BE1026845B1 - Composition for use in local infiltration analgesia (LIA) - Google Patents

Abstract

The present invention relates to a pharmaceutical solution comprising the ingredients: a non-steroidal anti-inflammatory and an anesthetic. The invention also relates to a pre-filled syringe comprising the pharmaceutical solution and a method of manufacturing the pre-filled syringe.

Description

COMPOSITION FOR USE IN LOCAL INFILTRATION ANALGESIA (LIA)

TECHNICAL DOMAIN

The invention relates to a pharmaceutical solution suitable for analgesic use, preferably for local infiltration analgesia (LIA).

STATE OF THE ART

After a surgical procedure, one of the most frequent complications immediately after surgery is the appearance of pain. Post-operative pain leads to patient discomfort and may also cause increased morbidity. Combating pain is an important part of perioperative care today. The pain relief starts already during the operation and continues during the awakening period. Synthetic opioids are mostly used for pain relief around the surgery. People often switch to morphine or piritramide immediately after surgery as post-operative pain relief. However, for such opioids, the risk of habituation and dependence should be taken into account and chronic use should be avoided.

EP 105 467 1 describes the use of ropivacaine in the treatment of muscle bone pain, musculoskeletal pain. Furthermore, new techniques and pharmaceuticals have been developed with regard to pain management to treat postoperative pain and avoid the use of strong opioids.

Kerr and Kohan 2008, developed the LIA technique in which a specific pharmaceutical solution is administered to combat pain after reconstructing or replacing a hip or knee with a prosthesis. Essving et al. 2010, report reduced morphine use and pain sensitivity after placement of a full knee prosthesis using LIA.

The pharmaceutical solutions are often formulated during surgery in the operating theater or by the pharmacy attached to the hospital on the basis of the necessary raw materials and / or specialties.

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However, these preparations are not standardized, cannot be traced and as a result, a good and consistent quality of the pharmaceutical solution cannot be guaranteed. Moreover, such ad hoc preparations are subject to a very high margin of error. In addition, during the preparation of the pharmaceutical solutions, no measures are taken regarding their aseptic preparation, which increases the risk of contamination when used.

The present invention aims at least to solve some of the above-mentioned problems or disadvantages.

SUMMARY OF THE INVENTION

For this purpose, the invention provides a pharmaceutical solution according to claim 1. Preferred forms of the device are set out in claims 2 to 11.

In a second aspect, the present invention relates to a pre-filled syringe comprising a pharmaceutical solution according to claim 12. A preferred form of the pre-filled syringe is described in subclause 13.

In a third aspect, the present invention relates to the pre-filled syringe for pain relief after an orthopedic surgical procedure according to claim 14. Preferred forms of claim 14 are described in claims 15 to 18.

A final aspect concerns a method according to claim 19.

DETAILED DESCRIPTION

The present invention provides a pharmaceutical solution that satisfies the pharmaceutical technical aspects. The solution is fully standardized and guarantees efficient and effective acute pain relief with each administration. In addition, this pharmaceutical solution is also stable, as prescribed according to the pharmaceutical guidelines, which offers good and consistent quality for the benefit of the patient.

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Unless otherwise defined, all terms used in the description of the invention, including technical and scientific terms, have the meaning generally understood by those skilled in the art of the invention. For a better assessment of the description of the invention, the following terms are explicitly explained.

One, de and in this document refer to both the singular and the plural unless the context clearly assumes otherwise. For example, a segment means one or more than a segment.

When around or around this document is used with a measurable quantity, a parameter, a duration or moment, and the like, variations of +/- 20% or less, preferably +/- 10% or less, more at preferably +/- 5% or less, even more preferably +/- 1% or less, and even more preferably +/- 0.1% or less than and of the quoted value, insofar as such variations apply in the described invention. However, this should be understood to mean that the value of the quantity by which the term is used approximately or round is itself specifically disclosed.

The terms include, comprising, consisting of, comprising, containing, containing, containing, contents, containing are synonyms and are inclusive or open terms which indicate the presence of what follows, and which do not exclude or prevent the presence of other components, features, elements, members, steps, known from or described in the prior art.

The term pharmaceutical product or pharmaceutical solution or pharmaceutical composition includes a substance or combination of substances that treat pain and / or restore or improve physiological functions.

The term active ingredient of the present invention includes the pharmaceutically active agent of the pharmaceutical product. In addition to an active substance, the pharmaceutical product can also comprise auxiliary substances.

Quoting numerical intervals through the endpoints includes all integers, fractions, and / or real numbers between the endpoints, including these endpoints.

