(19)
(11)EP 3 501 522 A1

(12)EUROPEAN PATENT APPLICATION

(43)Date of publication:
26.06.2019 Bulletin 2019/26

(21)Application number: 17210419.2

(22)Date of filing:  22.12.2017
(51)International Patent Classification (IPC): 
A61K 31/616(2006.01)
A61P 9/10(2006.01)
(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
Designated Extension States:
BA ME
Designated Validation States:
MA MD TN

(71)Applicant: Asamedic AS
0607 Oslo (NO)

(72)Inventor:
  • GØRBITZ, Carl, Henrik
    N-0374 oslo (NO)

(74)Representative: Onsagers AS 
P.O. Box 1813 Vika
0123 Oslo
0123 Oslo (NO)

  


(54)COMPOSITIONS COMPRISING ACETYLSALICYLIC ACID AND A PHOSPHATE SALT


(57) The present invention relates to a novel two-component composition comprising acetylsalicylic acid (ASA) and a salt of phosphoric acid which is particularly useful in providing an aqueous solution of ASA for immediate peroral administration.


Description


[0001] The present invention relates to a new two-component composition useful in the treatment and prevention of imminent myocardial infarction. In particular, the invention relates to a pharmaceutical two-component composition, comprising a first component and a second component, wherein the first component comprises acetylsalicylic acid (ASA), and the second component comprises an aqueous solution, and wherein a salt of phosphoric acid is comprised in either the first component or in the second component or in both the first and the second component. The two-component composition enables an immediate dissolution of ASA upon mixing of the first and second components of the present two-component composition, and is in particular useful in the treatment of imminent myocardial infarction. The present two-component composition is in particular useful as a first aid treatment of patients in need for immediate administration of ASA in order to avoid the development of a heart attack, or reduce the extent of damage of a heart attack.

Background of the invention



[0002] 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 worldwide. 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/).

[0003] 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.

[0004] 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.

[0005] 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. To ensure quick absorption and high bioavailability, ASA should be dissolved at the time of administration. ASA however has a poor solubility rendering it difficult to provide an aqueous ASA solution quickly. Further, ASA and salts of ASA hydrolyses rapidly in water (Connors et al., Chemical stability of Pharmaceuticals, A Handbook for Pharmacists, pages 151 - 160), so it is not possible to store dissolved ASA over time.

[0006] Hence, in order to successfully treat an upcoming myocardial infarction, a patient needs to have ASA available in a form that can be dissolved and administered (swallowed) very quickly and without need of additional water or adequate saliva production.

[0007] 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 acetylsalicylic acid.

[0008] 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.

[0009] 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.

[0010] WO2015/061521 discloses an effervescent tablet comprising high levels of ASA and an alkaline substance (e.g. sodium hydrogen carbonate), and vitamin C.

[0011] 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.

[0012] US20120316140 A1 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.

[0013] US5776431 A discloses water-soluble aspirin compositions comprising aspirin, potassium citrate (tri) monohydrate or sodium citrate (tri) dihydrate, and a surface-active agent (e.g. sodium lauryl sulfate). Such a composition comprising 500 mg aspirin is dissolved in 150 ml water

[0014] Multi-compartment capsules comprising different chambers for ingredients with different physical states have been described in US2005008690 A1 and EP2777802 A1. A successful incorporation of ASA into such a capsule is however not disclosed in said document.

[0015] The drawbacks with the prior art tablets and capsules are that the patients need to have a glass of water accessible in order to dissolve the tablets, and that the complete dissolution time may take several minutes. Thus, the prior art tablets are not optimal for quickly administration of ASA, i.e. said tablet are not optimal for increasing the chance of survival of patients experiencing symptoms of a myocardial infarction.

[0016] 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.

[0017] 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.

[0018] Taken together, even though products containing ASA for emergency use are available (see, e.g., http://dummypage2.tripod.com/index.htm#origin), such products will be inadequate in lack of water or poor saliva production.

[0019] WO2017001468 discloses a two-component composition comprising aspirin and a carbonate in one component and a dissolution solution with a surfactant in the other component. However, in retrospect the applicant has realized that this solution wasn't optimal.

