HUT70439A - Injectable solution for administration of one or more active compounds in situ and process for its preparation - Google Patents

Abstract

SUMMARY OF THE INVENTION The present invention relates to an injectable solution for the administration of one or more active ingredients and to a process for the preparation thereof, wherein the active ingredient is dissolved in a biologically acceptable solvent from which the active ingredient precipitates at the time of injection, thereby forming a solid phase of a solution in situ.

Description

FIELD OF THE INVENTION The present invention relates to injection solutions for administering one or more in situ precipitating agents, and to a process for their preparation.

The preparation of large quantities of sterile suspensions, i.e. compositions containing at least two solid and liquid phases, presents many difficulties. Suspensions are by definition thermodynamically unstable and the different phases separate over time. Sterilization of such formulations with water often accelerates phase separation. Suspensions should not be used for aseptic delivery through a 0.2 μιη filter. Only a few such suspension formulations are commercially available. Novalucol and Roxiam may be mentioned as examples of oral compositions. Oil suspensions for injection are available for use in the central nervous system. Thus, there is a need for injection suspensions which can either be sterilized by steam or passed through a 0.2 μιη filter.

NL 9000634 discloses stable aqueous suspensions of water-soluble local anesthetics and / or narcotic analgesics, wherein the local anesthetic and / or narcotic analgesic particles have a defined diameter and the aqueous suspension contains a non-ionic surfactant surface. . These suspensions are sterilized by steam or gamma rays. In the case of heat sterilization, the suspending particles are melted and flushed together in whole or in part in the whole of the burner 3 · 9 · · 9 · · · · · · · · · · · · · · · · ··· In order to re-form the suspension, the sediment is cooled to a temperature below the freezing point of the aqueous medium by shaking. However, this is a very complicated sterilization method, time consuming and the size of the recovered particles cannot be controlled.

EP 197 308 also discloses a suspension comprising water-insoluble topical anesthetics for injection. During steam sterilization of the suspension, the above problem occurs, i.e., the local anesthetic particles melt and need to be resuspended.

EP 213 851 discloses semi-solid matrices for injection which mechanically inhibit the release of the active compound. In fact, the matrix is degraded when injected. In this case, the composition is semi-solid and non-solid.

It is well known that chelation with metal ions can provide solutions. This is disclosed in U.S. Patent No. 4,259,331. In this case, the mixed metal chelate releases a certain amount of active compound at the time of injection. Thus, it is advisable to prepare a solution for injection that does not contain metal ions but at the same time precipitates the active ingredient once administered.

Benzone et al. (Dialog International Services, Volume 5: B10SIS) further discusses the effect of polyethylene glycol (PEG) on nerve impulses in mammals. PEG is a polymeric compound used as a carrier for steroid depot formulations. The study showed that PEG did not cause neurolysis at concentrations below 40%.

Cassuto et al. (Anesthesiology 68, 895, 1988) disclose another method of alleviating postoperative pain, namely the use of Xylocain spray, a solution containing lidocaine base dissolved in ethanol, which is applied topically to patients undergoing cardiac plastic surgery. supply.

Acta Anaesthesiol Scand 36, 112-114 (1992) also discloses the use of the aforementioned lidocaine aerosol for postoperative pain following gynecological small-laparotomy. The base form of lidocaine, which has been used in both of these studies, can also be used in vivo, i.e. the solubility of the agent in these tissue fluids is good enough to cause both sensory and motor blockade. This is also supported by the present invention. However, the Xylocain spray used in previous studies also contained a number of additives that should be avoided in wounds.

J. CLin. Pharm. and Therap. 15, 197-204, (1990) and in a further article (Slow-release effect of pH-adjusted bupivacaine, in vitro demonstration). Borquet et al. The effect of alkalinized bupivacaine hydrochloride on slow drug release is described. In addition, Correspondance in * · · · · · · · · · · · · · · · ·

Plast. Reconst. Surg. 8, 4, 543, 84, (1989) and Comment in Ann. R. Coll. Surg. Engl. 17, 72, (1989) suggest the possibility of topical application of the alkalinized bupivacaine hydrochloride solution for the local treatment of postoperative pain.

Slow release of painkillers has also been observed for base forms, such as the publication on Drug Level and Ind. Pharm 17, 67, (1991), in which the authors describe how to prepare and inject nalbuphine suspensions. Three suspending agents, methylcellulose, sodium carboxymethylcellulose, and PEG, were added to make an injection suspension. However, these agents can cause side effects and therefore the suspension preferably contains as little excipient as possible.

