WO2014174405A1

WO2014174405A1 - Pharmaceutical preparation

Info

Publication number: WO2014174405A1
Application number: PCT/IB2014/060726
Authority: WO
Inventors: Johannes Arnoldus Vosloo WEBB; Basil FRANK
Original assignee: Individual
Current assignee: Individual
Priority date: 2013-04-22
Filing date: 2014-04-15
Publication date: 2014-10-30
Anticipated expiration: 2015-10-22
Also published as: ZA201506465B

Abstract

The invention discloses a pharmaceutical preparation in effervescent form for oral administration, which includes an antibiotic compound; an alkaline compound; an acid compound; and a disinfectant; and which preparation, when dissolved in water, results in a solution having a pH of less than 7. The antibiotic compound includes Amoxycillin trihydrate (C₁₆H₁₉N₃O₅S.3 H₂O), and/or sulphonamides and derivatives thereof combined with trimethoprim (cotrimoxazole), erythromycins and derivatives thereof, and/or any other suitable derivative of penicillin (e.g. cephalosporins), and/or a combination of penicillin and clavulanic acid or its salts (e.g. potassium clavulanate).

Description

PHARMACEUTICAL PREPARATION

FIELD OF INVENTION

The present invention relates to a pharmaceutical preparation. BACKGROUND TO INVENTION

Some antibiotic compounds, such as penicillin and penicillin derivatives, are unstable after having been reconstituted with water from a powder base. It is generally accepted that the reconstituted penicillin in suspension at room temperature (25°C) only has a shelf life of approximately seven days. The shelf life of a similar suspension stored in a refrigerator amounts to approximately fourteen days.

In many countries, especially those with third world communities, cooling facilities are not readily available. Often the patients reside far away from treatment centres, clinics and hospitals. Medicines, predominantly antibiotics, therefore have to be transported over long distances at temperatures, which are not favourable to the stability of the reconstituted antibiotic suspension, especially penicillin and its derivatives.

Another problem is the measurement of an exact dosage. An exact volume of bacteria- free water has to be added to the powder base to obtain the correct active ingredient per dose.

In almost all cases the therapeutic dosage of penicillin suspension is 5 millilitres and the entire course of 5ml dosages has to be completed. To measure out this exact volume before administration is problematic for many patients if not in possession of the correct measure. This is also very often interpreted as one teaspoon per administration - a volume of a teaspoon may vary between three and seven millilitres resulting in sub-therapeutic and supra-therapeutic plasma levels respectively of the active ingredient.

On standing the active ingredient may concentrate (together with other insoluble excipients) at the bottom of the suspension and if the reconstituted suspension is not thoroughly agitated prior to administration similar incorrect dosages will result. To worsen matters the bitter, unpleasant after-taste, typical of penicillin suspensions, leads to reluctancy for the patient to comply to the medication regime - if at all.

A further problem, in particular in under-developed countries or areas, is that sanitary conditions are detrimental to health, this including poor quality of drinking water available.

It is an object of the invention to provide a pharmaceutical preparation, which will assist in overcoming the previously mentioned problems.

SUMMARY OF INVENTION

According to the invention, a pharmaceutical preparation for oral administration is provided in effervescent form including an antibiotic compound, an alkaline compound, an acid compound, and a disinfectant, which preparation, when dissolved in water, results in a solution having a pH of less than 7, preferably a pH between 3,0 and 6,5.

Also according to the invention there is provided a pharmaceutical preparation for oral administration in effervescent form, which, in combination but separately includes, firstly, an antibiotic compound, an alkaline compound, an acid compound, which preparation, when dissolved in water, results in a solution having a pH of less than 7, preferably a pH between 3,0 and 6,5, and, secondly, a disinfectant.

The preparation may further include clavulanic acid or its salts (e.g. potassium clavulanate).

The antibiotic compound further may include Amoxycillin trihydrate (C16H19N3O5S.3H2O), and/or assulphonamides and derivatives thereof combined with trimethoprim (cotrimoxazole), erythromycins and derivatives thereof, or any other suitable derivative of penicillin (e.g. cephalosporins), or a combination of penicillin and clavulanic acid or its salts (e.g. potassium clavulanate).

The preparation may include Anti-Retrovirals.

The alkaline compound may be sodium bicarbonate. The preparation may include at least one binding agent, a sweetener, a surfactant, a glidant, a lubricant, a flavourant, a wetting agent, a colourant, and an antifoam agent in suitable quantities.