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In a first aspect, the invention relates to a pharmaceutical solution comprising the ingredients: a non-steroidal anti-inflammatory, selected from the group of ketorolac, piroxicam, ibuprofen, diclofenac or a combination thereof; and an anesthetic selected from the group of ropivacaine, bupivacaine, levobupivacaine or a combination thereof.

Analgesics and anesthetics are two types of analgesic drugs with different effects. Analgesics relieve pain without complete loss of sensation or muscle movement. Anesthetics, on the other hand, block all sensation, including pain. Some forms of anesthesia cause loss of consciousness, such as general anesthesia, others, such as local or regional anesthesia, eliminate all pain sensations from the parts of the body to be treated or treated while maintaining consciousness.

Analgesics are divided into non-opioid and opioid analgesics.

The group of non-opioid medications is often used in mild to moderate pain, distinguishing three major groups of products: acetaminophen, salicylates, and nonsteroidal anti-inflammatory medications (NSAID).

Paracetamol has an antipyretic and analgesic effect. However, paracetamol does not have an anti-inflammatory effect, so it is not recommended for inflammatory pains. It is the first choice pain reliever because it is efficient and has few side effects during normal use. Examples of paracetamol medications include Algostase Mono®, Curpol®, Dafalgan®, Dolol-Instant®, Dolprone®, Lemsip®, Momentum®, Panadol®, Paracetamol EG®, Paracetamol Teva®, Perdolan®, Pe-Tam®, Sanicopyrine ®, Sinaspril®, White Cross Mono®.

Salicylates (acetylsalicylic acid) have an analgesic, fever-reducing and anti-inflammatory effect. Salicylates show more side effects than paracetamol. Examples include Acenterine®, Alka Seltzer®, Asa Mylan®, Asaflow®, Aspegic® (Lysine Acetyl Salicylate), Aspirin®, Cardegic® (Lysine Acetyl Salicylate), Cardioaspirine®, Cardiphar®, Dispril®, Sedergine®.

NSAIDs are especially useful for an inflammatory problem. NSAIDs not only have an analgesic effect, albeit to varying degrees, but also an antipyretic and anti-inflammatory effect. Given their side effects, NSAIDs become single

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BE2018 / 5865 used when really needed. Examples include: Apranax®, Arcoxia®, Arthrotec®, Biofenac®, Brexine®, Brufen®, Buprophar®, Butazolidin®, Cataflam®, Celebrex®, Diclofenac EG®, Diclofenac Sandoz®, Diclofenac Teva®, Diclofenac-K-Ratiopharm ®, Diclofenac-Ratiopharm®, Docmeloxi®, Docpiroxi®, Dolcidium®, Dolofin®, Duraprox®, Dynastat®, Epsilon®, Feldene®, Froben®, Ibumed®, Ibuprofen EG®, Ibuprofen Sandoz®, Ibuprofen Teva®, Ibuprofen ®, Indocid®, Malafene®, Meloxicam EG®, Meloxicam Sandoz®, Meloxicam Teva®, Meloxicam-Ratiopharm®, Merck-Piroxicam®, Mobic®, Motifene®, Naproflam®, Naprosyne®, Naproxen Sandoz®, Naproxen Teva®, Naproxen Topgen®, Naproxene EG®, Nurofebryl®, Nurofen®, Optalidon New Formula®, Perdofemina®, Perdophen®, Perviam®, Piromed®, Piroxicam EG®, Piroxicam Sandoz®, Piroxicam Teva®, Piroxicam-Ratiopharm®, Piroxitop® , Piroxymed®, Polydene®, Polyflam®, Prexigem®, Rofenid®, Spidifen®, Taradyl®, Tilcotil®, Tolindol®, Voltaren®.

The group of opioid analgesics contain weak and strong opioids and are chemically related to opium, a substance obtained from poppy seeds. Mild opioids are used for mild to severe pain. This medication has a ceiling effect. Examples of weakly acting opioids are: Algocod®, Dafalgan Codeine®, Docparacod®, Panadol Codeine®, Perdolan Codeine®, Contramal®, Doctramado®, Dolzam®, Tradonal®, Tramadol EG®, Tramadol Sandoz®, Tramadol Teva®, Tramium ®, Zaldiar®. Powerful opioids are the most powerful pain killers from the WHO pain ladder. Examples include: Docmorfine®, Kapanol®, Morphine Teva®, MS Contin®, MS Direct®, Oramorph®, Subutex®, Temgesic®, Transtec®, Durogesic®, Fentanyl Sandoz®, Matrifen®, Palladone®, Oxycontin®.

