JPH0256425A - Antitussive oral composition - Google Patents

Abstract

PURPOSE: To orally administer a tryptophan-contg. medicinal composition for antitussive therapy. CONSTITUTION: This composition, which contains tryptophan as active ingredient, is obtained by incorporating the active ingredient with pref. an antitussive agent for oral use (e.g. dextromethorphan (salt)) and also common medicinal support at one's discretion followed by pharmaceutical manufacturing by conventional means. In this case, the weight ratio of the tryptophan to antitussive agent is (2:1) to (5,000:1), and these two ingredients account for 5-95wt.% and 1-50wt.% of this composition for solid and liquid formulations, respectively. The solid formulations include tablets, capsules, granules, lozenges and bulk powders, while, the liquid formulations include solutions, suspensions, syrups and emulsions. The daily dose of this composition is 2.0-3,000mg/kg.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to antitussive oral pharmaceutical compositions containing tryptophan.

BACKGROUND OF THE INVENTION The cough reflex is an essential mechanism by which secretions from the lungs and trachea are removed. Generally, such secretions are removed by capillary muscle escalators. However, if this mechanism is defective or becomes difficult to counteract, for example due to excessive secretion, cough becomes the primary means of secretion removal.

The cough reflex is initiated by stimulation of mechanical receptors and is controlled by afferent pathways in the vagal (X), 8-pharyngeal (IX), and upper laryngeal nerves to the cough center in the brainstem. Coughing is caused, for example, by foreign bodies, dirt, debris, mucus, gas, and smoke in the lower respiratory tract. Irritation of various sensory nerves in the nose, sinuses, pharynx, ear, stomach, pericardium, or diaphragm can also produce cough. However, in many of these conditions, chronic or paroxysmal cough becomes tiring and debilitating, especially if it impairs sleep.

Oral cough preparations such as tablets, lozenges, syrups, solutions, suspensions, etc. containing effective antitussive agents have been used for a long time to relieve cough symptoms. The most popular of such preparations contain either dextromethorphan (or its hydrobromide salt) or codeine (or its sulfate salt) as the active antitussive agent. These treatments, among many others, have been developed by Drug Evaluations (Dr.
ugEvaluations), 6th edition, Chapter 21 [American Medical Φ Association (Ameri
can MedicalAssoclaLIon),
1986].

Tryptophan has now been discovered to have antitussive activity in humans and lower animals. Although the use of tryptophan in cough suppressants has not yet been reported, tryptophan has been used extensively in medicines [e.g., Spinweber, Psychopharm But Ietln,
Volume 17, page 81, 1981 and Smi
th) and Prokup, Niney・
England Journal of Medicine (Ncw)
IEngland Journal of' MCdi
cine), Vol. 267, p. 1338, 1982] or Calcium (Wyatt, U.S. Special Kitsuki 4,419, published December 6, 1983).
, No. 345] and carbohydrates (September 14, 1983)
Sleep inducers effective in combination with other substances such as Wurtman European Patent Application No. 88,621 published on
See U.S. Pat. No. 4,210.637 of Wardman et al., July 1, 1980; (The Extra
Pharmacopeja), 28th edition, No. 61-2
Page, Pharmaceutical Press (Phariac)
(see Eutjcal Press), 1982]
It was found that

The usefulness of tryptophan in the above disorders is due to the fact that serotonin is synthesized from tryptophan in the following metabolic pathway: Nitributophane 5-Hydroxytryptophan H 5-Hydroxy Tryptamine (Serotonin) Kamei et al. have shown that the serotonergic system plays a role in regulating the cough reflex [E1 Book Journal of Pharmacology, Vol. 42, No. 450, 198
6th year (Japan Journal orPharn+
aco1ology, 42:450, 19g [i)] In another study, Kamei et al. showed that 5-HTP administration led to a significant increase in brain serotonin content and activity.
, 'Dose-response relationship between systemically administered monotryptophan or oral L-5-hydroxytryptophan and Raphe unit activity in rats', Neuropharmacology, Vol. 15, p. 339.

Despite the fact that serotonin's direct precursor 5-hydroxytryptophan (5-HTP)
) was shown to not significantly suppress the cough hoe reflex (Japanese Journal of Pharmacology, Vol. 42, p. 531, 1986).