The acid compound may include citric acid monohydrate or anhydrous citric acid.

The disinfectant may be a chemical agent or combination of agents that destroy or inhibit the growth of pathogenic microorganisms in the non-sporing or vegetative state.

The disinfectants need not necessarily kill all microorganisms but reduce them to a level that is harmful to neither health, nor the quality of perishable goods.

The disinfectant may include agents used to treat inanimate objects and materials and may also include agents used to treat the skin and other body membranes and cavities.

The disinfectants may include chlorine-releasing disinfectants, such as chloramines, halazone, sodium dichloroisocyanurate and sodium hypochlorite.

Examples of iodine releasing disinfectants are tetraglycine hydroperiodide or iodine itself.

The disinfectant further may include any one or more selected from the group of alkylaryltrialkylammonium chloride, alkyltrimethylammonium chloride, benzalkonium chloride, benzoic acid and its salts, benzododecinium bromide, benzoxonium chloride, halazone, sodium dichloroisocyanurate. The salts thereof may be used or, alternatively, the following derivatives: dichloroisocyanuric acid, potassium dichloroisocyanurate, trichloroisocyanuric acid, and sodium hypochlorite.

In one application a preparation produced in accordance with the invention forms a suitable composition to be used for oral administration to adults, children and infants.

The preparation may include pro-biotics.

The preparation may include anti-inflammatories.

The preparation may include a further active pharmaceutical ingredient.

Yet further according to the invention, a pharmaceutical preparation, includes (a) a amoxycillin trihydrate (C16H19N3O5S.3H2O) as antibiotic compound;

(b) an alkaline compound;

(c) an acid compound; and

(d) a disinfectant; and which is provided as wafers and/or trans-dermal patches. DETAILED DESCRIPTION OF INVENTION

The invention will now be described by way of example.

According to the invention, a pharmaceutical preparation for oral administration is provided in effervescent form including Amoxycillin trihydrate (C16H19N3O5S.3H2O) as antibiotic compound, an alkaline compound, an acid compound, and a disinfectant, which preparation, when dissolved in water, results in a solution having a pH of less than 7, preferably a pH between 3,0 and 6,5.

The preparation further includes clavulanic acid or its salts (e.g. potassium clavulanate).

The antibiotic compound further includes sulphonamides and derivatives thereof combined with trimethoprim (cotrimoxazole), erythromycins and derivatives thereof, or any other suitable derivative of penicillin (e.g. cephalosporins), or a combination of penicillin and clavulanic acid or its salts (e.g. potassium clavulanate).

The preparation can include Anti-Retrovirals.

The alkaline compound is sodium bicarbonate.

The preparation includes at least one binding agent, a sweetener, a surfactant, a glidant, a lubricant, a flavourant, a wetting agent, a colourant, and an antifoam agent in suitable quantities.

The acid compound includes citric acid monohydrate or anhydrous citric acid. The disinfectant is a chemical agent or combination of agents that destroy or inhibit the growth of pathogenic microorganisms in the non-sporing or vegetative state.

The disinfectant include agents used to treat inanimate objects and materials and can also include agents used to treat the skin and other body membranes and cavities.

The disinfectants include chlorine-releasing disinfectants, such as chloramines, halazone, sodium dichloroisocyanurate and sodium hypochlorite.

The disinfectant further includes any one or more selected from the group of alkylaryltrialkylammonium chloride, alkyltrimethylammonium chloride, benzalkonium chloride, benzoic acid and its salts, benzododecinium bromide, benzoxonium chloride, halazone, sodium dichloroisocyanurate. The salts thereof may be used or, alternatively, the following derivatives: dichloroisocyanuric acid, potassium dichloroisocyanurate, trichloroisocyanuric acid, and sodium hypochlorite.

The preparation in accordance with the invention may be provided in water soluble and/or water soluble effervescent tablet, powder or granular form. When in powder or granular form it may be packed in suitable quantities in sachets and/or other suitable containers.

The preparation in accordance with the invention therefore can be stored and transported easily, is not as reactive to temperatures as is the case with liquid preparations, and accurate doses can be taken even by the most unsophisticated persons because each tablet or sachet with powder or granules contains the exact quantity of active ingredient. An exact measuring device such as a calibrated teaspoon can be included in the final package if the dosage form is supplied as bulk water soluble powder or granules.