None of the previous documents solves the problem of providing a stable injection of an active ingredient in which the suspension has the advantage that it has a much longer duration of action. The present invention solves these problems.

It has been found that difficulties in the preparation of sterile injectable suspensions can be avoided by preparing an injection solution for administration of one or more active ingredients in a biologically acceptable solvent so that the active ingredient is precipitated upon use due to changes in solubility conditions, i.e. phase occurs in situ. Sterilization of the solution may be achieved by methods which are not applicable to suspensions, namely by steam sterilization or by passage through a 0.2 µm filter.

Another advantageous feature of the invention is that the active ingredient is precipitated under in situ conditions, i.e., the solid phase may also play a depot role in the tissue due to its solubility properties or the presence of other substances (binders). Consequently, high doses of the active ingredient can be administered in vivo without severe toxic reactions. The present invention describes a solution for injection in which the active ingredient can be, for example, a local anesthetic, an analgesic or a combination of the two, so as to provide both the analgesic and anesthetic effects which are sometimes required. The active ingredient may also be a steroid or an agent acting on the central nervous system.

Preferably, the active ingredient is a local anesthetic such as lidocaine, prilocaine, mepivacaine, bupivacaine, ropivacaine or etidocaine, but it may also be another local anesthetic. The local anesthetic is most preferably lidocaine.

The physicochemical properties of the active ingredient, such as its solubility, the effect of pH, salts and temperature on solubility, are important parameters for controlling the in situ precipitation of the active ingredient.

The topical anesthetic of the present invention is administered in a neutral form which is less soluble than the hydrochloride form. It has been found that the neutral form of the analgesic increases the duration of motor and sensory blockade compared to a solution containing the local anesthetic in the form of the hydrochloride.

Since the neutral form is insoluble in water, a lipophilic vehicle is employed which dissolves the active ingredient and thereby renders it suitable for injection. Upon administration, this solution, i.e., the active ingredient and the vehicle, changes due to changes in environmental conditions, resulting in the precipitation of the active ingredient. In this way, the injection system acts as if it were a suspension. The neutral form is unchanged and can be, for example, in the form of a base.

The optimal excipient for the particular active ingredient of the present invention has been experimentally determined and its activity has been demonstrated in vivo. The physicochemical properties of the active ingredient determine its solubility. The lower limit of solubility can be characterized by the lowest effective concentration (therapeutic concentration) of the active ingredient. The upper solubility limit should correspond to the desired amount of active substance precipitated.

The carriers are mixtures of biologically acceptable solvents and mixtures of one or more of the following: water, alcohol and polyethylene glycol or another biologically acceptable solvent. Particularly preferred carriers of the invention may be:

a) ethanol, 99.5%,

(b) a mixture of ethanol and water,

c) polyethylene glycol 300 (PEG 300),

d) a mixture of PEG 300 and ethanol,

e) PEG 300, a mixture of ethanol and water,

f) polyethylene glycol 400 (PEG 400),

g) a mixture of PEG 400 and ethanol,

h) PEG 400, a mixture of ethanol and water,

(i) propylene glycol,

(j) a mixture of propylene glycol and water,

(k) a mixture of propylene glycol and ethanol,

(l) glycerol,

(m) a mixture of glycerol and ethanol; or

n) a mixture of glycerol, ethanol and water.

Most preferably, the biologically acceptable solvent is:

(a) a mixture of ethanol and water,

(b) PEG 300 or

c) A mixture of PEG 400 and ethanol.

In a particularly preferred embodiment of the invention, the sterile injectable solution contains 5 to 80% by weight of lidocaine in a mixture of 10 to 35% by weight of ethanol and 2 to 65% by weight of water.

In a further preferred embodiment of the invention, the sterile injectable solution contains 15-20% by weight of lidocaine dissolved in 80-85% by weight of PEG 300.

In a further preferred embodiment of the invention, the sterile injectable solution contains from 5 to 20% by weight of lidocaine dissolved in a mixture of 2 to 10% by weight of ethanol and 75 to 90% by weight of PEG 400.

The sterile injectable solution of the invention may be administered intramuscularly, epidurally, spinally, intrathecally, rectally, topically, orally, or by inhalation.

The sterile injectable solution is prepared by mixing the active ingredient to be used with a solvent in a vial. The bottle is sealed and shaken to dissolve the active ingredient. To fully dissolve the active ingredient, the bottle is stored at room temperature for up to one day. Thereafter, the solution is sterilized either by steam or, if prepared under aseptic conditions, through a 0.2 µm filter.

