Liquid nasal spray containing low-dose naltrexone

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a pharmaceutical composition in the form of a liquid solution for nasal administration of spray containing naltrexone in an amount of 0.005-0.02 wt/vl %.

EFFECT: invention provides eliminating the undesired side effects with preserving naltrexone activity.

6 cl, 3 ex

 

The technical field to which the invention relates

The present invention relates to compositions for nasal administration of medications category of opioid antagonists.

The level of technology

Opioids are drugs that produce analgesic and antinociceptive response to various degrees of effectiveness depending on pharmaceutical substances. There are numerous pharmaceutical substances category of opioid and/or an opiate, such as morphine, fentanyl, hydromorphone, tramadol, codeine, buprenorphine, oxycodone, methadone. All medications in this category are used in clinical practice due to their ability to cause an anesthetic effect, but can generate a (different) other effects that are not in accordance with the expected therapeutic result and are combined under the term "adverse reactions". The presence of these adverse reactions, poorly tolerated by the patient, often results, depending on their intensity and severity, early cessation of opioid treatment, even in the case where it is necessary to control your pain.

It is known that the pharmacological effects of the compositions of opioids due to the pharmacodynamic effect of mutual� - acting opioids with specific receptors, called "opioid receptors". Receptor binding causes the activation of the action of both inhibitory and excitatory in nature, in connection with the double conformation of the receptor; such effects are strictly correlated with the clinical expression, as a rule, with the mixing of anesthesia (useful, antinociceptive manifestation) and adverse reactions (harmful, stimulating the expression). The presence of adverse reactions (side reactions) is now widely documented in the literature, variables describing both the symptoms and their frequency; the presence of adverse reactions is statistically significant, in all cases, when the patient uses the drug opioid category, exactly the same as the level of cessation of therapy is also statistically significant, due to the presence of adverse reactions, especially in the presence of symptoms such as vomiting, dizziness, sensory violation of orientation. The presence of side reactions can be predicted, but displays the individual range, both in terms of the type caused by a symptom, and in relation to the intensity with which it is manifested. Treatment is indicated in the literature, in the presence of adverse reactions, associated with only three choices: temporarily suspended the administration of the drug, additional mode �to enable drug-drug, which can control the symptoms, opioid replacement molecules on equianalgesia dose (change of direction or rotation of opioids).

Below are the most common adverse reactions.

Drowsiness: this is the effect which usually manifests itself in the initial phase of adoption of opiates, for which tolerance develops during the first 3-4 days. This effect may be accompanied by sensory confusion, and dizziness. If drowsiness lasts for a long time and is excessive, it can be a sign of incorrect indications for use of opioids, as if the pain is not sensitive to the opioid, not compounded analgesics pharmacological effects.

- Urinary retention: urinary catheterization or the use of micro-doses of naloxone can sometimes be a necessity. There is the development of tolerance.

- Constipation: tolerance does not develop, the most common side effect is often one of the most unpleasant. You must ensure that there is no intestinal obstruction. It is treated with softening feces means, laxatives and moisture. Some studies have reported improvements with the use of naloxone oral (Kreek, M. J).

- Nausea and vomiting: These reactions increased�he laughs at the expense of vestibular stimuli. They occur in 5-15% of cases, with the rapid development of tolerance. Opiates reproduce these effects through the triple mechanism of action. They act directly on Bulbo-mesencephalic chemoreceptor, activating the emetic centers: this component is managed with haloperidol (0.5-1 mg/1-2 times/day) or prochlorperazine (5,10 mg/2-3 days) or corticosteroids. The effect on the vestibular centers induces vomiting when walking: for this component

- drugs against vertigo and motion sickness, such as transdermal scopolamine, have some degree of effectiveness;

- there is reduced motility of the stomach, which is caused by metoclopramide (10 mg for 3 days). If there is an apparent intolerance to morphine, it can be substituted with methadone, which reproduces this effect to a lesser degree.

- Itching: the mechanism of action that reproduces this symptom is not known. Appears to be receptor mediated and/or antagonization small doses of naloxone. Effective drug for reducing pruritus is a hydroxizin, local anesthetics, corticosteroids and antihistamines are less useful.

However, if you have taken an excessive dose, the condition perebazirovano "complications" can� to develop, producing the effect of sedation, with the alteration of the sensory state, which can reach coma and effects on breathing with a serious reduction of respiration and secondary breathing, bradypnea and/or prolonged apnea.