Therefore, it was unexpected that tryptophan, but not 5-HTP, significantly suppressed the cough reflex.

Therefore, it is an object of the present invention to provide tryptophan serum oral pharmaceutical compositions with high efficacy in cough treatment.

SUMMARY OF THE INVENTION The present invention relates to a method for treating cough in humans or animals, which method is characterized by orally administering to said humans or animals a safe and effective tryptophan-containing pharmaceutical composition.

All percentages and ratios used herein unless otherwise indicated! I! According to H.

DETAILED DESCRIPTION OF THE DEVELOPMENT The present invention provides a method for treating cough in humans or animals such as animals by administering a safe and effective amount of a pharmaceutical composition containing tridi1fan to the human or animal in need of treatment. Concerning stop treatment methods. The amount of pharmaceutical composition administered depends on the amount of tryptophan required per dose, its stability, release characteristics, and the tryptophan percentage in the formula, which is a function of other pharmaceutical parameters. Usually about 2 to 300
0 mg/kK/day, preferably from about 6 to about 360111 kg/day, most preferably from about 14 to about 180 mg/kg/day.
kg/day of tryptophan is administered as described herein. The child can be given once or preferably repeatedly in multiple doses (2-6) or by sustained release administration over the course of treatment. Generally, each individual dose of a pharmaceutical composition of the invention will be about 1.0 to about 500 mg/kg, preferably about 3 to about 60 mg/kg.

Most preferably within the range of about 7 to about 30 mg/kg. Higher doses than those listed above are effective in preventing cough, but the same precautions as with any drug must be taken in some individuals to prevent side effects.

By safe effective mouth is meant a melon that exhibits antitussive efficacy and can thereby relieve or prevent coughs with a reasonable benefit/risk ratio, as in any medical treatment.

Obviously, the antitussive pharmaceutical composition to be administered will depend on the specific condition to be treated, the extent of the condition to be treated, the duration of treatment, the physical condition of the patient, the nature of the concomitant therapy (if any), the use of It will vary depending on factors such as the particular treatment and carrier used, and the solubility and concentration of the pharmaceutical composition used.

Tryptophan is known as Nitryptophan. It is generally believed that the biologically active isomer of tryptophan is in the L configuration. Tryptophan is commercially available, for example, from Ajinomoto Co. (1 bottle, Tokyo).

Several drugs have been shown to increase plasma and/or brain tryptophan concentrations, and these can be included in the desired formulation. Examples of these compounds include lithium, sodium salicylate, aminophylline and clofibrate;
Curzon, G.) and No. yt.

P, J, (Kott, P, J,), “Environmental 1.B Physical and Related Aspects of Tryptophan Metabolism with respect to the Central Nervous System” CRC Critical Reviews in Tokincology.
ies in Toxicology).

Vol. 5, p. 187, 1977; Getsa, G.

L. (Gessa, G., I.) and Tagliamont, A.

(TagliamonLe, A,), “Serum af!
11) Liptophan: tryptophan brain concentration and 5-
Aromatic amino acids in the brain control hydroxytryptophan synthesis.
c1ds In the I)raln).

1974, Ciba ψ Foundation Symposium (
C1ba Foundation SymposluL
ll>, Elsevler; Gessa, G. L., and Tagliamont, A., “Possible role of free serum tryptophan on the control of brain tryptophan levels and serotonin synthesis”, Atopanses in Biochemicals. Psychopharmacology (Advances In Bloch)
cIlical Psychopharmacolog
y).

Vol. 11, p. 119, 1974.

All of the above is incorporated herein by reference.

Preferably, tryptophan is administered with a safe dose of an oral antitussive. As used herein, the term "oral antitussive" refers to a drug that is taken orally and acts systemically to relieve cough [Federal Register]
Federal? egisLer).

52, No. 155, August 1987, 121-1, page 30055].

Oral antitussives approved for use in A are not particularly limited, and include, for example, dextromethorphan and its acid salts, preferably hydrobromic acid, clofibrate hydrochloride, carbetapentane citrate, calamiphene disilate, diphenhydramine and its salts. Non-narcotic types such as hydrochloride, hominoben etc., as well as codeine and its sulfate or phosphate salts,
There are narcotic types such as noskabine hydrochloride, hydrocodone and its bitartrate salt, hydromorphone hydrochloride, etc.