The non-opioid medication is characterized by their analgesic effect, but with a ceiling effect. This means that after administering a certain amount of this medication it is no longer useful to administer an extra dose to obtain an analgesic effect. In such a case, this medication is combined with a weakly acting opioid. These opioids, like the non-opioid medications, have a ceiling effect. If pain relief is not effective with previous medications, strong acting opioids are employed.

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The combination of an NSAID and an anesthetic is important to obtain an effective, analgesic effect. This combination can also be administered to those who commonly use morphine or other strong opioids and provide pain relief.

In one embodiment, the concentration of the non-steroidal anti-inflammatory in the pharmaceutical solution is between 0.05 and 1 mg / ml, preferably between 0.05 and 0.9 mg / ml, more preferably between 0.05 and 0.8 mg / ml, more preferably between 0.05 and 0.7 mg / ml, more preferably between 0.05 and 0.6 mg / ml, more preferably between 0.1 and 0.5 mg / ml, more preferably between 0.1 and 0.4 mg / ml, more preferably between 0.1 and 0.35 mg / ml ml, more preferably between 0.15 and 0.3 mg / ml, most preferably between 0.2 and 0.3 mg / ml.

These final concentrations appear to be most optimal in terms of post-operative pain relief, antipyretic and anti-inflammatory effect, as well as in stability of the composition. At higher or lower concentrations, stability is difficult to ensure.

In a preferred form, the non-steroidal anti-inflammatory used is ketorolac.

Ketorolac or ketorolac tromethamine is an NSAID. Ketorolac is administered by intramuscular or intravenous injection. Ketorolac can also be administered orally or through a nasal spray. Oral therapy is used only as a continuation of the intramuscular or intravenous starting point. Preferably ketorolac is administered intramuscularly.

Ketorolac is used for short-term pain relief lasting no more than five days. After a surgical procedure, post-operative pain is the first pain to be controlled, with ketorolac being suitable for post-operative pain treatment.

In a preferred form, the concentration of ketorolac in the pharmaceutical solution will be between 0.1 and 0.5 mg / ml.

These concentrations of ketorolac in the pharmaceutical solution have sufficient analgesic, antipyretic and anti-inflammatory properties when administered to a

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B BE2018 / 5865 treat fabric. Preferably, the concentration of ketorolac in the solution is between 0.1 and 0.4 mg / ml, more preferably between 0.1 and 0.35 mg / ml, more preferably between 0.15 and 0.3 mg / ml, most preferably between 0.2 and 0.3 mg / ml ml. In addition to the analgesic, antipyretic and antiphlogistic effect of ketorolac in the pharmaceutical solution, ketorolac is also stable at such concentrations.

In one embodiment, the concentration of the anesthetic in the pharmaceutical solution is preferably between 1.25 and 5 mg / ml, more preferably between 1.5 and 4.5 mg / ml, more preferably between 1.75 and 4 mg / ml, more preferably between 1.75 and 3.75 mg / ml, more preferably between 1.75 and 3.25 mg / ml, more preferably between 1.8 and 2.75 mg / ml, more preferably between 1.8 and 2.5 mg / ml, more preferably between 1.8 and 2.4 mg / ml more preferably between 1.85 and 2.3 mg / ml, more preferably between 1.85 and 2.2 mg / ml, more preferably between 1.9 and 2.1 mg / ml, more preferably between 1.95 and 2.05 mg / ml, most preferably 2 mg / ml.

These final concentrations appear to be the most optimal to combat postoperative pain. Furthermore, these concentrations also guarantee the stability of the composition. At higher or lower concentrations, stability is difficult to ensure.

In a preferred form, the anesthetic used is ropivacaine.

The local anesthetic ropivacaine is preferred for its reduced cardiotoxicity compared to, for example, bupivacaine and levobupivacaine. In addition, ropivacaine also has intrinsic vasoconstrictor properties.

In a preferred form, the concentration of ropivacaine in the pharmaceutical solution will be between 1.25 and 5 mg / ml.