Furthermore, any water used for taking the preparation should be suitably disinfected if possible.

Example

The invention will now be described by way of an example.

According to an example in accordance with the invention, the preparation may have the following composition in proportions by mass (Pilot batch Scale for 1 000 tablets):

Constituents

Chemical name Approved name (if any) Quantity Active Purpose if or Inactive inactive

(6R)-6-(a-D-p-hydroxyphenyl Amoxycillin Trihydrate 0,1440 kg Active

glycylamino) pennicillanic (equivalent to anhydrous

acid trihydrate Amoxycillin)

Citric acid Monohydrate Citric Acid Monohydrate 0,9458 kg Inactive Effervescent agent

Povidone 1 -Vinyl-2-pyr-rolidinone 0,21 13 kg Inactive Binder

polymer

Sodium Bicarbonate Sodium Bicarbonate 1 ,0000 kg Inactive Effervescent agent

L-aspertyl-L-phenylalanine Aspartame 0,1069 kg Inactive Sweetener methyl ester

Sodium Lauryl Sulphate Sodium Lauryl Sulphate 0,0080 kg Inactive Surfactant Magnesium Stearate Magnesium Stearate 0,0016 kg Inactive Glidant

Raspberry Flavour Raspberry Flavour 0,0400 kg Inactive Flavourant

Polyethylene Glycol 4000 Macrogol 4000 0,0071 kg Inactive Wetting agent and Lubricant

Ethanol (96%) Ethanol (96%) 0,10001 Inactive Wetting agent

Polyethylene Glycol 6000 Macrogol 6000 0,0300 kg Inactive Wetting agent and lubricant

Azorubin Disodium salt of 2-(sulfo 1 - 0,0050 kg Inactive Colourant naphthyl-2-azo) -1 - naphthol-4- sulphonic acid,

CI number 14720

Silica-filled Polydimethyl- 0,0003 kg Inactive Antifoam siloxane agent

Disinfectant See Note below

Clavulanic acid or its salts See Note below

Purified water Purified water 0,00331 Inactive Wetting agent

Total mass per tablet (without water and ethanol (96%): 2,5000g

Total mass of granules (excluding water and ethanol (96 %): 2,5000kg General note:

1 . Ethanol (96 %) and purified water are used as wetting/ granulating agents and are removed during the manufacturing process.

2. The total mass Amoxyllin Trihydrate per tablet is 0,1440g, equivalent to 0,1250g Anhydrous Amoxycillin.

Note on Disinfectant:

The disinfectants need not necessarily kill all micro-organisms but reduce them to a level that is harmful to neither health, nor the quality of perishable goods.

The disinfectants may include chlorine-releasing disinfectants, such as chloramines, halazone, sodium dichloroisocyanurate and sodium hypochlorite, calcium hypochlorite.

The salt of clavulanic acid may be in the form of potassium clavulanate. Example of Preparation

An example of the preparation of a trial batch of 1 100 tablets of 2500 mg per tablet in accordance with the invention is as follows:

Important:

1 . The temperature is to be not less than 20°C and not more than 25°C.

2. Admixing is carried out in conditions with low relative humidity of not more than 48 % RH.

The manufacturing steps are as follows:

1 . Measure the mass of polyethylene glycol 4000 (0,0078Kg).

2. Measure the volume of ethanol (96%) 0,0484 litres.

3. Add (2) to (1 ) in a suitable Erienmeyer flask and heat on water-bath to 60°C with constant stirring until dissolved and determine volume.

4. (3) is solution I.

5. Measure the mass of polyethylene glycol 6000 (0,0330Kg).

6. Measure the mass of Azorubin (0,0055Kg).

7. Measure the mass of Silica-Filled Polydimethylsiloxane (0,0003Kg).

8. Measure the mass of purified water (0,0036 litres).

9. Measure the volume of ethanol (96 %) (0,0616 litres).

10. Add (5), (6) and (7) to a suitable Erienmeyer flask containing (8) and (9) and heat on a water-bath to 65°C with constant stirring until completely dissolved and determine volume.

1 1 . (10) is solution II.