The usual adult doses of such antitussive agents, also used per dose in the present composition, are shown in Table 1.

Table 1 Regular adult dose oral antitussives (lll1g)
Dextromethorphan HB r 10-30 Clofedianol HCI 15-25 Carbetapentane Citrate 1.5-30 Calamifuene Nidisylate 15-20 Noscapine HCL
15-30 diphenhydramine H
CI 15-25 codeine sulfate
10-20 hydrocodone bitartrate
5-10 Hydromorphone HCI
2 Hominoben 8(1-
160 Preferred oral antitussive agents are dextromethorphan, codeine, diphenhydramine, pharmaceutically acceptable salts thereof, and mixtures thereof. More preferred are dextromethorphan and codeine, pharmaceutically acceptable salts thereof and mixtures thereof. Most preferred is dextromethorphan and pharmaceutically acceptable salts thereof.

Tryptophan and oral antitussives range from about 221 to about 500
0:1, more preferably about 3:1 to about 'yooO:1
Even more preferably, the ratio of tryptophan to oral antitussive agent is from about 8:1 to about 400:1, and most preferably from about 16:1 to about 100:1.

A variety of oral dosage forms can be used, including solid forms such as tablets, capsules, granules, lozenges and powders, and liquid forms such as syrups, suspensions and solutions. These oral forms have a safe whitening amount, usually at least about 0.1% in the pharmaceutical composition. δ.

Solid oral dosage forms preferably contain from about 5 to about 95% active ingredient, more preferably from about 10 to about 95%, and most preferably from about 25 to about 95%.

Liquid oral dosage forms preferably contain from about 1 to about 50%, more preferably from about 1 to about 25%, most preferably from about 3 to about 1
Contains 0% active ingredients. Tablets can be prepared by compression, tablet milling, enteric coating, dragee coating, film production by containing suitable binders, lubricants, diluents, disintegrants, coloring agents, flavoring agents, preservatives and flow agents. Coated or multi-compressed.

Liquid oral dosage forms include aqueous and non-aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from boiling granules, and containing suitable solvents, preservatives, emulsifying agents, suspensions, etc. Contains clouding agents, diluents, sweeteners, colorants and fragrances.

Preferred carriers for oral administration include gelatin, propylene glycol, ethyl oleate, cottonseed oil and sesame oil.

Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms are found in Robert, published September 211, 1975, which is incorporated herein by reference. It is described in U.S. Pat. No. 3,903.297. Techniques and compositions for making solid oral dosage forms are described in Marsha II, “Solid Oral Dosage Forms,” Modern Pharmacy Takes, incorporated herein by reference.
Modern Pharn+accuLics) Volume 7, [Bunker and Rhodes (RI+
359-4200 Capsules (Hard and Soft Gelatin) and Bil.
(Edited by ArLhur 0sol)], 1553-1
593 pages.

Described in 1980.

Since many oral antitussive agents are commonly used in the form of water-soluble salts, they can be easily incorporated into conventional aqueous squirt syrups and solution formulations.

Water-insoluble or sparingly soluble antitussives are usually in the form of salts, dispersed as ills, suspensions, oil-in-water emulsions, etc., each with suitable dispersing agents, suspending agents, or emulsifying agents, each readily apparent to the pharmaceutical formulator. It can also be incorporated into an aqueous orally acceptable pharmaceutical carrier such as.

When manufacturing the pharmaceutical composition of the present invention, an oral antitussive and/or
Alternatively, the tryptophan component is incorporated into an aqueous orally acceptable pharmaceutical carrier consistent with conventional pharmaceutical practice. An "aqueous orally acceptable pharmaceutical carrier" is a carrier in which the entire or predominant solvent content is water. Typical carriers include simple aqueous solutions, syrups, dispersions, suspensions and aqueous emulsions such as oil-in-water. The most preferred carrier is a suspension of the pharmaceutical composition in an aqueous vehicle containing a suitable suspending agent. Suitable suspending agents include, but are not limited to, Aviccl RC-591 (
FMC (commercially available microcrystalline cellulose/sodium carboxymethyl cellulose mixture), guar gum, and the like.