[0020] Therefore, there is 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



[0021] The present inventor has found that a stable ASA formulation can be provided with a two-component system comprising the active ingredient ASA in a first compartment and an aqueous solution in a second compartment, and with a salt of phosphoric acid in either the first compartment or in the second compartment or in both, which upon mixing of the content of the two compartments quickly provides an aqueous solution of ASA that may be administered to or taken by a patient in need thereof.

[0022] In particular, the present invention provides a two-component system comprising a first and a second component, wherein the first component comprises a therapeutically effective amount of acetylsalicylic acid (ASA) and optionally one or more pharmaceutically acceptable excipients; and wherein the second component comprises an aqueous solution and optionally one or more pharmaceutically acceptable excipients; and wherein at least one pharmaceutically acceptable salt of phosphoric acid is comprised in either the first component or in the second component or in both the first and the second component, and wherein the salt of phosphoric acid is selected from the group consisting of hydrogen phosphate salt and phosphate salt, and wherein the pH obtained after dissolution of ASA in the second component is above approx. 6.5.

[0023] When the salt of phosphoric acid is comprised in the first component it is to be understood that aqueous solution comprised in second component is pure water, optionally water with one or more pharmaceutically acceptable excipients.

[0024] According to one aspect, the present invention concerns a two-component composition comprising a first and a second component, wherein the first component comprises a therapeutically effective amount of acetylsalicylic acid (ASA) and optionally one or more pharmaceutically acceptable excipients; and wherein the second component comprises an aqueous solution comprising at least one pharmaceutically acceptable salt of phosphoric acid and optionally one or more pharmaceutically acceptable excipients; and wherein the salt of phosphoric acid is selected from the group consisting of hydrogen phosphate salt and phosphate salt, and wherein the pH obtained after dissolution of ASA in the second component is above approx. 6.5.

[0025] According to another aspect, the salt of phosphoric acid is a hydrogen phosphate salt and the pH obtained after dissolution of ASA in the second component is between approx. 7 to 8, especially pH 7.7.

[0026] According to yet another aspect, the salt of phosphoric acid is a phosphate salt.

[0027] In yet another aspect, the hydrogen phosphate salt is disodium and/or dipotassium hydrogen phosphate.

[0028] In yet another aspect, the phosphate salt is or trisodium and/or tripotassium phosphate.

[0029] In yet another aspect, the two-component composition of the present invention consist of a first and a second component, wherein the first component consist of a therapeutically effective amount of acetylsalicylic acid (ASA); and wherein the second component consist of an aqueous solution; and wherein at least one pharmaceutically acceptable salt of phosphoric acid is comprised in either the first component or in the second component or in both the first and the second component, and wherein the salt of phosphoric acid is selected from the group consisting of hydrogen phosphate salt and phosphate salt, and wherein the pH obtained after dissolution of ASA in the second component is above approx. 6.5.

[0030] In yet another aspect, the second composition of the two-component composition of the invention comprises a preservative.

[0031] In one aspect, the preservative is a paraben or benzalkonium chloride

[0032] In one aspect of the present invention, the preservative is selected from the group consisting of methyl paraben, ethyl paraben, propyl paraben, and benzalkonium chloride.

[0033] In yet another aspect, the paraben is selected from the group consisting of sodium methyl paraben and sodium propyl paraben.

[0034] According to yet another aspect, a two-component composition is provided wherein the first composition comprises ASA in the range of 100 - 600 mg, such as 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg.

[0035] According to yet another aspect of the invention, the volume of the aqueous solution of the second component is in the range of 6 ml - 50 ml. According to one aspect, the volume of the second component is in the range of 8-15 ml, such as about 15 ml.

[0036] In one aspect, the two-component composition according to the invention comprises 300 - 325 mg ASA in the first component and wherein the volume of the second component is in the range of 8-15 ml.

[0037] According to another aspect, a two component composition is provided comprising of a) a first component consisting of from 300 - 325 mg ASA, and b) a second component comprising 8-15 ml of an aqueous solution consisting of disodium hydrogen phosphate and a preservative selected from the group consisting of sodium methyl paraben, sodium ethyl paraben, sodium propyl paraben and benzalkonium chloride.