12. Measure the mass of amoxycillin trihydrate (0,1584Kg). Measure the mass of Povidone (0,0495Kg). Add (13) to (12) in a suitable stainless steel container and mix with Hobard mixer or suitable equivalent for 30 minutes. Wet powder mixture (14) with solution I in a suitable stainless steel container with Hobard mixer or equivalent until granules appear to be of even size. Dry granules obtained in (15) in Labcon FSOH or other suitable convection over for 48 hours at not more than 25°C until loss or drying is less than 1 ,000 % (or at 50° for six hours). Pass through 700μιη sieve to obtain granules. Ascertain mass of granules is (0,2157Kg). (18) is granule I. Measure the mass of citric acid monohydrate (1 ,0404Kg). Measure the mass of povidone (0,0550Kg). Mix with in suitable stainless steel container with Hobard or suitable mixer for 30 minutes. Wet mixture obtained in (22) with approximately 44 % of solution II and mix in suitable stainless steel container with Hobard or suitable mixer until granules appear to be of even size. Dry in a Labcon or other suitable convention over for 48 hours at not more than 35°C until loss on drying is less than 1 ,000 % (or at 50° for six hours). Pass through a 700 μιη sieve. Ascertain mass granules approximately (1 ,1 125Kg). (26) is granule 2. Measure the mass of sodium bicarbonate (O,7335Kg). Measure the mass of aspartame (0,1 176Kg). Measure the mass of Povidone (0,0729Kg). Mix (28), (29) and (30) in a suitable stainless steel container with Hobard or other suitable mixer for 30 minutes. Wet mixture obtained in (31 ) with 56% of solution II and mix in suitable stainless steel container with Hobard or other suitable mixer until granules appear to be of even size. Dry in a Labcon or other suitable convention oven for 48 hours at not more than 35°C until loss on drying is less than 1 ,000 %. Pass granules through 700 μιη sieve. Ascertain mass granules approximately (0,9457g). (35) is granule III. Measure the mass of sodium bicarbonate (0,3665Kg). Measure the mass of sodium lauryl sulphate (0,0088Kg). Measure the mass of magnesium stearate (0,0018KG). Measure the mass of raspberry flavour (0,0440Kg). Measure the mass of Povidone (0,0550Kg). Mix (37), (38), (39) (40) and (41 ) in a suitable stainless steel container with Hobard or other suitable mixer for 30 minutes. Add to mixture obtained in (42) to granules I, II and III in suitable stainless steel container and mix with Hobard or other suitable mixer for 30 minutes. Ascertain total mass granules (2,750Kg). Add disinfectant as required. 46. Add the clavulanic acid or salt(s) as required.

47. Note:- The clavulanic acid or salt(s) as well as the disinfectant may be included at any time during the production procedure as practically required.

48. Compact into tablets with aid of 16 station Cadmac or other suitable tableting machine equipped with 24mm punches and dyes to hardness of not less than 8,42Kp (84,2N) and not more than 1 1 ,39Kp (1 13,9N) and thickness of not less than 3,80mm and not more 4,20mm. Tablet mass to be not less than 2,2508g and not more than 2,752g.

The tablet should dissolve in a suitable quantity (about 50 ml) of water in less than 5 minutes resulting in a pH of not less than 5,04 and not more than 6,16, and being in the form of a red clear solution with pink foam layer having a raspberry odour and tasting sweet raspberry flavour. Note: It is suggested that the pH should not be less than 3,0 and not more than 6,5.

Dosage and directions for use:

Adults: Dissolve two effervescent tablets completely in 100ml water (approximately half a glass) and drink entire volume immediately. Repeat every 8 hours.

Children two to ten years: Dissolve one effervescent tablet completely in 50ml water (approximately quarter of a glass) and drink entire volume immediately. Repeat every eight hours.

Children from six months to two years: Dissolve one effervescent tablet in 50ml of water (approximately a quarter of a glass) and give entire volume immediately. Repeat every eight hours for five days.

The disinfectant for the water can be included in the tablet or can be provided as a separate tablet, powder or granule. The disinfectant tablet, powder or granule can be used to disinfect the water before adding the antibiotic tablet powder or granule, or alternatively the two tablets powders or granules can be added simultaneously to the water. In the latter case, the two tablets, powders or granules could be placed side- by-side to facilitate use by uneducated persons. Similarly, the disinfectant may also be provided in powder or granular form packed into sachets or other suitable dosage form and placed side-by-side to facilitate use by uneducated persons.

The clavulanic acid or its salts (e.g. potassium clavulanate) may be included in the tablet or can be provided as a separate tablet powder or granule. The two tablets may be added simultaneously to the water. In the latter case uneducated persons could place the two tablets side by side to facilitate use. Similarly, the clavulanic acid or its salts may also be provided in powder or granular form packed into sachets or other suitable dosage form and placed side-by-side to facilitate use by uneducated persons.

The afore-mentioned antibiotics are "fat-soluble", i.e. not water-soluble, such as Eritromycin. The invention also suggests to make a fat-soluble substance completely soluble/mixable with water. The latter is based on the requirements of the solubility of ARVs.

Claims

PATENT CLAIMS

1 . A pharmaceutical preparation in effervescent form for oral administration, which includes

(a) an antibiotic compound;

(b) an alkaline compound;

(c) an acid compound; and

(d) a disinfectant; and which preparation, when dissolved in water, results in a solution having a pH of less than 7.

2. A preparation as claimed in claim 1 , in which the pH is between 3,0 and 6,5

3. A preparation as claimed in claim 1 or claim 2, which includes clavulanic acid and/or its salts.

4. A preparation as claimed in claim 3, in which the salt is potassium clavulanate.

5. A preparation as claimed in any one of the preceding claims, in which the antibiotic compound includes Amoxycillin trihydrate (C16H19N3O5S.3H2O), and/or sulphonamides and derivatives thereof combined with trimethoprim (cotrimoxazole), erythromycins and derivatives thereof, and/or any other suitable derivative of penicillin (e.g. cephalosporins), and/or a combination of penicillin and clavulanic acid or its salts (e.g. potassium clavulanate).

6. A preparation as claimed in any one of the preceding claims, which includes Anti- Retrovirals.

7. A preparation as claimed in any one of the preceding claims, in which the alkaline compound is sodium bicarbonate.

8. A preparation as claimed in any one of the preceding claims, which includes at least one binding agent, a sweetener, a surfactant, a glidant, a lubricant, a flavourant, a wetting agent, a colourant, and/or an antifoam agent in suitable quantities.

9. A preparation as claimed in any one of the preceding claims, in which the acid compound includes citric acid monohydrate and/or anhydrous citric acid.

10. A preparation as claimed in any one of the preceding claims, in which the disinfectant is a chemical agent or combination of agents that destroy or inhibit the growth of pathogenic microorganisms in the non-sporing or vegetative state.

1 1 . A preparation as claimed in any one of the preceding claims, in which the disinfectants need not necessarily be capable of killing all microorganisms but reduce them to a level that is harmful to neither health, nor the quality of perishable goods.

12. A preparation as claimed in any one of the preceding claims, in which the disinfectant includes agents used to treat inanimate objects and materials and may also include agents used to treat the skin and other body membranes and cavities.

13. A preparation as claimed in any one of the preceding claims, in which the disinfectants include chlorine-releasing disinfectants.

14. A preparation as claimed in claim 13, in which the chlorine-releasing disinfectants include chloramines, halazone, sodium dichloroisocyanurate and/or sodium hypochlorite.

15. A preparation as claimed in any one of the preceding claims, in which the disinfectants include iodine releasing disinfectants.

16. A preparation as claimed in claim 15, in which the iodine releasing disinfectants include tetraglycine hydroperiodide and/or iodine itself.

17. A preparation as claimed in any one of the preceding claims, in which the disinfectant includes at least one selected from the group consisting of alkylaryltrialkylammonium chloride, alkyltrimethylammonium chloride, benzalkonium chloride, benzoic acid and its salts, benzododecinium bromide, benzoxonium chloride, halazone, sodium dichloroisocyanurate.

18. A preparation as claimed in claim 17, which includes salts of the disinfectant.

19. A preparation as claimed in claim 17, which includes the following derivatives: dichloroisocyanuric acid, potassium dichloroisocyanurate, trichloroisocyanuric acid and/or sodium hypochlorite.

20. A preparation as claimed in any one of the preceding claims, which is adapted for oral administration to adults, children and/or infants.

21 . A preparation as claimed in any one of the preceding claims, which includes pro- biotics.

22. A preparation as claimed in any one of the preceding claims, which includes antiinflammatories.

23. A preparation as claimed in any one of the preceding claims, which includes a further active pharmaceutical ingredient.

24. A pharmaceutical preparation, which includes

(a) a amoxycillin trihydrate (C16H19N3O5S.3H2O) as antibiotic compound;

(b) an alkaline compound;

(c) an acid compound; and

(d) a disinfectant; and which is provided as wafers and/or trans-dermal patches.

25. A pharmaceutical preparation substantially as hereinbefore described.