, wherein the amount of acetylsalicylic acid in the first component is in the range of 300 - 325 mg, and the volume of the second component is in the range of 8-15 ml.

1 1. Two-component composition according to any of the claims 1-10 for use in the treatment of imminent myocardial infarction.

12. A capsule comprising a first and a second chamber, wherein the first chamber comprises a composition comprising acetylsalicylic acid, a carbonate selected from the group consisting of calcium carbonate and magnesium carbonate, and optionally one or more pharmaceutically acceptable excipients, and the second chamber comprises an aqueous dissolution solution comprising at least one surfactant.

13. Capsule according to claim 16, wherein the first chamber comprises acetylsalicylic acid and calcium carbonate, and the second chamber comprising a dissolution solution comprising ethanol, a nonionic surfactant, a pH regulating agent, and optionally one or more sweetening agents and flavoring agents.

14. Capsule according to claim 16, wherein the second chamber comprises ethanol, polysorbate80, citric acid, benzoic acid.

15. Method for treating imminent myocardial infarction by administering an aqueous solution of acetylsalicylic acid comprising the steps of: a) providing a two-component composition according to any of the claims 1- capsule according to any of the claims 12-14; b) mixing the first component or said composition or the chamber comprising a pharmaceutically acceptable amount of acetylsalicylic acid with the dissolution solution comprised in the second component/chamber obtaining an aqueous solution of acetylsalicylic acid; c) administering to the person in need thereof mixture obtained in step b).

16. Method according to claim 15, wherein the aqueous solution of

acetylsalicylic acid is obtained in about one minute.

17. Method according to claim 15, wherein the aqueous solution of

acetylsalicylic acid is obtained in about 15-20 sec.