These final concentrations of ropivacaine in the pharmaceutical solution have an adequate analgesic effect when administered to the tissue to be treated. Preferably, the concentration of ropivacaine in the pharmaceutical solution is between 1.5 and 4.50 mg / ml, more preferably between 1.75 and 4 mg / ml, more preferably between 1.75 and 3.75 mg / ml, more preferably between 1.75 and 3.25 mg / ml, more preferably between 1.8 and 2.75 mg / ml, more preferably between 1.8 and 2.5 mg / ml,

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BE2018 / 5865 more preferably between 1.8 and 2.4 mg / ml, more preferably between 1.85 and 2.3 mg / ml, more preferably between 1.85 and 2.2 mg / ml, more preferably between 1.9 and 2.1 mg / ml, more preferably between 1.95 mg / ml and 2.05 mg / ml, most preferably 2 mg / ml. This concentration of ropivacaine in the pharmaceutical solution remains stable upon storage, which ensures the analgesic effect of ropivacaine.

In another or further embodiment, the ratio of ropivacaine to ketorolac in the pharmaceutical solution is 12: 1 to 4: 1 for optimal pain relief. Preferably, the ratio between ropivacaine and ketorolac is 10: 1 to 5: 1, more preferably between 10: 1 to 6: 1. Such a ratio between ropivacaine and ketorolac in the pharmaceutical solution guarantees the stability of both components in the solution.

In a further or subsequent embodiment, the pharmaceutical solution contains adrenaline. Adrenaline is a hormone and a neurotransmitter. It is produced in the adrenal medulla and in some nerve cells. At too high concentrations of adrenaline, this substance is harmful to the body.

Preferably, the adrenaline will be present at a concentration between 1 and 10 µg / ml, preferably between 3 and 6 µg / ml.

In a preferred embodiment, the pharmaceutical solution comprises between 0.1 and 0.5 mg / ml ketorolac, between 1.25 and 5 mg / ml ropivacaine, and optionally between 1 and 10 µg / ml adrenaline.

Preferably, a saline solution such as a NaCl solution is used as a solvent in the pharmaceutical solution. The NaCl concentration is preferably between 0.5 and 1.5 Μ, more preferably between 0.75 and 1 Μ, such as 0.9 Μ. These concentrations of NaCl serve as a physiological solvent, as these salt concentrations approximate the salt concentrations in the blood.

The combination of ketorolac, ropivacaine and adrenaline in the pharmaceutical solution according to the preferred concentrations offers an analgesic, antipyretic, antiphlogistic and anesthetic effect and appears to have a long-term stability and thus a longer shelf life. The pharmaceutical solution of the present invention has a standardized concentration of ketorolac, ropivacaine and

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BE2018 / 5865 adrenaline. The effectiveness of the pharmaceutical solution is hereby guaranteed.

In one embodiment, the pharmaceutical solution has a stability of at least 80 days, preferably at least 90 days, at a temperature comprised between 2 and 8 ° C.

Pharmaceutical products are subject to change upon storage. There may be a decrease in the level of the active substance, the formation of toxic or non-toxic decomposition products, changes in appearance, loss of sterility and other forms of spoilage. When storing a pharmaceutical product, a distinction is made between physical decomposition and chemical decomposition that affect the stability of the product.

A physical decomposition of the pharmaceutical product includes changes in the properties of the product, without a change in the molecular structure. Usually these changes concern the dosage form, for example the shakeability of a suspension, the viscosity of a liquid. It can also involve cloudiness in solutions, crystal growth, agglomeration or changes in pH. The physical decomposition can also relate to the taste, color or odor of the product. These changes may affect the efficacy, usability and safety of the medicine.

When storing medicines, chemical (decomposition) reactions often take place, as a result of which the content of, for example, the active substance decreases. The most common chemical decomposition reactions include hydrolysis, oxidation, isomerization and photolysis. These reactions usually proceed faster at a higher temperature. Other factors that can affect are pH or humidity.

At a sufficiently high humidity, pharmaceutical products, both liquid preparations and solid products, are susceptible to hydrolysis. The rate of hydrolysis is further influenced by the pH and temperature. The hydrolysis of a chemical compound can yield a product with poorer water solubility, which can result in a precipitate in an initially clear solution.

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A pharmaceutical product can also be susceptible to oxidation. Oxidation is prevented in two ways by, on the one hand, limiting contact with oxygen or, on the other hand, adding antioxidants. Adrenaline is sensitive to oxidation and on decomposition successively changes from colorless to yellow, dark yellow (amber) to brown. The oxidation goes faster the higher the pH. Adrenaline is most stable at a pH of 3.2 to 3.6. Accordingly, when storing the adrenaline as an injection liquid, it is advised to store the pre-filled syringe in a closed container containing a light barrier film, such as an aluminum foil, for example, to store the pharmaceutical solution out of the influence of light and replace it if there is any discoloration or precipitation in the solution. In one embodiment, the pharmaceutical solution is packaged aseptically in the light barrier film to protect the solution from photosensitive degradation.

