Field of die invention

The present invention is directed to an injectable solution for administration of one or more active compounds and a process for the preparation thereof.

Background of the invention

Sterile suspensions, i.e. formulations containing at least two phases, a solid and a liquid phase, are difficult to manufacture in large scale. Suspensions are by definition thermodynamically instable, and separation of the different phases will occur with time. Steam sterilization of such formulations often speeds up the separation. Aseptic preparation by filtration through a 0.2 μm filter is not applicable on suspensions. There are few suspension products on the market of this type. Novalucol and Roxiam are examples of mixtures for oral administration. Oil containing suspensions for injection are available for CNS indications. There is a need for an injectable suspension which can be sterilized either by steam sterilization or by filtration through a 0.2 μm filter.

Prior art

In NL 9000634 stable aqueous suspensions of water-soluble local anaesthetics and/or narcotic analgesics are disclosed where the local anaesthetics and/or narcotic analgesics have a specific particle diameter and said aqueous suspensions also containing a non-ionic surface-active agent. These suspensions are being sterilized by steam sterilization or with the aid of gammarays. When sterilized by

heating the suspended particles melt and wholly or partly flow together. To obtain the suspension again the residence is cooled down to a temperature below the freezing point of the aqueous medium while shaking. However, this is a complicated way of sterilizing, it takes time and it is not possible to control the sizes of the particles recovered.

Also in EP 197 308 a ready made suspension including a water insoluble local anesthetics for injection is disclosed. During steam sterilization of the suspension the same problem as mentioned above arises, i.e. the particles of the local anesthetic melts and have to be resuspended.

EP 213 851 discloses injectable semi-solid matrices, which mechanically hinder the release of the active compound. In fact, it is the matrice that will be degraded once injected. Also the formulation here is semi-solid and not solid.

It is well-known that solutions can be obtained by chelation with metal ions. This is disclosed in e.g. US 4 259 331. Here the mixed metal chelate releases an amount of active compound by injection. However it is desirable to prepare an injectable solution not including metal ions, but which solution still precipitates the active compound once injected.

Further in Dialog International Services, file 5.B10SIS, Benzon et al present a study concerning the effect of polyethylene glycol (PEG) on mammalian nerve impulses. PEG is a polymeric compound used as a vehicle for depot steroid preparations. According to the study,

PEG in a concentration of up to 40% does not cause neurolysis.

Another way of controlling postoperative pain is described by Cassuto et al in Anaesthesiology 895,_68, 1988, namely the administering of Xylocaine spray, i.e. a solution if Hdocaine base in ethanol, topically in surgical wounds of patients undergoing hermiorraphy.

Also in Acta Anaesthesiol Scand 112-114, 36, (1992) the use of the same lidocaine aerosol is described for post-operative pain following minor gynaecological laparotomy. The base form of lidocaine which is used in both these two studies is available in vivo, i.e. the solubility in the tissue fluids is high enough to give both sensory and motor block. This is also confirmed by the present invention.

® Xylocaine spray used in the earlier studies contains, howeve number of additives, which should be avoided in wounds.

In J. Clin. Pharm. and Therap. 197-204, 15, 1990 and in a report called "Slow-release effect of pH-adjusted bupivacaine, in vitro demonstration" Bourqet et al and Bonhomme et al described studies of the slow-release effect of alkalinized bupivacaine hydrochloride solutions. Further, in Correspondance in Plast. Reconstr. Surg. 543, 84, 1989 and in Comment in Ann. R. Coll. Surg. Engl. 17, 72, 1989 the possibility to administer alkanized bupivacaine hydrochloride solutions topically to control post-operative pain has been pointed out.

Slow-release of analgetics have also been observed for base forms of analgetics such as nalbuphine in Drug Devel and Ind Pharm 67, F7,

1991, where it is described how suspensions of nalbuphine are prepared and injected. To be able to prepare an injectable suspension three suspending agents, methylcellulose, sodium carboxymethyl- cellulose, and PEG are added. However, these agents give possible side-effects and therefore a suspension containing as few auxiliaries as possible is desirable.

None of the prior art documents solves the problem how to prepare a stable injectable suspension of an active agent, where said suspension has the advantage that the effect thereof is much prolonged. According to present invention said problems can be solved.

Oudine of the invention

It has been found that the difficulties of preparing sterile suspensions for injection can be avoided by preparing an injectable solution for administration of one or more active compounds solved in a biologically acceptable solvent whereby the active compound upon administration precipitates, due to changes of d e conditions of solubility, i.e. the solid phase of die suspension is formed in situ. Sterilization of a solution can be performed by methods not applicable on suspensions namely by steam sterilization or by filtration through a 0.2 μm filter.