Such suspending agents are well known to those skilled in the art. The amount of water in the compositions of the invention can vary over a very wide range depending on the total weight and volume of the two essential active ingredients and other optional non-active ingredients, but The water content is usually about 20 to about 75%, preferably about 20 to about 75% by weight/volume.
It is within the range of about 40%.

Although water itself forms the perfect carrier, typical spray formulations include solutions such as propylene glycol, glycerin, or sorbitol to aid in the dissolution and introduction of water-insoluble ingredients, such as sorbitol, into the composition. Preferably, co-solvents such as the like are disclosed. Thus, in general, the compositions of the present invention preferably range from about 5% to about 25% volume/volume, most preferably from about 10% to about 20% volume/volume. Contains 6 co-solvents.

For example, sodium citrate buffers, sodium phosphate buffers, etc., consistent with conventional pharmaceutical practice, to provide and maintain the pH of the composition from about 3 to about 9, preferably from about 4 to about 7. Buffers are commonly used. The compositions of the present invention may optionally contain one or more other known therapeutic agents, particularly those commonly used in cough/cold formulations, such as pseudoephedrine hydrochloride, phenylpropaturamine hydrochloride, phenylephedrine hydrochloride, and ephedrine hydrochloride. removers; analgesics such as acetaminophen and ibuprofen; expectorants or mucolytics such as glyceryl guaiacholate, guaifuenesin, terpine hydrate, ammonium chloride, N-acetylcysteine and amproxil; and chlorphenylene maleate. May contain antihistamines such as Lamin, doxylamine succinate, prompheniramine maleate and diphenhydramine hydrochloride, all of which are incorporated herein by reference. Sunshine et al. U.S. Patent Section 4.6
19.934. Bronchodilators such as theophylline and albutyrol are also useful.

To obtain a final product with good taste and good appearance, e.g. natural or artificial flavoring agents, fragrances, coloring agents, etc.; Other optional ingredients well known in the pharmaceutical industry, such as antioxidants such as and preservatives such as methyl or propylparaben or sodium benzoate, may also be included in amounts normally known for these ingredients. .

The compositions and methods described herein are used according to industry-recognized formulas to exert antitussive activity.

The following examples describe embodiments of the invention in which both essential and optional ingredients are mixed.

Example 1 A suspension for oral administration is prepared by mixing the following ingredients: Ingredients Weighed Tributophan 2000.0+
ng microcrystalline cellulose and carboxy 375. O
n+g methylcellulose sodium sucrose 13.5g glycerin (ioo, flng
Sorbitol solution (70%) 1.5g
Potassium sorbate 30.0mg
Saccharin sodium 60.0+
ng gluconic acid 75.
Off1g air freshener 45
．． 0mg blue agent 5.
0mg purified water appropriate amount total amount 30.
A pH 4.3 syrup is prepared by mixing the above ingredients and filling under aseptic conditions into 6 oz. bottles. 30ml of this formulation is administered to adults in need of treatment, thereby suppressing cough.

Example 2 Oral stage 5. The syrup for use is manufactured by mixing the following ingredients: Ingredients
Amount L -1-IJ But77 N LOO0, Oa + g Citric acid 5.7 mg Glycerin 12.0 + ng Sorbitol solution (70%) Appropriate amount Total amount 30. Om1 Colorant and Fragrance Adequate amount of citric acid is dissolved in glycerin at a temperature of about 40-60°C. Add Ll cryptophane to this mixture while stirring. The resulting mixture is cooled to room temperature and fragrance and color are added. A sorbitol solution is then added, thereby obtaining a thick syrup liquid. 30 ml of this liquid is administered to an adult in need of treatment, thereby suppressing cough.

Example 3 Hard capsules for oral administration are manufactured as follows:
500 mg of L-tryptophan as a dry powder is packed into a No. 0 hard shell capsule using techniques known in the art. 1
~4 capsules are administered to a person in need of treatment, thereby suppressing cough.

Example 4 Soft gelatin capsules for oral administration are manufactured by mixing the following ingredients: Ingredients Weighed 1 trypton 7 yen 250.0 ng + sesame oil
750.0+ng L-tryptophan is mixed with sesame seeds and packed into soft gelatin capsules using methods known in the art. 100% each composition
Two to four capsules obtained containing Oa+g are administered to adults in need of treatment, thereby suppressing cough.