The following examples serve to illustrate the invention:

Example 1:

lidocaine 5.0 crowd% Ethanol, 99.5% 34.0 crowd% Water 61.0 crowd%

A sterile injectable solution was prepared according to the general preparation procedure described above. When administered by intravenous injection, persistent motor and sensory blockade were induced.

Example 2:

Lidocaine 10.0% by weight

Ethanol, 99.5% 36.0% by weight

Water

54.0% by weight

Sterile solution for injection we made the above known- liked general manufacturing procedure. In the carrier long-term motor and sensory use when injected blockade. Example 3: lidocaine 75.0% by weight Ethanol, 99.5% 20.0% by weight Water 5.0% by weight Sterile solution for injection we made the above known-

according to the general manufacturing procedure.

Example 4: lidocaine 80.0% by weight Ethanol, 99.5% 15.0% by weight Water 5.0% by weight Sterile solution for injection produced above know- made general production e according to the procedure. Example 5: lidocaine 17.8% by weight PEG 300 82.2% by weight Sterile solution for injection produced above know- made general production e according to the procedure. Example 6: lidocaine 17.8% by weight PEG 300 82.2% by weight Sterile solution for injection produced above know-

according to the general manufacturing procedure.

. example:

lidocaine 8.6 crowd% Ethanol, 99.5% 3.4 crowd% PEG 400 88.0 crowd%

A sterile injectable solution was prepared according to the general preparation procedure described above. When administered by intravenous injection, it is durable motor and sensory

blockade. Example 8: crowd% lidocaine 17.4 Ethanol, 99.5% 3.4 crowd% PEG 400 79, 2 crowd%

A sterile injectable solution was prepared according to the general preparation procedure described above. When administered by intravenous injection, persistent motor and sensory blockade were induced.

Example 9:

prilocaine 10.0 crowd% Ethanol, 99.5% 35.5 crowd% Water 55.0 crowd%

A sterile injectable solution was prepared according to the general preparation procedure described above.

Example 10:

Prilocaine 20.0% by weight

PEG 300 80.0% by weight

A sterile injectable solution was prepared according to the general preparation procedure described above.

Example 11:

prilocaine 10.0 crowd% Ethanol, 99.5% 5.0 crowd% PEG 400 85.0 crowd%

A sterile injectable solution was prepared according to the general preparation procedure described above.

Example 12:

prilocaine

Ethanol, 99.5%

PEG 400

15.0% by weight

5.0% by weight

85.0% by weight

Sterile injectable solution was reconstituted according to the general preparation procedure described above.

Example 13:

mepivacaine 7.7 crowd% Ethanol, 99.5% 50.0 crowd% Water 42.3 crowd%

A sterile injectable solution was prepared according to the general preparation procedure described above.

Example 14:

mepivacaine 10.0 crowd% Ethanol, 99.5% 60.0 crowd% Water 30.0 crowd%

A sterile injectable solution was prepared according to the general preparation procedure described above.

Example 15:

bupivacaine 1.1 crowd% Ethanol, 99.5% 37.5 crowd% PEG 400 30.0 crowd% Water 31.5 crowd% Example 16: bupivacaine 1.1 crowd% Ethanol, 99.5% 49, 6 crowd% PEG 400 49, 3 crowd% Sterile injection solution was prepared above

according to the general manufacturing procedure.

you know17. example:

ropivacaine

Ethanol, 99.5%

PEG 400

Sterile injectable solution was made by general preparation e

Example 18:

ropivacaine

Ethanol, 99.5%

PEG 400

Sterile injectable solution was made by general preparation e

1.0% by weight

48.2% by weight

50.8% by weight was prepared as described above.

1.0% by weight

29.7% by weight

69.3% by weight was prepared as described above.

acquaintance14 ·· ·

Biological effect

Materials and methods:

Male guinea pigs (Dunkin-Hartley, HB Sahlins Försöksdjursfarm, Malmo, Sweden) weighing 300-600 g were used for the study. The animals were placed in triplicate cages and provided with any amount of food and water.