Another advantage with die present invention is that the active compound precipitates in situ, i.e. the solid phase might also act as a depot in the tissue, due to its solubility properities or the presence of other materials (excipients). Consequently, large doses of the active

compound can be administered in vivo, without obtaining severe toxic reactions. The present invention discloses an injectable solution where the active compound could be e.g. a local anaesthetic agent, an analgesic agent or a combination of these two agents giving both an analgesic and an anaesthetic effect, which sometimes is desirable. The active compound could also be a steroid or a drug for CNS indications.

The active compound is preferably a local anaesthetic agent such as lidocaine, prilocaine, mepivacaine, bupivacaine, ropivacaine or etidocaine but it can also be some other local anaesthetic agent. Most preferably the active compound is lidocaine.

The physico-chemical properities of the active compound, i.e. solubility, the influence of pH, salts and temperature on die solubility, are important parameters to control the precipitation of the active compound in situ.

The local anaesthetic agent used according to d e present invention is in its neutral form which is less soluble than the hydrochloride form. It has been found tiiat the neutral form of the anaesthetic agent enhances the duration of motor and sensory block compared to a solution of said anaestetiiic agent in hydrochloride form.

Since the neutral form is not soluble in water a lipophilic vehicle was determined which solves die active compound and thus made it suitable for injection. Upon administration this solution, i.e. the active compound and die vehicle, is changed due to changes of die conditions resulting in precipitation of the active compound. Thus the

injectable system acts as if it was a suspension. The neutral form is unchanged and can be e.g. the base form.

The optimal vehicle for a specific active compound according to present invention, is determined experimentally and die function confirmed in vivo. The physico-chemical properties of the active compound determines the solubility of the active compound. The lower limit of solubility is determined by d e lowest effective concentration of the active compound (therapeutic concentration). The upper limit of the solubility should be equal to the desired amount of precipitated active compound.

The vehicles are biologically acceptable solvents and a mixture of one or more of water, an alcohol and a polyetiiylene glycol or another biologically acceptable solvent. Especially preferred vehicles according to the invention are:

a) ethanol, 99.5% b) a mixture of ethanol and water c) polyethylene glycol 300 (PEG 300) d) a mixture of PEG 300 and etfianol e) a mixture of PEG 300, ethanol and water f) polyethylene glycol 400 (PEG 400) g) a mixture of PEG 400 and etiianol h) a mixture of PEG 400, ethanol and water i) propylene glycol j) a mixture of propylene glycol and water k) a mixture of propylene glycol and ethanol

1) glycerol

m) a mixture of glycerol and etiianol 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

According to an especially preferred embodiment of the invention the sterile injectable solution contains 5-80 w/w% of lidocaine solved in a mixture of 10-35 w/w% of ethanol and 2-65 w/w% of water.

According to a anotiier preferred embodiment of die invention the sterile injectable solution contains 15-20 w/w% of lidocaine solved in 80-85 w/w% of PEG 300.

According to a further preferred embodiment of die invention the sterile injectable solution contains 5-20 w/w% of lidocaine solved in in a mixture of 2-10 w/w% of ethanol and 75-90 w/w% of PEG 400.

The injectable sterile solution according to present invention can be administered intramuscularly, epidurally, spinally, intratechally, rectally, topically, orally or in the lung.

The sterile injectable solution is prepared by mixing the specific active compound witii the solvent in a flask. The flask is sealed and tiien shaken to solve the active compound. To completely solve the

active compound the flask is left in room temperature during maximum one day. After that the solution is sterilized either by steam sterihzation or when prepared aseptically and filtered ti rough a 0.2 μm filter.

The following examples illustrate the invention more in detail

Example 1

Lidocaine 5.0 % by weight Ethanol, 99.5% 34.0 % by weight

Water 61.0 % by weight

A sterile injectable solution was prepared in accordance witii the general preparation procedure above. A long duration of motor and sensory block was obtained when injected in vivo.

Example 2

Lidocaine 10.0 % by weight

Ethanol, 99.5% 36.0 % by weight Water 54.0 % by weight

A sterile injectable solution was prepared in accordance witii the general preparation procedure above. A long duration of motor and sensoric block was obtained when injected in vivo.

Example 3

Lidocaine 75.0 % by weight

Ethanol, 99.5% 20.0 % by weight

Water 5.0 % by weight

A sterile injectable solution was prepared in accordance with die general preparation procedure above.

Example 4 Lidocaine 80.0 % by weight

Ethanol, 99.5% 15.0 % by weight

Water 5.0 % by weight

A sterile injectable solution was prepared in accordance with the general preparation procedure above.