[0038] The present invention furthermore provides a two-component composition according to the present invention for use in the treatment of imminent myocardial infarction. According to one aspect, the first component comprising ASA is dissolved in the second component comprising the aqueous solution, thus providing a ready-to-use aqueous solution of acetylsalicylic acid ASA prior to administration. According to yet another aspect of the invention, said ready-to-use aqueous solution of ASA is obtained in approx. 2 minutes or less, such as within approx. one minute or less. According to yet another aspect, said ready-to-use aqueous solution of ASA is obtained in within approx. 35 sec., such as within approx. 30 or within 25 sec.

[0039] Furthermore, the present invention provides a container comprising a first and a second chamber, wherein the first chamber comprises a therapeutically effective amount of ASA and optionally one or more pharmaceutically acceptable excipients; and wherein the second chamber comprises an aqueous solution and optionally one or more pharmaceutically acceptable excipient; and wherein at least one pharmaceutically acceptable salt of phosphoric acid is comprised in either the first chamber or in the second chamber or in both the first and in the second chamber, and wherein the salt of phosphoric acid is selected from the group consisting of hydrogen phosphate salt and phosphate salt, and wherein the pH obtained after dissolution of ASA in the second chamber is above approx. 6.5.

[0040] According to one aspect of the present container, the pharmaceutically acceptable salt of phosphoric acid is comprised in the aqueous solution of the second chamber.

[0041] According to one aspect of the present container, the salt of phosphoric acid is a hydrogen phosphate salt such as disodium hydrogen phosphate or dipotassium hydrogen phosphate, or a combination thereof; and wherein the pH obtained after dissolution of ASA in the second chamber is between approx. 7 to 8, especially pH 7.7.
In another aspect of the present container, the salt of phosphoric acid is a phosphate salt such as trisodium phosphate or tripotassium phosphate, or a combination thereof.

[0042] In yet another aspect, the aqueous solution in the second chamber of the container further comprises a preservative, such as a preservative selected from the group consisting of a paraben or benzalkonium chloride.

[0043] In one aspect, said paraben is selected from the group consisting of sodium methyl paraben and sodium propyl paraben.

[0044] Finally, the present invention provides a method for treating imminent myocardial infarction by administering an aqueous solution of ASA to a patient in need thereof, said method comprising the steps of:
  1. a) providing a two component composition or two-chambered container comprising according to the present invention;
  2. b) mixing the first component of said composition or the content of the first chamber of said container comprising a pharmaceutically effective amount of ASA with the aqueous solution of the second composition or of the second chamber, respectively, and thereby obtaining an aqueous solution of ASA;
  3. c) administering to the person in need thereof the mixture obtained in step b).


[0045] According to one aspect, a method is provided, wherein the aqueous solution of ASA obtained in step b) is provided within about two minutes or less, such as about one minute or less.

[0046] According to another aspect of the present method, an aqueous solution of ASA is obtained within about 35 sec., such as within approx. 30 or within 25 sec.

Definitions



[0047] The term "cardiovascular disease" as used herein refers to diseases where the patients suffering from the cardiovascular disease is in risk of having a heart 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.

[0048] 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.

[0049] The terms "treating" or "treat" as used herein refers to reduction in severity and/or reduction of the further development of a heart attack, and improvement or amelioration of damage that may be caused by a heart attack.

[0050] 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.

[0051] The terms "aspirin" or "acetylsalicylic acid" or "ASA" are used interchangeably herein.

[0052] The term "component" as used herein in respect of the first and second component of the present two-component composition refers herein to a component comprising at least one ingredient or compound, and which may also be a mixture of different ingredients or compounds. This is evident from the herein description of the first and the second component of the present invention, e.g. from the fact that the first component comprises ASA and optionally one or more pharmaceutically acceptable excipients; and that the second component comprises an aqueous solution and optionally one or more a pharmaceutically acceptable excipient; and at least one pharmaceutically acceptable salt of phosphoric acid further is comprised in either the first or in the second or in both components.

[0053] When the salt of phosphoric acid is comprised in the first component it is to be understood that the term "aqueous solution" as used herein with regard to the second component refers to pure water, optionally water with one or more pharmaceutically acceptable excipients.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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



[0059] 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).

[0060] 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 necessitate that a glass of water be 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.

[0061] The present invention solves this problem by providing a product that ensures 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 saliva production of the patient.