Another form of chemical decomposition of the pharmaceutical product includes photolysis, where the product decomposes under the influence of light. All kinds of decomposition reactions can follow, but oxidation is most common (photo oxidation). Ultraviolet (UV) light results in most direct photochemical decompositions. Photolysis can be limited or prevented by preventing light from reaching the medicine during and after preparation.

Decomposition products are often ineffective and sometimes even toxic. The shelf life as a result of decomposition is determined on the one hand by legal requirements on the content of the active substance relative to the stated strength, but on the other hand also by the toxicity of any decomposition products. It is customary to accept a content deviation of 5 to 10%. At the start of the storage period, the content is between 95 and 105% of the declared content. At the end of the retention period, it should be between 90 and 110%. After at least 80 days, preferably at least 90 days, the pharmaceutical solution according to the present invention still falls within the established content limits that the solution must meet.

In addition, microbiological aspects play a role in the shelf life of medicines. The pharmaceutical solution according to the present invention should be free from micro-organisms. Testing the sterility of the solution is described in the European Pharmacopoeia, EP 2.6.1. In addition to testing sterility, it is also important to know the amount of endotoxins in the solution.

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The determination of the endotoxins are described in the European Pharmacopoeia, EP 2.6.14. The microbiological quality of the solution may deteriorate after preparation due to the multiplication of the microorganisms present or if outside microorganisms contaminate the preparation, during storage or during use. The microbiological shelf life depends on the degree and nature of the initial contamination, the chance of contamination of the preparation in the packaging and the suitability of the preparation for propagation of microorganisms. Good microbiological quality can be achieved in the preparation by starting from good quality raw materials, working hygienically, if necessary applying a germ-reducing treatment, such as sterilization, and ensuring that the packaging is clean and sterile. The construction and size of the packaging, and the hygiene during use determine the chance of infection. The composition of the preparation and the conditions under which the preparation is stored determine the suitability for propagation of microorganisms, in particular the microbiological vulnerability. The microbiological shelf life often improves at a low temperature. Preferably, the pharmaceutical solution according to the present invention is stored at a temperature between 2 and 25 ° C, more preferably between 15 and 25 ° C. In another embodiment, the pharmaceutical solution of the present invention is stored at a temperature comprised between 2 and 8 ° C, more preferably between 2 and 6 ° C, most preferably at 4 ° C.

Testing the stability of pharmaceutical products is necessary to know the quality, safety and efficacy of the product. A person skilled in the art is familiar with the various techniques in which the stability of a pharmaceutical solution is tested. The stability test is preferably performed to determine an active pharmaceutical ingredient (API) or a final pharmaceutical product (FPP). Photometric titration, ion chromatography, near infrared spectroscopy (NIRS) are possible analysis methods to determine the API content. Preferably, liquid chromatography with ultraviolet detection (LC-UV) is used to measure the degradation of the active pharmaceutical ingredient. Preferably, the stability of ketorolac is measured according to the method described in the U.S. Pharmacopoeia, USP 41. The stability of adrenaline is preferably measured according to the method described in the British Pharmacopoeia, BP 2018.

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In a preferred embodiment, the pharmaceutical solution is prepared aseptically.

In a second aspect, the invention relates to a pre-filled syringe suitable for being provided with a hypodermic needle comprising a pharmaceutical solution as described above. In this way, the composition can be used in a standardized manner. The doctor does not need to know how to prepare in the operating theater, but can rely on a standardized, stable and aseptic composition, ready for use and at the optimal concentrations. This excludes variation, and the margin of error becomes practically zero. In addition, the risk of contamination is also drastically reduced, since an aseptic composition is administered into the wound.

The pre-filled syringe of the present invention is preferably filled aseptically with the aseptic pharmaceutical solution.

The pre-filled syringe is suitable to be provided with a hypodermic needle. Non-limiting examples of needles are a 4 cm long 18-G needle, a 10 cm long 19-G needle, or equivalent. The pharmaceutical solution can be administered intramuscularly using this needle. Preferably, the pharmaceutical solution is injected by means of a moving needle technique, known to the person skilled in the art, whereby the needle is placed about 0.5 to 1 cm under the tissue, the injection liquid is injected into the tissue while the needle is withdrawn from the tissue, and where the needle makes a specific back and forth motion. In one embodiment, the pre-filled syringe includes a leak-free connection to the injection needle, the connection comprising a screw connection or a non-threaded connection. Preferably, the pre-filled syringe includes a screw connection to the injection needle.