These complications are conditions that are hazardous to life and requires urgent medical care, treated with medications category of opioid antagonists; they include molecules of naloxone and naltrexone. These drugs are usually administered intravenously, despite the risks and complications associated with this method of application; excessive or improper administration of these products can cause the development of the syndrome, which may be severe (which can occur, for example, in persons who have used opioids for a long time or in high doses, for example, when drug addiction or users with oncological pain) and can cause serious damage (e.g., cardiac tachyarrhythmias, pulmonary edema, severe psychomotor agitation).

The patent application WO 00/62757 describes compositions for oral or nasal administration of opioid antagonists and, in particular, described liquid solutions of naloxone, in which the active ingredients are present in a concentration of 0.5-5% wt./about.

Of th�coast patent application MI2001A000907 reports on the use of very low doses of naltrexone in patients treated with opioids for reducing their undesirable side effects; opioid and opioid antagonist are administered simultaneously in the compositions in oral method of application.

It is clear, however, that it would be extremely helpful to have the compositions for administration of opioid antagonists at low concentrations after nasal administration method.

Disclosure of the invention

Described pharmaceutical compositions for the introduction of liquid solutions with a low dose of naltrexone by nasal administration method.

The implementation of the invention

Unexpectedly it was found that you can enter naltrexone in the form of liquid solution at low dose by nasal application method with excellent results as to attenuate undesirable side effects associated with the administration of opioids, and in the case of over-soaking.

Low dose, in accordance with the invention, means the dose is below 1% (wt./vol.).

Liquid formulations for nasal administration, in accordance with the invention contain a quantity of naltrexone (usually as hydrochloride salt) between 0.001 and 1.0% (wt./vol.), preferably 0,005-0,5% (wt./vol.), more preferably 0,005-0,02% (mass./vol.).

Liquid solutions, in accordance with the invention typically are aqueous solutions or aqueous-alcoholic solutions in which the alcohol is preferably presented�t a ethanol in the amount of approx. 5% (wt./vol.). In addition, the solutions contain a buffer, the purpose of which is to maintain the pH at a value at which the opioid antagonist is in the form of a salt, such as hydrochloride. The buffers can be selected from the following: citric acid/sodium citrate, citric acid/sodium hydroxide, dibasic sodium phosphate/citric acid, dibasic sodium phosphate/monobasic potassium phosphate, acetic acid/sodium acetate. Fillers used for compositions of this type contain antimicrobial preservatives, agents that increase the correct tonicity and agents that increase the viscosity of the fluid (viscosity improvers).

Among antimicrobial preservatives the authors of this invention may be noted: benzalkonium chloride, methylparaben, propylparaben, sodium benzoate, benzoic acid, generationy alcohol or mixtures thereof, preferably in amounts between 0.005 to 0.50 percent (wt./vol.), preferably from 0.005 to 0.30% (wt./vol.), more preferably 0,01-0,1% (wt./vol.).

Agents that increase the correct tonicity represent, for example: sodium chloride, dextrose, lactose or mixtures thereof, preferably in amounts between 0.1% and 5.0% (wt./vol.), preferably of 0.1-2.0% (wt./vol.), more preferably 0,1-0,9% (wt./vol.).

The viscosity improvers can be selected from: hydroxypropylmethylcellulose (hypromellose), hydroxyethylcellulose, guide�of oxypropylation, methylcellulose, microcrystalline cellulose, carboxymethylcellulose sodium, xanthan gum, or mixtures thereof, preferably in amounts of between 0,01 to 2,0% (wt./vol.), preferably of 0.02 to 1.0% (wt./vol.), more preferably from 0.05 to 0.5% (wt./vol.).

The compositions according to the invention is obtained by the following standard methods used for the preparation of solutions for nasal application.

The following components are dissolved in a certain volume of water, preservatives, buffer salts, means for increasing the osmotic concentration of a solution (osmolality), and then the viscosity improver. When the resulting solution is transparent, dissolve the active substance and the solution was adjusted to the desired volume with water.

Some examples of possible compositions according to the invention is given below.

Example 1

To prepare 100 ml of solution is as follows.