[0062] Acetylsalicylic acid (ASA) is commonly known as aspirin, having the following structure:



[0063] ASA is 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 quickly provide a solution to be administered immediately when a patient experiences symptoms 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 (Connors et al., Chemical stability of Pharmaceuticals, A Handbook for Pharmacists, pages 151 - 160).

[0064] The present invention provides a two-component composition comprising separately i) a first component composition comprising ASA and optionally one or more pharmaceutically acceptable excipients; and ii) a second component comprising an aqueous solution and optionally one or more pharmaceutically acceptable excipients; and iii) a pharmaceutically acceptable salt of phosphoric acid comprised in either the first component or in the second component or in both the first and in the second component. Further, the salt of phosphoric acid is selected from the group consisting of hydrogen phosphate salt and phosphate salt, and the pH obtained after dissolution of ASA in the second component is above approx. 6.5, such as above approx. 6.8 or above approx. 7. Optimally, the pH of the solution obtained after adding and dissolving ASA in the aqueous solution should be in the range of approx. 7-8, especially approx. 7.7.

[0065] The two-component composition according to the present invention represents an improvement of emergency treatment of patients having an imminent heart attack, or being in the process of developing a heart attack, in that it provides:
  • a ready to use solution comprising ASA,
  • Immediate treatment of imminent myocardial infarction without the need of a glass of water,
  • Immediate treatment of myocardial infarction independent of saliva production in a given 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.


[0066] Although the present two-component composition is 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 or prevention of any other medical condition where administration of aspirin to a patient is desired.

[0067] According to the present invention, the ASA present in the first composition/compartment is quickly dissolved when mixed or added to the aqueous solution comprised in the second composition/compartment. Further, a salt of phosphoric acid selected from the group consisting of hydrogen phosphate salt and phosphate salt is comprised in the first component and/or in the second component. According to one embodiment, the salt of the phosphoric acid is disodium hydrogen phosphate or trisodium phosphate.

[0068] The salt of phosphoric acid as used according to the present invention should provide the formation of an easily soluble acetylsalicylate, such as sodium acetylsalicylate or potassium acetylsalicylate. The aqueous solution of the salt of phosphoric acid should have sufficient buffer capacity in order to slow or counteract the pH reduction affected upon mixture with ASA.

[0069] Without being bound by theory, it is believed that ASA comprised in the first component when mixed with the second component becomes ionized contributing to the quick providing of a dissolution of ASA.

[0070] In order to avoid hydrolysis of ASA, the pH of the solution obtained after adding and dissolving ASA in the aqueous solution should be above approx. 6.5, such as above approx. 6.8 or above approx. 7. Optimally, the pH of the solution obtained after adding and dissolving ASA in the aqueous solution should be in the range of approx. 7-8, especially approx. 7.7.

[0071] According to yet one aspect, when the salt of phosphoric acid is a hydrogen phosphate salt, the solution obtained upon mixing of the first and the second component provides a solution of ASA having a pH in the range of 7 - 8, especially approx. 7.7.

[0072] The final pH to be obtained after dissolution of ASA is in one aspect merely influenced by ASA and the salt of phosphoric acid.

[0073] The desired pH of the aqueous solution of the second component may furthermore be obtained by including a suitable pH regulating agent.

[0074] According to one embodiment, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate and/or tripotassium phosphate, or a combination thereof is used in the second component. According to yet another embodiment disodium hydrogen phosphate and/or trisodium phosphate is used in the second component.

[0075] A further aspect of the present invention is that the dissolution of ASA does not necessitate the use of a surfactant. According to one aspect of the present invention, the second component of the present two-component system comprises an aqueous solution optionally comprising one or more pharmaceutically acceptable excipients, provided that the one or more pharmaceutically acceptable excipient is not a surfactant.

[0076] A well know technique to increase the dissolution rate of a poorly soluble drug is micronization. When a drug is micronized the surface area of the drug is increased and the drug will thus dissolve more rapidly.

[0077] Thus, a further aspect of the present invention is to have micronize ASA in the first composition. Micronization of drug can sometimes lead to aggregation. If aggregation of micronized ASA occurs, a surfactant can be added to the first composition.

[0078] In order to preserve the aqueous solution comprised in the second composition/compartment of the two-component composition according to the present invention, one or more preservatives are added to the aqueous solution. Preservation of the aqueous solution is of especially relevance, when the salt of phosphoric acid is comprised in the first component or when only a little part of the salt of phosphoric acid is comprised in the second compartment.