In one embodiment, the syringe has a volume between 20 and 100 ml, preferably 50 ml.

The pharmaceutical solution and syringe of the present invention are well suited for use in reducing pain after an orthopedic surgical procedure. The pharmaceutical solution is administered by syringe during the orthopedic, surgical procedure.

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Post-operative pain is characteristic of orthopedic, surgical procedures. The administration of the pharmaceutical solution with analgesics during the surgical procedure already combats the pain upon awakening the procedure. This procedure is known as LIA. The administration of a standardized solution guarantees the efficacy of the solution, resulting in an acute pain relief and a faster rehabilitation. Also, the administration of this pharmaceutical solution has the advantage that the use of strong opioids is reduced in combating postoperative pain. However, it is important that the composition is stable, standardized and has a long shelf life.

Examples of a procedure that allows use of the described pharmaceutical solution include placement of a prosthesis, preferably a total hip prosthesis, a total knee prosthesis, a unicompartmental knee prosthesis, or a patellofemoral prosthesis. As mentioned, such procedures are associated with severe pains after the surgery. Administration of the solution as described above during the procedure can prevent, relieve and / or eliminate the pain. Also, in orthopedic, surgical procedures in which other joints such as, for example, a shoulder joint, a hand joint or a foot joint are treated, the use of the described pharmaceutical solution is possible for the pain treatment. The described pharmaceutical solution is also used in an arthroscopy or in an orthopedic, surgical procedure in which one or more ligaments are replaced.

Preferably, the pharmaceutical solution is infiltrated into the wound during the procedure.

In a further preferred form, posterior, proximal and medial structures at the wound site are infiltrated with the pharmaceutical solution to treat postoperative pain. Preferably, the pharmaceutical solution is infiltrated after removing the joint to be replaced and before placing the prosthesis. Followed by an infiltration after insertion of the prosthesis and a final infiltration for stitching the wound.

In one embodiment, the pharmaceutical solution is administered in different phases, with 50 ml of solution injected at each phase

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BE2018 / 5865, preferably at different locations in the wound. In one embodiment, at least one pre-filled syringe is used during the procedure.

Preferably, one pre-filled syringe, preferably with 50 ml volume, is used just after removing the joint to be replaced to treat all these affected structures. These structures should be treated first, since once the prosthesis is placed, these structures are no longer accessible with a needle.

In a further embodiment, two pre-filled syringes with 50 ml volume are used.

Preferably, a second pre-filled syringe is used to treat affected structures after prosthesis placement. The different structures around the affected tissue are treated and a faster recovery can take place.

The present invention also relates to a method of making a pre-filled syringe comprising the pharmaceutical solution as described above. The method preferably comprises in the order as described:

- introducing a volume of anesthetic into the syringe, the volume ensuring a final concentration of anesthetic between 1.25 and 5 mg / ml, the anesthetic preferably being ropivacaine; thereafter

- introducing a volume of NSAID into a syringe, the volume ensuring a final concentration of NSAID between 0.05 and 1 mg / ml, the NSAID preferably being ketorolac; and

- introducing a volume of adrenaline into the syringe, the volume ensuring a final adrenaline concentration of between 1 and 10 µg / ml.

The operations preferably take place aseptically and in an aseptic environment, starting from sterile solutions and sterile packaging components. The aseptic environment in which the operations are performed has a maximum of 29 particles per cubic meter of air with a particle size greater than or equal to 5 μm and a maximum of 3,520 particles per cubic meter of air with a particle size greater than or equal to 0.5 μm. The syringe can be used during or after the operation

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BE2018 / 5865 be vented. Finally, the syringe will be labeled and packaged. Preferably a 50 ml syringe is prepared.

This method has the advantage that every pharmaceutical solution is a standardized solution and meets the desired pharmaceutical qualities, in particular stability and sterility.

EXAMPLES

The invention will now be further elucidated by means of the following example, without, however, being limited thereto.

EXAMPLE 1

A pharmaceutical solution according to the present invention is 2 mg / ml ropivacaine, 0.2 mg / ml ketorolac and 3.4 µg / ml adrenaline.

The sterile preparation of the composition was carried out as follows:

- withdrawing 13.33 ml of 0.75% ropivacaine and introducing the volume withdrawn into the syringe,

withdrawing 1 ml of 1% ketorolac and introducing the withdrawn volume into the syringe,

- withdrawing 0.17 ml of 0.01% adrenaline and introducing the volume increased into the syringe,

withdrawing 35.5 ml of 0.9% NaCI solution and introducing the withdrawn volume into the syringe, and

- venting the syringe, resulting in a pre-filled syringe with a pharmaceutical solution.

Twenty independent preparations of the pharmaceutical solution were prepared. Fifteen of the twenty solutions were subjected to a stability study, in which the degradation of the active substances (API) was quantified by means of ion chromatography, in particular liquid chromatography with an ultraviolet detection (LC-UV). The degradation of ropivacaine, ketorolac and adrenaline was measured on each sample in triplicate at 5 different time points over a 90 day course at 30 ° C ± 2 ° C at a relative humidity (RH) of 65% RH ± 5% RH. The average content of

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BE2018 / 5865 ropivacaine for an initial measurement, day 0, 102.65%, after 14 days 101.54%, after 45 days 100.27%, after 60 days 98.58% and after 90 days 96.52%. The average content of ketorolac in the first measurement is 102.97%, after 14 days 102.29%, after 45 days 100.67%, after 60 days 98.34% and after 90 days, 96.33%. Also the average adrenalin level is measured between the 90.00% and 110.00% content limits over a 90 day period.

The five remaining pharmaceutical solutions were used to test the sterility of the product. Aerobic and anaerobic bacterial growth, as well as fungal growth, were tested. The soybean casein digest medium, a liquid medium, was inoculated with the pharmaceutical solution to determine aerobic bacterial and fungal growth. The liquid thioglycolate medium was also inoculated to determine anaerobic growth. Positive and negative controls were included in the test for both media. Both media were incubated at 25 ° C and 35 ° C for at least 14 days, respectively. During incubation, the media were visually observed daily for turbidity and macroscopic evidence of microbial growth. After 14 days of analysis, no growth was observed in the test samples and the negative control.

EXAMPLE 2

A pharmaceutical solution according to the present invention is 2 mg / ml ropivacaine, 0.3 mg / ml ketorolac and 5 µg / ml adrenaline.

The sterile preparation of the composition was carried out as follows:

- withdrawing 13.33 ml of 0.75% ropivacaine and introducing the volume withdrawn into the syringe,

withdrawing 1.5 ml of 1% ketorolac and introducing the withdrawn volume into the syringe,

- withdrawing 0.25 ml of 0.01% adrenaline and introducing the volume increased into the syringe,

withdrawing 34.92 ml of 0.9% NaCI solution and introducing the withdrawn volume into the syringe, and

- venting the syringe, resulting in a pre-filled syringe with a pharmaceutical solution.

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Sixteen independent preparations of the pharmaceutical solution were prepared. Ten solutions were subjected to a stability study, where the degradation of the APIs was quantified using NIRS. The degradation of ropivacaine, ketorolac and adrenaline was measured in quintuplets per sample at 5 different time points over a 90 day course at 25 ° C ± 2 ° C at a relative humidity (RH) of 60% RH ± 5% RH. The average ropivacaine content in the pharmaceutical solution measures 103.21% just after preparation of the solution, 102.45% after 14 days, 100.56% after 45 days, 98.41% after 60 days, 97.12% after 90 days. The average content of ketorolac at the 5 different times measures 102.78%, 101.42%, 99.23%, 97.94% and 97.13% respectively. The mean level of adrenaline measures 100.67% on day 0, 100.04% on day 14, 99.78% on day 45, 99.28% on day 60 and 98.87% on day 90.

The endotoxin content of the residual pharmaceutical solutions was determined using the kinetic chromogenic method described in the European Pharmacopoeia 2.6.14, resulting in an average endotoxin content of 0.09 EU per ml.

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EXAMPLE 3

A pharmaceutical solution according to the present invention is 2 mg / ml bupivacaine, 0.26 mg / ml ketorolac and 5 µg / mg adrenaline.

The sterile preparation of the composition was carried out as follows:

withdrawing 13.33 ml of 0.75% bupivacaine and introducing the volume withdrawn into the syringe,

- withdrawing 1.3 ml of 1% ketorolac and introducing the withdrawn volume into the syringe,

- withdrawing 0.25 ml of 0.01% adrenaline and introducing the volume increased into the syringe,

withdrawing 35.12 ml of 0.9% NaCl solution / 0.02 and introducing the volume withdrawn into the syringe, and

- venting the syringe, resulting in a pre-filled syringe with a pharmaceutical solution.

To verify accuracy, the API assay was performed on 10 independent solution preparations, evaluating each solution in triplicate, and repeating the API analysis in duo under the same operating conditions. The API determination was determined using photometric titration at 5 different time points over an 80 day course at 25 ° C ± 2 ° C at a relative humidity (RH) of 60% RH ± 5% RH. The mean bupivacaine content is 101.65% just after the preparation of the solution, after 10 days 101.14%, after 32 days 100.36%, after 60 days 98.79%, after 80 days 97.08%. The average content of ketorolac is 99.19% just after preparation, after 10 days 98.85%, after 32 days 97.65%, after 60 days 96.41%, after 80 days 95.81%. And the average adrenaline level at the first measurement, on day 0, is 100.54%, on day 10 100.16%, on day 32 99.83%, on day 60 99.04% and on day 90 98.75%.

Claims (19)

CONCLUSIONS A pharmaceutical solution comprising the ingredients: - a non-steroidal anti-inflammatory, selected from the group of ketorolac, piroxicam, ibuprofen, diclofenac or a combination of these; and - an anesthetic selected from the group of ropivacaine, bupivacaine, levobupivacaine or a combination thereof. Pharmaceutical solution according to claim 1, characterized in that the concentration of the non-steroidal anti-inflammatory in the solution is between 0.05 and 1 mg / ml. Pharmaceutical solution according to claim 1 or 2, characterized in that the concentration of the anesthetic in the solution is between 1.25 and 5 mg / ml. Pharmaceutical solution according to any one of the preceding claims 1-3, characterized in that the pharmaceutical solution contains adrenaline, at a concentration of between 1 and 10 µg / ml, preferably between 3 and 6 µg / ml. Pharmaceutical solution according to any one of the preceding claims 1-4, characterized in that the non-steroidal anti-inflammatory is ketorolac. Pharmaceutical solution according to any one of claims 1 to 5, characterized in that the anesthetic is ropivacaine. Pharmaceutical solution comprising: - between 0.1 and 0.5 mg / ml ketorolac; - between 1.25 and 5 mg / ml ropivacaine; and optional - between 1 and 10 pg / ml adrenaline. Pharmaceutical composition according to any of the preceding claims 1-7, characterized in that the solution comprises 2 mg / ml ropivacaine, 0.2 mg / ml ketorolac and 3.4 µg / ml adrenaline. Pharmaceutical solution according to any one of the preceding claims 1-8, characterized in that the solution comprises 2 mg / ml ropivacaine, 0.3 mg / ml ketorolac and 5 µg / ml adrenaline. Pharmaceutical solution according to any one of the preceding claims 1-9, characterized in that the solution has a stability of at least 80 days, preferably at least 90 days, at a temperature between 2 and 8 ° C. Pharmaceutical solution according to any one of the preceding claims 1-10, characterized in that the solution is prepared aseptically. 2018/5865 BE2018 / 5865 A pre-filled syringe suitable for being provided with a hypodermic needle, comprising a pharmaceutical solution according to any one of the preceding claims 1-11. Pre-filled syringe according to claim 12, characterized in that the syringe has a volume between 20-100 ml, preferably 50 ml. A pre-filled syringe according to any one of claims 12 or 13 for reducing pain after an orthopedic surgical procedure, characterized in that the pharmaceutical solution is administered during an orthopedic surgical procedure. Pre-filled syringe for use according to claim 14, characterized in that the procedure is a placement of a prosthesis, preferably a total hip prosthesis, a total knee prosthesis, a unicompartmental knee prosthesis or a patellofemoral prosthesis, a general arthroscopy and / or a replacement of one or more ligaments. Pre-filled syringe for use according to claim 14 or 15, characterized in that the solution is infiltrated into the wound during the procedure. Pre-filled syringe for use according to any one of the preceding claims 1416, characterized in that at least one 50 ml pre-filled syringe is used during the procedure. A pre-filled syringe for use according to any one of the preceding claims 1417, characterized in that two pre-filled 50 ml syringes are used during the procedure. A method of manufacturing a pre-filled syringe comprising the pharmaceutical solution according to any of the preceding claims 1-11, the method comprising, preferably in the order as described: - introducing a volume of anesthetic into the syringe, the volume ensuring a final concentration of anesthetic between 1.25 and 5 mg / ml, the anesthetic preferably being ropivacaine; thereafter - introducing a volume of NSAID into a syringe, the volume ensuring a final concentration of NSAID between 0.1 and 0.5 mg / ml, the NSAID preferably being ketorolac; and - introducing a volume of adrenaline into the syringe, the volume ensuring a final adrenaline concentration of between 1 and 10 µg / ml.