Example 5

Lidocaine 17.8 % by weight

PEG 300 82.2 % by weight

A sterile injectable solution was prepared in accordance witii the general preparation procedure above.

Example 6 Lidocaine 17.8 % by weight

PEG 300 82.2 % by weight

A sterile injectable solution was prepared in accordance witii die general preparation procedure above.

Example 7

Lidocaine 8.6 % by weight

Ethanol, 99.5% 3.4 % by weight

PEG 400 88.0 % by weight

A sterile injectable solution was prepared in accordance with the general preparation procedure above. A long duration of motor and sensoric block was obtained when injected in vivo.

Example 8

Lidocaine 17.4 % by weight

Ethanol, 99.5% 3.4 % by weight

PEG 400 79.2 % by weight

A sterile injectable solution was prepared in accordance with the general preparation procedure above. A long duration of motor and sensoric block was obtained when injected in vivo.

Example 9 Prilocaine 10.0 % by weight

Ethanol, 99.5 % 35.0 % by weight

Water 55.0 % by weight

A sterile injectable solution was prepared in accordance with the general preparation procedure above.

Example 10

Prilocaine 20.0 % by weight

PEG 300 80.0 % by weight

A sterile injectable solution was prepared in accordance with the general preparation procedure above.

Example 11

Prilocaine 10.0 % by weight

Ethanol, 99.5 % 5.0 % by weight

PEG 400 85.0 % by weight

A sterile injectable solution was prepared in accordance with the general preparation procedure above.

Example 12 Prilocaine 15.0 % by weight

Ethanol, 99.5 % 5.0 % by weight

PEG 400 85.0 % by weight

A sterile injectable solution was prepared in accordance witii the general preparation procedure above.

Example 13

Mepivacaine 7.7 % by weight

Ethanol, 99.5 % 50.0 % by weight Water 42.3 % by weight

A sterile injectable solution was prepared in accordance with die general preparation procedure above.

Example 14

Mepivacaine 10.0 % by weight

Ethanol, 99.5 % 60.0 % by weight

Water 30.0 % by weight

A sterile injectable solution was prepared in accordance with the general preparation procedure above.

Example 15 Bupivacaine 1.1 % by weight

Ethanol, 99.5 % 37.5 % by weight

PEG 400 30.0 % by weight

Water 31.5 % by weight

A sterile injectable solution was prepared in accordance with the general preparation procedure above.

Example 16

Bupivacaine 1.1 % by weight Ethanol, 99.5 % 49.6 % by weight

PEG 400 49.3 % by weight

A sterile injectable solution was prepared in accordance witii the general preparation procedure above.

Example 17

Ropivacaine 1.0 % by weight

Etiianol, 99.5 % 48.2 % by weight

PEG 400 50.8 % by weight

A sterile injectable solution was prepared in accordance with the general preparation procedure above.

Example 18

Ropivacaine 1.0 % by weight

Ethanol, 99.5 % 29.7 % by weight

PEG 400 69.3 % by weight

A sterile injectable solution was prepared in accordance witii the general preparation procedure above.

Biological effect Material and metiiods

Male guinea-pigs (Dunkin-Hartley, HB Sahlins Fδrsδksdjursfarm, Malmδ, Sweden), weighing 300-600 g, were used. The animals were housed 3 to a cage with free access to food and water.

Method 1

Sciatic nerve block. Male Guinea-pigs of the Dunkin-Hartley strain (291-563 g) were used according to a modification of the technique of Shackell described in Anesth. Analg. 20-22, 14 (1935). The hind leg was extended to die full length, and the landmark for needle insertion was located by palpation of the great trochanter of the femur head. This bony prominence together with the lateral aspect of the Os Coxa and adjacent tissues forms a well defined space in which the sciatic nerve is located. The vehicle with or without local anaesthetic was injected (0,2 ml) into this pocket. Frequency of block, time of onset, duration of motor block (hind limb paralysis) and sensory block (flexor reflex block) were measured. The period of motor block was defined as loss of weight support from the hind leg to the ability to walk. The sensory block was defined as onset of unresponsiveness to painful stimuli applied by pinching the foot-pads to the return of flexor reflex.

Results

The injectable solutions of lidocaine solved in mixtures of ethanol and water and d e solutions of lidocaine solved in mixtures of ethanol and PEG 400 were compared to a reference solution containing 2 % , by weight of the water soluble lidocaine

hydrochloride, with regard to their ability to relieve postoperative pain. As seen from table 2, all these solutions according to the present invention giving longer durations of motor block and sensoric block compared to me reference solution.

Table 1 Compositions of injectable solutions of lidocaine

Table 2. Durations, motor and sensoric block