[0079] Any pharmaceutical acceptable preservative being effective as preservatives at a pH of 7-8 may be used. According to one embodiment, parabens are used as preservative in the second component of the present two-component composition.

[0080] Parabens (hydroxybenzoates) is a class of preservatives commonly used in pharmaceutical compositions. Parabens are inter alia used in order to prevent growth of microorganisms and are active against a broad spectrum of microorganism. According to one aspect of the invention, parabens applicable as preservatives in accordance with the present invention may be selected from the group consisting of methylparaben, ethylparaben, and propylparaben.

[0081] Alternative preservatives besides parabens suitable for use in a two-component composition according to the present invention is preservatives being effective as preservative at a pH in the range of 4-10. A non-limiting example of an alternative preservative that may be used is benzalkonium chloride.

[0082] Some parabens may be poorly soluble in water. In order to provide a more convenient and efficient manufacturing process for the preparation of the aqueous solution of the second component of the present invention, an alkali salt of a paraben may be used. A sodium salt of a paraben is particularly applicable.

[0083] According to one aspect, the sodium salt of methyl paraben (Nipagin M sodium™) or the sodium salt of propyl paraben (Nipasol M sodium™) is used as a preservative in the aqueous solution of the second component of the present composition.

[0084] According to the present invention, the first component comprises a pharmaceutically effective amount of ASA. Said first component may comprise from 50 mg to 2000 mg ASA, such as 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg. For the purpose of treating imminent myocardial infarction or reducing the damages thereof, the first component of the present invention typically comprises from 300 to 325 mg of ASA.

[0085] 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. The skilled person will understand that said size of the device can vary simply depending on the exact design of the device. In order for the device to be easily carried by the broad population the volume of the second aqueous solution of the second component is typically 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 volume of the aqueous solution is in the range of 10-15 ml. According to one embodiment, the first component comprises from 100 mg to 600 mg, such as 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg ASA, which is to be dissolved in 6 - 50 ml of the aqueous solution of the second component of the present two-component composition.

[0086] According to another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises from 8 to 15 ml of the aqueous solution.

[0087] According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises approx. 8 ml of the aqueous solution.

[0088] According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises approx. 10 ml of the aqueous solution.

[0089] According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises approx. 11 ml of the aqueous solution.

[0090] According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises approx. 12 ml of the aqueous solution.

[0091] According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises approx. 14 ml of the aqueous solution.

[0092] According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises approx. 15 ml of the aqueous solution.

[0093] According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises approx. 16 ml of the aqueous solution.

[0094] According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises approx. 17 ml of the aqueous solution.

[0095] According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises approx. 18 ml of the aqueous solution.

[0096] According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises approx. 19 ml of the aqueous solution.

[0097] According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises approx. 20 ml of the aqueous solution.

[0098] According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises approx. 21 ml of the aqueous solution.

[0099] According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises approx. 22 ml of the aqueous solution.

[0100] According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises approx. 23 ml of the aqueous solution.

[0101] According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises approx. 24 ml of the aqueous solution.

[0102] According to yet another embodiment, the first component comprises from 300 to 325 mg ASA, and the second component comprises approx. 25 ml of the aqueous solution.

[0103] According to one embodiment, the present invention provides a two-component composition comprising a first and a second component, the first component comprising 300 - 325 mg ASA; and the second component consisting of from 8-15 ml of an aqueous solution consisting of 1 mg/ml of a paraben, such as methyl-p-hydroxy benzoate; and wherein a phosphate salt, such as disodium hydrogen phosphate, is comprised in either the first component or in the second component or in both the first and the second component; and wherein the pH obtained after dissolution of ASA in the second component is above approx. 6.5.

[0104] According to one aspect, a two-component composition is provided comprising a first component comprising ASA in the range of 300 - 325 mg, and a second component comprising an aqueous solution comprising disodium hydrogen phosphate; and wherein the pH obtained after dissolution of ASA in the second component is above approx. 7, i.e. between approx. 7 to 8, especially pH 7.7.