Example 5 A tablet for oral administration is manufactured by mixing the following ingredients: Ingredients
Melon L-1-Liptophan 500
mg malt dextrin 50m
g croscarmellose 25+n
gMagnesium stearate 5II
1 gL-tryptophan was added to 10% malt dextrin solution [Malrin M-100
(commercially available from Corn Products)].

The resulting granules are dried overnight at a temperature of about 45°C.

The dry granules were ground and croscarmellose (ACDI-S
(commercially available from GAF)1) and magnesium stearate. The resulting powder blend is compressed into 580 mg tablets as per industry routine.

One to four tablets obtained are administered to a person in need of treatment, thereby suppressing cough.

Example 6 A syrup for oral administration is prepared by mixing the following ingredients: Ingredients
Melon - tryptophan 500f
f1g malt dextrin 5o
II1g crystal sorbitol 50
0mg Magnesium Stearate I
IIIg Colorant and fragrance Appropriate amount Li millibutophane 10 v/w? Granulate with 6i sprout dextrin solution. The resulting granules are dried overnight at a temperature of about 45°C. Grind the dry granules and blend with the remaining ingredients. The resulting powder blend is prepared as standard in the art: 1.
Compress into 05g tablets. One to four tablets obtained are administered to a person in need of treatment, thereby suppressing cough.

Example 7 A suspension for oral administration is prepared by mixing the following ingredients: Ingredients
Gua Li Liptophan 2000.0
mg dextromethorphan HB r 30
．． 0+ng sucrose
13.5g glycerin OO
O, Omg sorbitol solution (70%)
1.5g potassium sorbate 3
0. Oa+g saccharin sodium
00.0mg gluconic acid
75.0mg fragrance
45. Off1g tube colorant
5.0+ng purified water appropriate amount
A total volume of 30.0 ml The above ingredients are mixed to prepare a suspension with a pH of 4.3, and filled under aseptic conditions into 6 ounce (approximately 180 ml) bottles. 30ml of this formulation is administered to adults in need of treatment, thereby suppressing cough.

Substantially similar results indicate that dextromethorphan was used at therapeutically significant levels of clofedianol, carbetapentane,
It is also obtained when substituted with caramiphene, noscarbine, diphenhydramine, codeine, hydrocodone, hydromorphone, hominoben, their pharmaceutically acceptable salts and mixtures thereof.

Example 8 A syrup for oral administration is prepared by mixing the following ingredients: Ingredients
Gua Li Liptophan 1000. Of
f1g dextromethorphan HB r 3
0.0mg citric acid
5.7mg glycerin 1
2.0+ng sorbitol solution (70%) appropriate amount Total volume 30.0ml Colorant and fragrance
An appropriate amount of citric acid is dissolved in glycerin at a temperature of about 40-60°C. Add Ll-Lyptophan to this mixture while stirring. The resulting mixture is cooled to room temperature and fragrance and color are added. A sorbitol solution is then added, thereby obtaining a thick syrup liquid. 30m of this liquid
1 to adults in need of treatment, thereby suppressing cough.

Substantially similar results were obtained when dextromethorphan
It is also obtained when substituted with caramiphene, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, hominoben, their pharmaceutically acceptable salts and mixtures thereof.

Example 9 Hard capsules for oral administration are manufactured as follows:
500 m of Li mylibutophane and 15 III g of dextromethorphan HBr as dry powders are packed into No. 0 hard shell capsules using techniques known in the art. One or two capsules are administered to a person in need of treatment, thereby suppressing cough.

Substantially similar results indicate that dextromethorphan was used at therapeutically significant levels of clofedianol, carbetapentane,
It is also obtained when substituted with caramiphene, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, hominoben, their pharmaceutically acceptable salts and mixtures thereof.

Example 10 A soft gelatin capsule composition for oral administration is prepared by mixing the following ingredients: Ingredients Amount L-Tryptophan 250.0m
gDextromethorphan HB r 15.
0mg sesame oil 735
．． Omg L-tryptophan and dextromethorphan are mixed with sesame oil and packed into soft gelatin capsules using methods known in the art. Each composition 1000a+g
The resulting capsules containing 1 to 2 capsules are administered to adults in need of treatment, thereby suppressing cough.

