GB2100982A - Antibronchospastic water-soluble pharmaceutical compositions - Google Patents
Antibronchospastic water-soluble pharmaceutical compositions Download PDFInfo
- Publication number
- GB2100982A GB2100982A GB08217983A GB8217983A GB2100982A GB 2100982 A GB2100982 A GB 2100982A GB 08217983 A GB08217983 A GB 08217983A GB 8217983 A GB8217983 A GB 8217983A GB 2100982 A GB2100982 A GB 2100982A
- Authority
- GB
- United Kingdom
- Prior art keywords
- antibronchospastic
- pharmaceutical
- composition
- theophylline
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Antibronchospastic water-soluble compositions comprise the compounds formed from theophylline and amino acids, e.g. lysin or arginine.
Description
SPECIFICATION
Antibronchospastic water-soluble pharmaceutical compositions.
The present invention relates to antibronchospastic water-soluble theophylline salts with basic amino acids. More particularly the invention pertains to pharmaceutical compositions consisting of theophylline water-soluble salts with lysine and arginine and to a process for preparing the same.
It is well known from the prior art pertaining to bronchodilator pharmaceutical preparations that the theophylline (1,3-dimethylxanthine) is a natural substance characterised by significant antibronchospastic properties to be ascribed to the inhibition ofthe phosphodiesterase and to the increase of the intracellularAMPC.
However, it is likewise known that the low watersolubility oftheophylline does not allow the preparation of solutions having therapeutically significant concentrations so as to confine its use to preparations in the form of capsules, tablets and suppositories.
The procedures usually adopted at the present time to obtain a therapeutically acceptable watersolubility are based on the salification ofthe theophylline by means of organic bases such as ethylenediamine, choline, glucamine, and the products obtained thereby are well known and have long been used in theraputic practice.
However it is to be pointed out that it has resulted from the clinical use, these products are not free from toxicity phenomena and in many cases do not have an acceptable tolerance.
Therefore it will be easily understood the increasing demand for a theophylline composition in which the necessary water-solubility is associated to a minor toxicity and an improved tolerance.
It appears that this problem may be satisfactory solved according to the present invention of preparing theophylline salts with basic amino acids, preferably lysine or arginine, which are pharmaceutically acceptable for producing pharmaceutical preparations having a theophyllinic activity.
The suggestion of utilising the lyophilised form is of great importance to allow the use of the composition in an aqueous solution, assuring an improved stability of the active constituent.
Accordingly it is the main object of this invention to provide an antibronchospastic, water-soluble composition consisting of theophylline salts with a basic amino acid. In the preferred embodiment, as aforesaid, lysine or argine is used as the basic amino acid.
The present invention will be now described in the following Examples with particular reference to some preferred embodiments.
Example 1.
Lysine Theophyllinate
Empirical formula : C13Hy-N0O4 Structural formula:
Molecular weight 326.36 N contents : 25.76% Composition : Theophylline 55.21%, Lysine 44.79%
Preparation process.
180.179 (1 mole) oftheophylline and 219.209 (1.5 moles) of lysine are hot-dissolved in 400ml of H20.
The solution is concentrated under vacuum until dryness, the bath temperature being kept lower than 50"C.
The residue is crystallised from 4.5 1 of 96% ethyl alcohol. The precipitate, obtained by cooling the solution under stirring, is filtered.
260 9: Yield 80% mp:195-205 C (decomposition)
Example II
Arginine Theophyllinate.
Empirical formula : CT3H22N804.H20 Structural formula:
Molecular weight :372/38 N Contents : 30.09% Composition : Theophylline 48.38%, Arginine
46.78%H20 4.84%.
Preparation process.
180.17 g (1 mole) oftheophylline and 174.20 g (1
mole) of arginine are hot-dissolved in 800 ml of H20.
The cooling of the solution forms a crystalline pre
cipitate (320 g) having a melting point of 200-205"C (decomposition). Yield 86%.
The identity and purity of the salts can be deter
mined by the following analytical operations:
(a) nitrogen test according to the Dumas method
(b) titration of amine nitrogen by the poten
tiometric method in anhydrous environment (sol
vent: glacial acetic acid) by means of HC104 0.1 N in
glacical acetic acid.