[0105] According to another aspect a two-component composition is provided comprising a first component comprising 300 mg ASA, and the second component comprising an aqueous solution comprising a salt of phosphoric acid, and wherein the pH obtained after dissolution of ASA in the second component is above approx. 7.

[0106] The present first and/or second component of the present two-component composition may optionally comprise further pharmaceutically acceptable excipients. For example, flavoring agents may be added 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. Non-limiting examples of compounds that may be used for the purpose of providing a certain taste is citric acid, acetic acid and lactic acid, peppermint essence or juice of fruit or berries, such as e.g. blackcurrant juice.

[0107] According to one aspect, a flavoring agent is added to the second component of the present two-component composition. For example, 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. Alternatively, 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.

[0108] 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 approx. 0.03 to 0.06 % (w/v) of the amount of second component.

[0109] The two component composition included in the present invention may be administered to the patient in need thereof using a device, capsule or container comprising said first component and the second component in separate departments or chambers of a device, capsule or container. A predetermined amount of the first component and predetermined amount the second component, will upon operation of the device, capsule or container 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.

[0110] For example, a container or capsule for segregated storage of two-component miscible substances as disclosed in WO00/66456 may be used in connection with the present invention for the treatment or prevention of myocardial infarction.

[0111] A package for keeping products separated before used as disclosed in WO98/38104 may also be applied for the purpose of present invention.

[0112] The skilled person will understand that a device, package, capsule or container for segregated storage of two-component miscible substances, such as a first component comprising a dry powder comprising ASA 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, container, package or device that will provide immediate dissolution of the ASA comprised in the first component composition upon mixing with the dissolution solution of the second component composition irrespective of the exact design of the capsule, container, package or device the two-components may be placed in as long as the two-components are separated during storage and prior to use.

[0113] The volume of the chamber of the capsule, container or storage device to be used with the present second component of the two-component composition is in size suitable for storage of an aqueous solution enabling the dissolution of the desired amount of ASA in accordance with the present invention. Similarly, the volume of the chamber of the capsule, container or storage device to be used with the present first component of the two-component composition of the present invention is in size suitable for storage of the desired amount of the first component.

Examples


Example 1 Preparation of two-component compositions according to the present invention



[0114] Aqueous solutions of salts of phosphoric acid were prepared by dissolving and mixing disodium hydrogen phosphate (Na2HPO4), or disodium hydrogen phosphate in combination with sodium dihydrogen phosphate (NaH2PO4), in water.

[0115] A device as disclosed in WO98/38104 provided by Bormioli Rocco S.p.A., Italy was used for the purpose of testing the dissolution characteristics of ASA in the phosphoric acid salt solutions.

[0116] 15 ml of the phosphoric acid salt solutions were filled into the container (bottle) of the test device (3phase kit with PET bottle, Bormioli Rocco S.p.A., Italy). 300 mg ASA was then placed in the powder compartment of the device. The cap comprising the powder compartment and the cutting element was assembled with the container comprising the solution.

[0117] The cap was then turned down until the seal keeping the powder and the solution separately was broken by the cutting element. The cutting of the seal resulted in that the ASA contained in the powder compartment was released into the solution in the container. The device was then shaken until all ASA was dissolved.

[0118] The results of the above testing, and the concentrations of the salt of phosphoric acid tested, is showed in table 1.
Table 1 Dissolution of 300 mg ASA in 15 ml phosphate solutions tested in the two component device
 Time for dissolution of 300 mg ASA in 15 ml phosphate solutionpH of the solutions after dissolution of ASA
0.5 M solution of Na2HPO4 within 30 sec. 7.14
0.45 M solution of Na2HPO4 within 25 sec. 7.0
phosphate buffer 1 M solution of Na2HPO4 and NaH2PO4 within 30 sec. 7.8


[0119] It is seen from table 1 that the aqueous solutions of disodium hydrogen phosphate provide a fast dissolution of ASA within 30 seconds.

[0120] Phosphate buffer 1 M solution of disodium hydrogen phosphate in combination with sodium dihydrogen phosphate also shows a fast dissolution of ASA. Further, phosphate buffers show increased hydrolytic cleavage of ASA (Bakar et al., J Pharm Sci., 1983 Sep, 72(9): 1024-6). However, this is not a problem since the product is to be consumed within a few minutes after dissolution.