Substantially similar results show that dextromethorphan has therapeutic #nn supralevels clophedianol, carbetapentane, caramiphene, noscabine, diphenhydramine, codeine, hydrocodone, hydromorphone, hominoben,
They are also obtained when substituted with their pharmaceutically acceptable salts and mixtures thereof.

Example 11 A tablet for oral administration is manufactured by mixing the following ingredients: Ingredients
Amount L-tryptophan 500a
+g dextromethorphan HBr 15
a+g malt dextrin 50
a+g croscarmellose 25
IIIg Magnesium Stearate
5igLl-ributophane and dextromethorphan in 10w/v% malt dextrin solution [Maltrin M-
100 (commercially available from Corn Products Co.)]. The resulting granules are dried overnight at a temperature of about 45°C. The dry granules were ground and mixed with croscarmellose (AC-DI-5
QL (commercially available from GAF Chu) and magnesium stearate. The resulting powder blend is compressed into 595+ng tablets as per industry routine. One or two tablets obtained are administered to a person in need of treatment, thereby suppressing cough.

Substantially similar results indicate that dextromethorphan was used at therapeutically significant levels of clofuedianol, carbetapencun,
It is also obtained when substituted with caramiphene, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, hominoben, their pharmaceutically acceptable salts and mixtures thereof.

Example 12 A chewable tablet for oral administration is manufactured by mixing the following ingredients: Ingredients Amount L
-Tryptophan 50
Axis g Dextromethorphan HBr adsorbate (10%)
150mg malt dextrin
50mg crystal sorbitol
500+ng Magnesium Stearate 1mg Mushiki Kumibi Hoshiyaku
Appropriate amounts of L-tryptophan and dextromethorphan adsorbates are granulated with a 10 C/V% malt dextrin solution. The obtained granules were heated to about 45°C.
Dry overnight at a temperature of . Grind the dry granules and blend with the remaining ingredients. The resulting powder blend is compressed into 1.05 g tablets as is routinely practiced in the art. One or two tablets are administered to a person in need of treatment, thereby suppressing cough.

Substantially similar results indicate that dextromethorphan was used at therapeutically significant levels of clophedianol, carbetapentane,
caramiphene, noscarbine, diphenhydramine, codeine, hydrocodeine, hydromorphone, hominoben,
They are also obtained when substituted with their pharmaceutically acceptable salts and mixtures thereof.

Claims (1)

[Claims] 1. A method for treating cough in humans or animals, which comprises orally administering a safe and effective amount of a tryptophan-containing pharmaceutical composition to a human or animal in need of treatment. 2. The method of claim 1, wherein the pharmaceutical composition is administered orally at a dose of 2.0 to 3000 mg/kg/day. 3. The method of claim 2, wherein the pharmaceutical composition is administered orally at a dose of 6 to 360 mg/kg/day. 4. The pharmaceutical composition is a tablet, capsule, granule, bulk powder,
4. The method of claim 3, wherein the method is in a form selected from the group consisting of syrup, suspension and solution. 5. The method of claim 4, wherein the pharmaceutical composition is administered orally at a dose of 14-180 mg/kg/day. 6. A method for treating cough in a human or animal, comprising: administering to a human or animal in need of such treatment a solid pharmaceutical composition according to claim 1 in the form of a tablet, lozenge, capsule, granule or bulk powder. A method characterized by: 7. A method for treating cough in humans or animals, comprising: administering to a human or animal in need of such treatment a liquid pharmaceutical composition containing: a) 1-90% tryptophan; and b) 1-99% liquid pharmaceutical carrier. A method characterized by throwing. 8. The method of claim 7, wherein the pharmaceutical composition contains 1-25% tryptophan and the liquid pharmaceutical carrier is selected from the group consisting of syrups, emulsions, suspensions and solutions. 9. The liquid pharmaceutical composition is in the form of a syrup and a co-solvent selected from the group consisting of sorbitol solution, propylene glycol, glycerin and mixtures thereof 20-75
9. The method of claim 8, further comprising % w/v. 10. The method of claim 9, wherein the liquid pharmaceutical composition has a pH of 3-9.