Add 1 ml of 2% wt./about. solution benzalkonium chloride, and 0.14 g of anhydrous citric acid, of 0.37 g of sodium citrate and 0.72 g of sodium chloride to 50 ml of water, with stirring. When the components were completely dissolved, add 0.1 g hypromellose and continue stirring until then, until you get a clear solution. At the end add 0.1 g of naltrexone hydrochloride until then, until it will dissolve completely. The volume was adjusted by�scientists solution with water to 100 ml and, if necessary, filtered.

Qualitative and quantitative composition

Hydroxypropyl methylcellulose with 0.2% wt./about.

Benzalkonium chloride 0.02% wt./about.

Anhydrous citric acid of 0.14% of the mass./about.

Dehydrate sodium citrate 0,37% wt./about.

Sodium chloride 0,72% wt./about.

Naltrexone hydrochloride 0,010% wt./about.

The resulting solution has the following physical characteristics:

pH=4,8

Density = 1,007 g/ml

Osmolality = 283 mosmol ' /kg;

Viscosity = 4,52 MPa*s (millipascal*sec).

Following the same methodology described in example 1, the following compounds.

Example 2

Qualitative and quantitative composition

Hydroxypropyl methylcellulose with 0.2% wt./about.

Propyl-parahydroxybenzoate sodium 0,02% wt./about.

Anhydrous citric acid of 0.14% of the mass./about.

Dehydrate sodium citrate 0,37% wt./about.

Sodium chloride 0,72% wt./about.

Naltrexone hydrochloride 0,010% wt./about.

The resulting solution has the following physical characteristics:

pH = 4,9

Density = 1,007 g/ml

Osmolality = 278 mosmol ' /kg;

Viscosity = 4.15 MPa*s.

Example 3

Qualitative and quantitative composition

Cellulose 0.5% mass./about.

Benzalkonium chloride 0.02% wt./about.

Anhydrous citric acid of 0.14% of the mass./about.

Dehydrate sodium citrate 0,37% wt./about.

Sodium chloride 0,72% wt./about.

Naltrexone hydrochloride 0,010 weight./about.

The resulting solution has the following physical characteristics:

pH = 4,8

Density = 1,008 g/ml

Osmolality = 292 mosmol ' /kg;

Viscosity = 2,27 MPa*s.

The compositions according to the present invention, can be administered, e.g., in the form of a spray using an applicator capable of spraying a certain amount of solution into the nasal cavity. The number is usually between 50 and 100 µl and may not necessarily be repeated, if necessary.

Experimental design

Experimental Protocol and the results obtained on clinical stage, during which naltrexone was administered to the patients treated with morphine presented below.

2.5 mg
The incidence of adverse reactions from morphine in patients (total 80) before treatment with Naltrexone
Constipation70%Dizziness13,3%
Nausea53,3%Drowsiness30%
Vomiting53,3% Pruritus30%
Lack of appetite46,7%Asthenia43,3%
Urinary retention40%-
Headache6,7%
Cancer patients receiving therapeutic treatment with oral morphine (mean dose 40 mg +/- 10 mg), treated with Naltrexone - dose every 12 hours: used 1/2 hour before morphine
The total number of patients: 75
Dose NaltrexoneA positive result (%)1The analgesia (%)2
2.5 mg25%45%
2.5 mg90%60%
Of 0.125 mcg100%60%
5 mcg40%55%
1 mg90%100%
1 mg65%90%
1 mg40%100%
1 mg70%65%
1 mg65%60%
1 mg100%70%
5 mcg60%45%
5 mcg60%55%
5 mcg0%70%
5 mcg70%100%
5 mcg50%90%
5 mcg45%60%
5 mcg85%90%
5 mcg45%65%
Dose NaltrexoneA positive result (%)1The analgesia (%)2
2.5 mg100%0%
1 mg100%100%
2.5 mg80%/td> 45%
2.5 mg80%45%
1 mg65%65%**
2.5 mg70%55%
2.5 mg50%60%**
2.5 mg80%45%
Of 0.125 mcg65%45%
1 mg90%100%
2.5 mg65%100%
5 mcg55%60%**
1 mg 75%55%
1 mg95%75%**
Dose NaltrexoneA positive result (%)1The analgesia (%)2
2.5 mg50%70%
2.5 mg40%60%
Of 0.125 mcg65%45%
Of 0.125 mcg40%55%**
1 mg65%65%**
5 mcg35%55%
2.5 mg50%60%
60%55%
1 mg70%70%**
2.5 mg60%100%
2.5 mg65%40%
5 mcg45%60%**
1 mg65%85%
5 mcg55%65%**
Dose NaltrexoneA positive result (%)1The analgesia (%)2
2,5 mg/day90%60%
0,125 µg/day 100%60%
5 mcg40%55%
1 mg90%100%
1 mg65%90%
1 mg40%100%
1 mg70%65%
5 mcg65%60%
1 mg100%70%
5 mcg60%45%
5 mcg60%55%
1 mg 0%70%
1 mg70%100%
1 mg55%65%**
5 mcg50%90%
Dose NaltrexoneA positive result (%)1The analgesia (%)2
5 mcg100%55%**
5 mcg100%100%
2.5 mg80%45%
2.5 mg80%45%
Of 0.125 mcg65%6%**
2.5 mg55%45%
1 mg50%60%
1 mg80%45%**
1 mg65%45%
1 mg80%100%
5 mcg45%100%
5 mcg50%60%
1 mg65%85%
5 mcg85%70%**
Spines of patients subjected to therapeutic treatment morphs�nom due to the receipt of the body through the spinal cord (mean dose of 4.8 mg +/- 0.4 mg), treated with Naltrexone - dose every 12 hours: used for1/2hours before epidural type
The total number of patients: 26
Dose NaltrexoneA positive result (%)1The analgesia (%)2
2.5 mg100%0%
2.5 mg100%100%
2.5 mg80%45%
2.5 mg80%85%
5 mcg65%35%
5 mcg70%85%
1 mg50% 60%
2.5 mg80%55%
1 mcg65%65%
2.5 mg95%100%
2.5 mg60%100%
5 mcg50%60%
1 mcg100%45%
Dose NaltrexoneA positive result (%)1The analgesia (%)2
5 mcg30%15%
5 mcg50%60%
2.5 mg45%45%
2.5 mg80%75%
1 mcg65%65%
5 mcg70%45%
2.5 mg45%60%
2.5 mg60%55%
1 mg65%95%
5 mcg95%100%
2.5 mg60%90%
5 mcg50%60%
1 mcg70%45%
Designation:
1: Percent reduction of adverse reactions.
2: Analgesic efficacy after administration of naltrexone
** Reduced efficiency after naltrexone

1. Pharmaceutical composition in the form of liquid solution for the introduction of a spray, by nasal application method, containing naltrexone in amounts of between 0.005 to 0.02% wt./about.

2. The composition according to claim 1, characterized in that the liquid solution is an aqueous or aqueous-alcoholic solution in which the alcohol is an ethanol, in an amount of about 5% wt./about.

3. The composition according to claims. 1 and 2, characterized in that said composition further comprises a buffer selected from: citric acid/sodium citrate, citric acid/sodium hydroxide, dibasic sodium phosphate/citric acid, dibasic sodium phosphate/monobasic potassium phosphate, acetic acid/sodium acetate buffer.

4. The composition according to claim 3, further comprising: an antimicrobial preservative agents that increase the concentration (tonicity), and agents which�s increase the viscosity of the solution.

5. The composition according to claim 4, characterized in that said antimicrobial preservatives such as benzalkonium chloride, methylparaben, propylparaben, sodium benzoate, benzoic acid, generationy alcohol or mixtures thereof, and are contained in amounts between 0.005 to 0.50 percent (wt./vol.), preferably from 0.005 and 0.30% (wt./vol.), more preferably 0,01-0,1% (wt./vol.).

6. The composition according to claims. 1 and 2 having the following composition:
(a) Methylcellulose with 0.2% wt./about.;
Benzalkonium chloride 0.02% wt./about.;
Anhydrous citric acid of 0.14% of the mass./about.;
Dehydrate sodium citrate 0,37% wt./about.;
Sodium chloride 0,72% wt./about.;
Naltrexone hydrochloride 0,010% wt./about.;
b) a hydroxypropyl Methylcellulose with 0.2% wt./about.;
Propyl-parahydroxybenzoate sodium 0,02% wt./about.;
Anhydrous citric acid of 0.14% of the mass./about.;
Dehydrate sodium citrate 0,37% wt./about.;
Sodium chloride 0,72% wt./about.;
Naltrexone hydrochloride 0,010% wt./about.;
b) Cellulose 0.5% mass./about.;
Benzalkonium chloride 0.02% wt./about.;
Anhydrous citric acid of 0.14% of the mass./about.;
Dehydrate sodium citrate 0,37% wt./about.;
Sodium chloride 0,72% wt./about.;
Naltrexone hydrochloride 0,010% wt./about.



 

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5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine and deals with a crystalloid cardioplegic solution, which contains salt solution, including sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium hydrogen carbonate, water for injections and a structural analogue of natural apelin X-Arg(NGY)-Pro-Arg-Leu-Ser-His-Lys-Cly-Pro-Nle-Pro-Phe-Z, where X=CH3, Y=H, Z=OH. The group of inventions also deals with the crystalloid cardioplegic solution, containing salt solution, including sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium hydrogen carbonate, water for injections and structural analogue of natural apelin X-Arg(NGY)-Pro-Arg-Leu-Ser-His-Lys-Cly-Pro-Nle-Pro-Phe-Z, where X=H, Y=NO2, Z=NH2.

EFFECT: group of inventions provides the recovery of the coronary flow, cardiac contractile and pump function in case of the reperfusion and the reduction of injury to membranes of cardiomyocytes.

2 cl, 2 dwg, 8 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is a pharmaceutical, ear, sterile, preservative-free composition in the form of a transparent aqueous solution, containing 0.01-0.025 % of fluocinilone acetonide optionally in a combination with 0.1-0.8% of ciprofloxacin or its pharmaceutically acceptable salt, a non-ionic surface-active substance, a tonicity-regulating agent and a viscosity-increasing agent.

EFFECT: composition is useful for the prevention and/or treatment of ear inflammation, optionally accompanied with a bacterial infection, and for the introduction of a single dose from a package.

15 cl, 8 ex

FIELD: medicine.

SUBSTANCE: invention represents a balanced infusion solution containing sodium, potassium and magnesium chlorides, a solvent and sodium L-arginine succinate of formula: Na+[NH=C(NH2)NH(CH2)3CH(NH2)COOH]+[OOC(CH2)2COO]2-. The ingredients in the solution are found in certain proportions, wt %.

EFFECT: invention provides enhanced detoxification activity, low toxicity and wide range of clinical applications.

11 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, namely to production of medications for treating dermatosis. Medication according to invention, made in form of cream, contains mometasone furoate, preservative, hydrophilic no-aqueous solvent, emulsifying agent of 1st kind, emulsifying agent of 2nd kind, emollient, disodium edetate (trilon B), pH-regulating agent, and purified water in quantities, given in invention formula.

EFFECT: invention can be applied for treating inflammatory diseases and itching in case of dermatosis, yielding to glycocorticosteroid therapy.

9 cl, 3 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiac surgery, and represents cardioplegic solution, which contains sodium chloride - 3.41-3.62, potassium chloride - 1.092-1.156 g, magnesium chloride - 3.190-3.485 g, calcium gluconate - 0.0105-0.0130 g, mannite - 4.365-4.520 g, L-carnosine - 20.1504-24.1650 g, N-acetylcarnosine - 8.056-11.032 g, L-histidine - 0.705-0.820 g, water for injections to 1000 ml.

EFFECT: invention ensures prevention of reduction of amplitude, speed of front and speed of pulse-wave reduction, as well as increase of diastolic pressure in left heart ventricle during reperfusion with preservation of buffer capacity and osmolarity of cardioplegic solution with physiological pH parameters.

4 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: composition has an action of the central nervous system; it is presented in the form of a solution, contains glycine, glycerol, a preserving agent and water. The invention also concerns a therapeutic agent and a biologically active addition based on the above composition.

EFFECT: group of inventions provides high bioavailability as the composition is presented in the liquid and ease of dosing.

12 cl, 2 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: each pellet comprises a water-soluble core, a naltrexone-containing antagonist layer coating the core, a polymer barrier coating the antagonist layer, an Oxycodone-containing agonist layer coating the polymer barrier and a control release layer coating the agonist layer.

EFFECT: drug preparation is applicable to release respiratory distress in an individual which is observed in case of a pre-administration damage of the drug preparation, by naltrexone release.

8 cl, 5 dwg, 3 tbl, 4 ex

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