Example 2 Further tests of salts of phosphoric acid solutions according to the present invention



[0121] Further aqueous solutions of salts of phosphoric acid were prepared. These phosphoric acid salt solutions were prepared in order to test the dissolution time of ASA at different final pH values i.e. the pH in the final ASA solution that are to be taken by the patient. Thus, the amount (mg) of the salt of phosphoric acid to be used was calculated based on the final pH to be obtained (theoretically pH).

[0122] In such calculations, general knowledge of pKa and molar mass (M) is used:

Acetylsalicylic acid: pKa 3.49, M = 180.16 g/mol

Phosphoric acid (H3PO4): pKa1 2.15, pKa2 7.19, pKa3 12.32, M = 97.99 g/mol

Disodium hydrogen phosphate (Na2HPO4): M = 141.96 g/mol

Trisodium phosphate dodecahydrate (Na3PO4·12H2O): M = 380.12 g/mol



[0123] In general, the pH in a dihydrogen phosphate / hydrogen phosphate buffer can be expressed as:

where pKa = -log(Ka) for H2PO4- = 7.2, n[HPO42-] = number of moles of HPO42- and n[NaH2PO4] = number of moles of NaH2PO4

[0124] For example, if the final pH to be obtained after dissolution of ASA theoretically is 7.2 and the aqueous solution of the second component comprises Na2HPO4, the amount of Na2HPO4 can easily be calculated as seem here:

If the desired pH is 7.2, substitution gives







where all mole numbers refer to what is in solution after chemical reaction.



[0125] From the reaction

         ASA + HPO42- → ASA- + H2PO4-

it follows that

where n(ASA)0, the starting number of moles of ASA is 0.00167 for an amount of 300 mg (Mw = 180.16 g/mol). From the mass balance



[0126] The starting number of moles of disodium hydrogen phosphate, n[Na2HPO4]0, for obtaining a pH of 7.2 is then equal to



[0127] The test device used in example 1 was used to test whether 300 mg ASA was dissolved within 25 seconds in 15 ml of different phosphoric acid salt solutions.

[0128] The results of the above testing, and the amount of the salts of phosphoric acid tested, are showed in tables 2 and 3.
Table 2 pH and dissolution of 300 mg ASA in 15 ml Na2HPO4 solutions in the two component device
pH (theoretically ) to be obtained after dissolution of ASAmol Na2HPO4 needed to obtain the theoretically pHmg Na2HPO4 needed to obtain the theoretically pH300 mg ASA in 15 ml solution dissolved within 25 secondsMeasured pH of the solutions after dissolution of ASA
7.2 3.34·10-3 474 Yes 7.0
7.7 6.67·10-3 950 Yes -
8.0 1.21·10-2 1730 Yes 7.7
Table 3 pH and dissolution of 300 mg ASA in 15 ml Na3PO4·12H2O solution in the two component device
pH (theoreticall y) to be obtained after dissolution of ASAmol Na3PO4·12H2O needed to obtain the theoretically pHmg Na3PO4·12H2O needed to obtain the theoretically pH300 mg ASA in 15 ml solution dissolved within 25 secondsMeasured pH of the solutions after dissolution of ASA
7.2 1.11·10-3 422 yes 7.6


[0129] It is seen from table 2 that ASA is dissolved in the Na2HPO4 solutions within 25 seconds when pH in the final solution is set to be between approximately 7 to 8.

[0130] The amount of Na2HPO4 needed increases tremendously if pH higher than 8 in the final solution is to be obtained. Thus, a pH above approximately 8 in the final solution is not practically reachable since the very high amount of Na2HPO4 needed is difficult to get dissolved.

[0131] Table 3 shows that ASA is dissolved in the Na3PO4·12H2O solution within 25 seconds when pH in the final solution is set to be approximately 7. A final pH of 9 or above in the final solution can simply be obtained and used in the present two component device when Na3PO4·12H2O or another phosphate salt is used.

Example 3 Salts of phosphoric acid comprised in the first component



[0132] In the following example 300 mg ASA and the salt of phosphoric acid is dissolved at the same time in 15 ml pure water.

[0133] First, the crystalline samples of ASA and disodium hydrogen phosphate (Na2HPO4) were crushed by hand with pestle and mortar into crystallites with typical sizes < 0.001 mm and < 0.03 mm, respectively (maximum sizes about 0.03 and 0.3 mm).