Method 1:

Sciatic nerve blockade

Male guinea pigs (291-563 g) of Dunkin-Hartley strain were used in the assay as described by Shackell, Anesth. Analg. 1-4.20-22, 1935)]. The hind leg of the animal was fully extended and the needle insertion site was determined by palpation of the femoral head. This bony protrusion, along with the lateral part of the iliac crest and the surrounding tissues, form a well-defined area where the sciatic nerve is located. The vehicle (0.2 ml) was injected here with or without a local anesthetic. Frequency of blockage and time to onset were measured for duration of motor blockade (paralysis of the hind leg) and duration of sensory blockade (inhibition of flexor reflex). The duration of motor blockade was calculated from the loss of hind limb support for weight loss to recovery of walking ability. Sensory blockade lasted from cessation of response to painful stimuli induced by toe pads to return to flexor reflex.

Results

Lidocaine injection solutions in ethanol / water and lidocaine solutions in ethanol / PEG 400 were compared with a reference solution containing 2% by weight of water-soluble lidocaine hydrochloride for postoperative analgesia. As can be seen in Table 2, all of the solutions of the invention produced more permanent motor and sensory blockade than the reference solution.

Table 1

Composition of injectable solutions of lidocaine

Sample number composition (G / 100g) lido- Cain Lidoka-Ethanol in -HCl PEG 400 Water pH I 5.0 34.0 - 61.0 9.5 II 10.0 36.0 - 54.0 10.3 III 8, 6 3.4 88.0 - 9.4 ARC 17.6 3.4 79.2 - 9.2 Ref. - 2.0 - 98.0 6, 8

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · freup - to request

Table 2

Durations, motor and sensory blockade

Sample concentration Moto Gyako- Sensory Gyako- number rationality blockade riság blockade riság O, O (minute) I 5, 0 > 96 h 5/6 160 minutes 5/6 η = 1 > 380> 96 h n = 2 > 96 h n = 2 II 10.0 > 24 h 3/3 3/3 > 24h III 8, 6 > 24 h 6/6 6/6 n = 1 121 ± 4.3 131.8 ± 9.5 n = 5 ARC 17.4 > 120 <24 h 3/3 3/3 n = 1 > 120 <24 h > 72 h n = 2 Ref. 2.0 22.4 ± 3.5 6/6 13.5 ± 2 6/6

Claims (12)

Claims An injectable solution for administering one or more active ingredients, characterized in that the active ingredient is dissolved in a biologically acceptable solvent from which the active ingredient is precipitated upon injection, thereby forming a solid phase of the solution in situ. Injection solution according to claim 1, characterized in that the neutral form of the compound is dissolved in a biologically acceptable solvent from which the active substance is precipitated upon injection, thereby forming a solid phase of the solution in situ. A solution for injection according to claim 1, characterized in that the active ingredient is a topical anesthetic and / or analgesic, a steroid or an agent acting on the central nervous system. A solution for injection according to claim 3, characterized in that the active ingredient is a local anesthetic such as lidocaine, prilocaine, mepivacaine, bupivacaine, ropivacaine or etidocaine. The solution for injection according to claim 3, characterized in that it is a local anesthetic with lidocaine. 6. The solution for injection according to claim 5, wherein the topical anesthetic is lidocaine. 7. The solution for injection according to claim 1, wherein the biologically acceptable solvent is one or more mixtures of water, an alcohol and a polyethylene glycol. 8. The solution for injection according to claim 6, wherein the biologically acceptable solvent is: (a) a mixture of ethanol and water, b) polyethylene glycol 300 (PEG 300) or c) a mixture of polyethylene glycol 400 (PEG 400) and ethanol. The injection solution according to claim 1, characterized in that the sterile injection solution contains 5-80% by weight of lidocaine, 10-35% by weight of ethanol and 2-65% by weight of water. 10. The solution for injection according to claim 1, wherein the sterile solution for injection contains 15-20% by weight of lidocaine and 80-85% by weight of PEG 300. 11. The injection solution according to claim 1, wherein the sterile injection solution contains 5-20% by weight of lidocaine, 2-10% by weight of ethanol and 75-90% by weight of PEG 400a. 12. The solution for injection according to claim 1, characterized in that the sterile solution for injection is administered intramuscularly, epidurally, spinally, intrathecally, rectally. rectally, locally, orally, or lung inhalation by given. 13. Procedure 1. claim of solution for injection Sarah, with signal Yi handmaid v e that the specific a certain amount of the active ingredient (s) is mixed with the respective solvent in a bottle which is then sealed, shaken and stored at room temperature for a maximum of one day, and then the solution is sterilized by steam sterilization or aseptically prepared on a 0.2 μιη filter filter through. The Trustee