(c) UV spectrophotometric titration in HC1 0.1 N.
The pharmaceutical activity has been preliminarily ) checked by the determination of: LD0peros in the mouse
Lysine theophyllinate 1.12 m Mole/kg
Arginine theophyllinate 1.75 m Mole/kg
Antibronchospastic activity in awake guinea-pigs z according to the modified Armitage's method (Brit.
J. Pharmacol. 16, 1961); the activity is expressed as an index with respect to the theophylline made
equal to 1.
Lysine theophyllinate 1.08 ) Arginine theophyllinate 0.8
Some data relevant to tests made in animals and
in men by using the pharmaceutical compositions of
the invention are reported herebelow.
The lysine theophyllinate has been administered
peros during 3 months to male and female Wistar
rats at the doses of36-145 mg/Kg/pro die.
The comparison with control animals has given
evidence of its good tolerance.
Subsequently the pharmeceutical composition
has been tested in clinical practice in 3 groups of
patients of paediatric age between 8 months and 13
years, suffering from asth matic affections. These
are determined:
- Respiratory functionality
- Hematologic and hematochemical values
- Hematic rates and, only in a group, the concent
ration oftheophylline in the saliva
- Cardiocircularity effects
- Tolerance.
In all the tests, the composition according to the
invention has been administered in the form of
drops and tablets every 6-8 hours at a dose of 4-6
mg/kg depending on the patient's age.
The pharmaceutical composition of the invention
has always dominated the symptomatology and
obtained a significant improvement ofthe
hemogasmetering and ventilation parameters.
The best absorption of the active constituent in the
administration is in the form of drops and tablets,
which may be otherwise deducted from the study of
the hematic levels of theophylline.
There is additionally an excellent gastroenteric
tolerance and an absence of clinical significant alter ationswith respect to the biohumoral parameters
under consideration.
The salts which form the object of the present
invention can be utilised in pharmaceutical prepara
tions as capsules, tablets, sugar-coated pills,
retarded release tablets and capsules, drops, syrups,
phials, and suppositories suited to administration in
human therapy.
The following Examples illustrate some preferred
preparations obtained by utilising the products of
the invention.
Example Ill.
Lysine theophyllinate
Divisible tablets for paediaric therapy.
Each divisible tablet contains: Lysinetheophyllinate mg 182
(corresponding to 100 mg of anhydrous theophylli
nate)
Starch mg 36
Carboxymethylcellulose mg 8
Talc mg 10
Magnesium stearate mg5.
Drops for pediatric use.
Each bottle containing lyophilized lysine theophyl
linate has the following composition:
Lysine theophyllinate mg 725 (corresponding to 400 mg of anhydrous theophyl
line)
Mannite mg 800
Each solvent bottle contains:
Alcohol (96%) ml 2
Purified water q. s. to 10 ml.
Claims (12)
1. An antibronchospastic pharmaceutical, water-soluble composition comprising a theophylline salt with a basic amino acid.
2. An antibronchospastic pharmaceutical composition as claimed in claim 1 and offormula:
in which the basic amino acid is lysine.
3. An antibronchospastic pharmaceutical composition as claimed in claim 1 and of formula:
in which the basic amino acid is arginine.
4. Antibronchospastic pharmaceutical preparations comprising a theophyllinic water-soluble composition as claimed in claim 1.
5. Antibronchospastic pharmaceutical preparations comprising a theophylline salt with lysine as claimed in claim 2.
6. An antibronchospastic pharmaceutical preparation comprising a theophylline salt with arginine as claimed in claim 3.
7. An antibronchospastic pharmaceutical preparation as claimed in any one of claims 4 to 6, and suited to the parenteral, oral, or rectal administration.
8. Lyophilised antibronchospastic pharmaceutical preparations as claimed in any one of claims 4 to 6, and suited to the oral and parenteral administration.
9. A process of preparing a composition as claimed in claim 2, comprising the steps of concentrating to dryness an aqueous solution of theophylline and lysine in a molar ratio of 1 1.5 and crystallising the residue from 96% ethanol.