[0134] 300 mg of the crushed ASA and 1000 mg of the crushed hydrogen phosphate salt were placed in the powder compartment of the test device (3phase kit with PET bottle, Bormioli Rocco S.p.A., Italy), and 15 ml of pure water was filled into the container (bottle) of the device. The cap comprising the powder compartment and the cutting element was assembled with the container comprising the solution.

[0135] The cap was then turned down until the seal keeping the powder and the solution separately was broken by the cutting element. The cutting of the seal resulted in that the ASA and hydrogen phosphate salt contained in the powder compartment was released into the water in the container. The device was then shaken until all ASA was dissolved.

[0136] All ASA was dissolved within 30 sec. pH of the solution after dissolution of ASA and the hydrogen phosphate salt was 7.


Claims

1. A two-component composition comprising a first and a second component, wherein the first component comprises a therapeutically effective amount of acetylsalicylic acid (ASA) and optionally one or more pharmaceutically acceptable excipients; and wherein the second component comprises an aqueous solution and optionally one or more pharmaceutically acceptable excipients; and wherein at least one pharmaceutically acceptable salt of phosphoric acid is comprised in either the first component or in the second component or in both the first and the second component, and wherein the salt of phosphoric acid is selected from the group consisting of hydrogen phosphate salt and phosphate salt, and wherein the pH obtained after dissolution of ASA in the second component is above approx. 6.5.
 
2. A two-component composition according to claim 1, wherein said pharmaceutically acceptable salt of phosphoric acid is comprised in the aqueous solution of the second component.
 
3. A two-component composition according to any of claims 1-2, wherein the salt of phosphoric acid is a hydrogen phosphate salt and wherein the pH obtained after dissolution of ASA in the second component is between approx. 7 to 8, especially pH 7.7.
 
4. A two-component composition according to any of claims 1-2, wherein the salt of phosphoric acid is a phosphate salt.
 
5. A two-component composition according to claim 3, wherein the hydrogen phosphate salt is disodium hydrogen phosphate or dipotassium hydrogen phosphate, or a combination thereof.
 
6. A two-component composition according to claim 4, wherein the phosphate salt is trisodium phosphate or tripotassium phosphate, or a combination thereof.
 
7. 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.
 
8. A two-component composition according to any of the above claims for use in the treatment of imminent myocardial infarction.
 
9. A two-component composition according to claim 8, wherein the aqueous solution of acetylsalicylic acid is obtained within about 35 sec.
 
10. A container comprising a first and a second chamber, wherein the first chamber comprises a therapeutically effective amount of acetylsalicylic acid (ASA) and optionally one or more pharmaceutically acceptable excipients; and wherein the second chamber comprises an aqueous solution and optionally one or more pharmaceutically acceptable excipients; and wherein at least one pharmaceutically acceptable salt of phosphoric acid is comprised in either the first chamber or in the second chamber or in both the first and in the second chamber, and wherein the salt of phosphoric acid is selected from the group consisting of hydrogen phosphate salt and phosphate salt, and wherein the pH obtained after dissolution of ASA in the second chamber is above approx. 6.5.
 
11. A container according to claim 10, wherein said pharmaceutically acceptable salt of phosphoric acid is comprised in the aqueous solution of the second chamber.
 
12. A container according to any of claims 10-11, wherein the salt of phosphoric acid is a hydrogen phosphate salt such as disodium hydrogen phosphate or dipotassium hydrogen phosphate, or a combination thereof; and wherein the pH obtained after dissolution of ASA in the second chamber is between approx. 7 to 8, especially pH 7.7.
 
13. A container according to any of claims 10-11, wherein the salt of phosphoric acid is a phosphate salt such as trisodium phosphate or tripotassium phosphate, or a combination thereof.
 
14. Method for treating imminent myocardial infarct 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 - 14 or a two-chambered container according to any of the claims 18-23;

b) mixing the first component of said composition or the content of the first chamber of said container with the aqueous solution of the second composition or of the second chamber, respectively, and thereby obtaining an aqueous solution of acetylsalicylic acid;

c) administering to the person in need thereof the mixture obtained in step b)


 





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Cited references

REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description




Non-patent literature cited in the description