10. A process of preparing the composition as claimed in claim 3, comprising the step of precipitat ing ing arginine theophyllinate from a hotsaturated, aqueous solution of theophylline and arginine in a molar ratio of :1.
11. An antibronchospastic, pharmaceutical water-soluble composition comprising a theophylline salt with a basic amino acid substantially as described hereinabove and with reference to the
Examples.
12. A process of preparing an antibronchospastic, pharmaceutical water-souble composition comprising a theophylline salt with a basic amino acid substantially as described hereinabove and with reference to the Examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT48730/81A IT1171321B (en) | 1981-06-22 | 1981-06-22 | WATER-SOLUBLE ANTIBRONCOSPASTIC PHARMACEUTICAL COMPOSITIONS CONSTITUTED BY THEOPHYLLINE SALTS WITH BASIC AMINO ACIDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2100982A true GB2100982A (en) | 1983-01-12 |
Family
ID=11268293
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08217983A Withdrawn GB2100982A (en) | 1981-06-22 | 1982-06-22 | Antibronchospastic water-soluble pharmaceutical compositions |
Country Status (6)
| Country | Link |
|---|---|
| BE (1) | BE893562A (en) |
| DE (1) | DE3223485A1 (en) |
| ES (2) | ES513302A0 (en) |
| FR (1) | FR2507892B1 (en) |
| GB (1) | GB2100982A (en) |
| IT (1) | IT1171321B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7452916B2 (en) | 1993-06-11 | 2008-11-18 | The Board Of Trustees Of The Leland Stanford Junior University | Enhancement of vascular function by modulation of endogenous nitric oxide production or activity |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0441119A3 (en) * | 1990-01-09 | 1992-10-14 | Richard D. Levere | The use of l-arginine in the treatment of hypertension and other vascular disorders |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB624696A (en) * | 1945-09-06 | 1949-06-15 | John Christian Krantz | Improvements in or relating to method of preparing a stable aqueous theophylline solution and the product resulting therefrom |
| US2711409A (en) * | 1951-06-07 | 1955-06-21 | Chattanooga Medicine Co | Salts of 8-halotheophylline and alkali metal salts of amino acids |
| FR91M (en) * | 1960-07-29 | 1961-01-09 | ||
| FR952M (en) * | 1961-02-28 | 1961-11-20 | ||
| FR2531713A2 (en) * | 1981-09-16 | 1984-02-17 | Panmedica Sa | New compositions based on 5-hydroxytryptophan, process for preparing them and medicaments containing them |
-
1981
- 1981-06-22 IT IT48730/81A patent/IT1171321B/en active Protection Beyond IP Right Term
-
1982
- 1982-06-18 DE DE19823223485 patent/DE3223485A1/en not_active Ceased
- 1982-06-18 BE BE0/208385A patent/BE893562A/en not_active IP Right Cessation
- 1982-06-18 FR FR8210634A patent/FR2507892B1/en not_active Expired
- 1982-06-21 ES ES513302A patent/ES513302A0/en active Granted
- 1982-06-22 GB GB08217983A patent/GB2100982A/en not_active Withdrawn
-
1983
- 1983-08-31 ES ES525280A patent/ES525280A0/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7452916B2 (en) | 1993-06-11 | 2008-11-18 | The Board Of Trustees Of The Leland Stanford Junior University | Enhancement of vascular function by modulation of endogenous nitric oxide production or activity |
Also Published As
| Publication number | Publication date |
|---|---|
| BE893562A (en) | 1982-10-18 |
| ES8502611A1 (en) | 1985-01-16 |
| IT1171321B (en) | 1987-06-10 |
| FR2507892A1 (en) | 1982-12-24 |
| FR2507892B1 (en) | 1986-06-27 |
| ES525280A0 (en) | 1985-01-16 |
| DE3223485A1 (en) | 1983-01-05 |
| IT8148730A0 (en) | 1981-06-22 |
| ES8401320A1 (en) | 1983-12-16 |
| ES513302A0 (en) | 1983-12-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |