Procedures for syringe sterilization

Abstract

Method for producing a sterile oxybutynin-containing composition in a preferably ready-to-use piston syringe, in particular a disposable piston syringe, and / or for producing a preferably ready-to-use, sterile piston syringe filled with an oxybutynin-containing composition, in particular a disposable piston syringe, wherein the piston syringe has a syringe body on one side and a syringe piston with a piston stopper on the other, wherein the syringe body is made of polypropylene, and wherein the final oxybutynin-containing composition obtained after completion of the process, in particular after process step b), is formed as a sterile aqueous composition, in particular a terminally sterilized composition, and has the following specification requirements (i) and (ii) and / or (iii), preferably (i), (ii) and (iii): (i) specified concentration of oxybutynin, preferably in the form of the hydrochloride, with a specified deviation of not more than ± 5%, based on the concentration of oxybutynin, (ii) specified specification pH value with a specified deviation of not more than ± 0.5 pH units, (iii) specified maximum quantity of oxybutynin degradation product(s), in particular reactively generated oxybutynin degradation product(s), preferably hydrolytically and / or oxidatively generated oxybutynin degradation product(s), preferably phenylcyclohexylhydroxyacetic acid; the procedure includes the following steps: a) Providing an oxybutynin-containing starting composition in the piston syringe and / or filling the piston syringe with an oxybutynin-containing starting composition and subsequently b) Heat sterilization, in particular steam sterilization, preferably steam sterilization, preferably terminal sterilization, of the oxybutynin-containing starting composition in the syringe and / or the syringe filled with the oxybutynin-containing starting composition to obtain the sterile oxybutynin-containing final composition in the preferably ready-to-use syringe and / or to obtain the preferably ready-to-use, sterile syringe filled with the oxybutynin-containing composition, wherein the migration and / or incorporation of the oxybutynin into the syringe body and / or the plunger stopper occurring in the process, in particular in process step b), and / or the degradation of the oxybutynin occurring in the process, in particular in process step b), in particular the reactive degradation of the oxybutynin, preferably the hydrolytically and / or oxidatively induced degradation, preferably the degradation to phenylcyclohexylhydroxyacetic acid, is controlled and / or compensated in such a manner and with the proviso that that the sterile oxybutynin-containing final composition obtained after carrying out process step b) meets the previously mentioned specification requirements (i) and (ii) and / or (iii), preferably (i), (ii) and (iii), and that the sterile oxybutynin-containing final composition is obtained in the preferably ready-to-use piston syringe or the preferably ready-to-use, sterile piston syringe filled with the oxybutynin-containing final composition, wherein the migration and / or incorporation of the oxybutynin into the syringe body and / or the plunger stopper occurring in the process, in particular in process step b), and / or the degradation occurring in the process, in particular in process step b), in particular the reactive degradation of the oxybutynin, preferably the hydrolytically and / or oxidatively caused degradation of the oxybutynin, preferably the degradation to phenylcyclohexylhydroxyacetic acid, is controlled and / or monitored, in particular prevented and / or minimized and / or compensated for, by at least one of the following measures and / or steps (1), (2), (3) and / or (4): (1) Adjustment and / or use of an increased concentration and / or amount of oxybutynin, preferably in the form of the hydrochloride, in the initial composition compared to the specified concentration and / or amount of oxybutynin, preferably in the form of the hydrochloride; (2) Adjustment of the pH value of the initial composition to a value that differs from the specified pH value, in particular an increased pH value; (3) Setting and / or selecting the sterilization conditions, in particular selected from the group consisting of sterilization type, sterilization duration, sterilization temperature, sterilization pressure, sterilization atmosphere and combinations thereof, preferably setting and / or selecting the F0 value of the sterilization; (4) Equipment and / or treatment, in particular coating, of the syringe body, preferably the inner wall of the syringe body, and / or the plunger stopper with at least one migration- and / or degradation-reducing agent.

Description

[0001] The present invention relates to the medical-technical field of sterilization or germ reduction of a special composition which comprises oxybutynin or oxybutynin hydrochloride as an active ingredient and which is introduced into or contained in a piston syringe, in particular a ready-to-use one.

[0002] In particular, the present invention relates to a method for producing a sterile oxybutyn-containing composition in a preferably ready-to-use piston syringe or for producing a preferably ready-to-use, sterile piston syringe filled with an oxybutyn-containing composition.

[0003] The present invention also relates to a sterile oxybutynin-containing composition as such, as it is used in particular for the prophylactic or therapeutic treatment of neurogenic bladder dysfunction, especially by means of instillation into the bladder.

[0004] Furthermore, the present invention also relates to a piston syringe filled with the sterile oxbutynin-containing composition as such, wherein the oxybutynin-containing composition contained in the piston syringe, including the piston syringe, has been steam sterilized according to the inventive method.

[0005] Furthermore, the present invention also relates to a packaging unit which has at least one piston syringe according to the invention, wherein the piston syringe is incorporated into or contained in a packaging.

[0006] Furthermore, the present invention also relates to corresponding kits based on the piston syringe according to the invention or the oxybutynin-containing composition according to the invention.

[0007] The present invention also relates to the use of a piston syringe in a process for producing a sterile oxybutynin-containing composition, and furthermore to the use of heat sterilization in a process for producing a sterile oxybutynin-containing composition in a preferably ready-to-use piston syringe.

[0008] The active ingredient oxybutynin (also known as 4-diethylaminobut-2-ynyl-2-cyclohexyl-2-hydroxy-2-phenylethanoate) or oxybutynin hydrochloride is an anticholinergic drug used to treat bladder dysfunction, particularly bladder dysfunction associated with or caused by detrusor overactivity and / or detrusor-sphincter dyssynergia.

[0009] Neurogenic bladder dysfunction (nBD), or neurogenic bladder emptying disorders, often represent a pathological condition of the bladder and the anatomical structures involved in urine storage and excretion that requires treatment. Neurogenic bladder dysfunction refers specifically to dysfunctions of the bladder or the relevant anatomical structures that occur as a result of a malfunction or injury to the nervous system, for example, due to spinal cord injuries, spina bifida ("open spine"), diabetes, multiple sclerosis, stroke, or Parkinson's disease. The suffering associated with bladder dysfunction can be very significant for patients, especially since the already limited quality of life is further reduced by the symptoms associated with the dysfunction.

[0010] In general, neurogenic bladder dysfunction (nBFS) refers to a disorder of urine storage or emptying, caused primarily by neurological changes or injuries in the spinal cord, in the brain regions relevant to bladder function, or in the periphery. Normal neural signal transmission for bladder control is often impaired or obstructed. As a result of the underlying neurological damage, the natural function of the bladder is disrupted with regard to its functional states, namely the filling phase and the emptying or micturition phase. The physiological process of bladder filling and emptying can even be impaired or prevented at multiple levels.

[0011] As a result of the neurological dysfunction, neurogenic bladder dysfunction (nBFS) often involves detrusor overactivity and / or detrusor-sphincter dyssynergia. This is frequently accompanied by a disruption in the interplay or coordination of the anatomical structures relevant to natural bladder function.

[0012] The detrusor muscle (musculus detrusor vesicae, or "extender of the bladder") is a powerful muscular system that surrounds the bladder and forms part of it. The detrusor is a smooth muscle that plays a crucial role in urination, or bladder emptying, under normal physiological conditions. Parasympathetic signals cause the muscle to contract, thereby pressurizing the bladder contents. The detrusor is also influenced by an intrinsic nerve plexus located in the bladder wall, which adjusts its tone according to the bladder's fullness.

[0013] In pathological cases of neurogenic bladder dysfunction, detrusor overactivity is often present, also referred to as neurogenic detrusor overactivity (NDO). Detrusor overactivity associated with a relevant underlying neurological disease is particularly characterized by pollakiuria, nocturia, and excessive urgency.

[0014] In detrusor-sphincter dyssynergia (DSD), the interaction of the anatomical structures involved in bladder emptying is disrupted. Detrusor overactivity is counteracted by spastic dysfunction of the pelvic floor muscles or the external bladder sphincter, leading to obstruction of the bladder outlet during urination. A frequently interrupted urinary stream and difficulty initiating urination are typical symptoms of detrusor-sphincter dyssynergia. Furthermore, pollakiuria and residual urine are often present.

[0015] In addition to the aforementioned symptoms, neurogenic bladder dysfunction is often associated with high intravesical pressures. This means that excessive pressure builds up in the bladder due to detrusor hyperactivity or detrusor-sphincter dyssynergia. This poses a risk to the upper urinary tract, as excessively high intravesical pressures often lead to or cause kidney damage.

[0016] In light of the above, there is a significant need in the current state of the art for therapeutic approaches that normalize or improve bladder function, or reduce symptoms, in cases of neurogenic bladder dysfunction, both with regard to urinary problems and the high bladder pressures present. A key objective, in addition to improving urination, is to reduce intrinsic pressure in order to prevent potential kidney damage or similar complications.

[0017] In this context, the therapy of neurogenic bladder dysfunction pursues several goals, namely in particular the protection of the upper urinary tract and kidney function, the improvement of continence, the restoration or improvement of the function of the lower urinary tract, and last but not least, the increase in quality of life.

[0018] In addition to conservative measures such as regular exercise, targeted bladder training, and the like, pharmacotherapeutic measures are also used to treat neurogenic bladder dysfunction. For example, a minimally invasive procedure can be performed to inject botulinum toxin into the bladder wall to reduce detrusor muscle activity. However, this procedure is relatively complex and must be performed by a physician, as the active substance must be injected into the bladder wall in a relatively precise manner. Furthermore, minimally invasive procedures such as sacral neuromodulation are also used. In this procedure, a pacemaker is implanted in the upper buttocks, which delivers weak electrical impulses to the sacral nerves via an electrode. However, the application of this method is limited by the underlying medical conditions.Furthermore, this is a significant surgical procedure, which involves additional risks.

[0019] Furthermore, pharmacological therapies using anticholinergics are known in the prior art. In this context, particular emphasis is placed on the administration of oxybutynin or oxybutynin hydrochloride, trospium chloride, propiverine, tolterodine, or similar substances. The prior art focuses on the systemic or oral administration of these active substances. However, systemic administration can be associated with a greater degree of systemic side effects, such as residual urine, constipation, accommodation disturbances, dry mouth, tachycardia, cardiac arrhythmias, and the like. Moreover, the concentration of the active substance at the site of action, namely the bladder, is sometimes not optimally controlled.

[0020] Furthermore, systemic administration of the active substance in the form of anticholinergics is disadvantageous in that a portion of the administered substance is metabolized during its first passage through the gastrointestinal tract or liver (so-called first-pass metabolism), sometimes producing inactive metabolites. This results in lower bioavailability at the site of action and makes it difficult to adjust or control the dosage at the site of action. Consequently, patients receiving systemic administration may not always be adequately controlled.

[0021] EP 1 088 565 A1 relates to a sealed package containing a set for intravesical instillation, comprising a sterilized disposable syringe with an opaque cylinder and a latex-free sealing ring at the front end of the syringe plunger, a sterilized adapter and a sterilized cap, wherein the syringe plunger is filled with an isotonic sodium chloride solution of a medicinal product.

[0022] EP 3 888 630 A1 relates to a process for producing a sterile oxybutynin-containing composition in a preferably ready-to-use piston syringe, wherein the syringe body is made of COP or COC and the piston stopper is made of a halogenobutyl rubber.

[0023] WO 2012 / 154779 A1 and US 2012 / 0289564 A1, which belongs to the same patent family, concern the use of a combination of oxybutynin and a substance that stimulates the formation of saliva for the treatment of overactive bladder, with a focus on oral application.

[0024] Furthermore, anticholinergics can be applied topically, for example via a transdermal patch or similar device. However, this systemic application can also lead to a higher incidence of systemic side effects. Additionally, the problem of premature metabolism also exists here.

[0025] Furthermore, anticholinergics such as oxybutynin or oxybutynin hydrochloride can be applied or instilled topically into the urogenital tract, particularly the bladder, for example, via a catheter or similar device. This local application or instillation delivers the active ingredient directly to its site of action, thereby increasing its targeted effect and bioavailability, and reducing systemic side effects. Moreover, with this method of administration, the drug is not prematurely metabolized by other organs. In some cases, this type of administration can even be performed by the patient themselves.

[0026] Oxybutynin, or oxybutynin hydrochloride, acts primarily as a competitive antagonist of acetylcholine at postganglionic muscarinic receptors, leading to relaxation and spasmolysis of the smooth bladder muscle and thus a reduction in detrusor overactivity. Specifically, bladder contractions are inhibited, and spasms are also relieved. Furthermore, the administration of oxybutynin or oxybutynin hydrochloride increases bladder volume and reduces contractions, thereby decreasing or delaying the urge to urinate in neurogenic bladder dysfunction. Oxybutynin or oxybutynin hydrochloride can also reduce intravesical (bladder) pressure, thus relieving pressure on the upper urinary tract. In addition, oxybutynin or oxybutynin hydrochloride exhibits properties of a local anesthetic.Oxybutynin hydrochloride belongs in particular to the group of parasympatholytics.

[0027] In the context of the prior art instillation or topical application into the bladder, oxybutynin or oxybutynin hydrochloride is generally used in the form of an aqueous composition (aqueous formulations) or aqueous solution, wherein the active ingredient-containing composition or solution is applied or administered into the bladder using appropriate application devices.

[0028] The sterility of a composition used for instillation or topical administration into the bladder is of paramount importance, particularly in order to avoid any infections of the bladder, which is especially susceptible to infection and may already be damaged by the disease.

[0029] To avoid contamination, the active ingredient-containing compositions can, for example, be prepared immediately before their use or administration. However, this is complex and also carries a certain risk of contamination during preparation. Alternatively, the active ingredient-containing compositions can be sterilized as such, for example, by microfiltration or similar methods, and then filled into a storage or application device. However, even in this case, undesirable contamination can occur, particularly with regard to possible germs or similar substances adhering to the storage or application device. In this context, separate sterilization of the storage or application device can also be considered.An application device can be provided, but this can also lead to unsatisfactory sterilization results, particularly due to the subsequent filling of the composition into the receiving or application device. In this context, work can also be carried out under sterile conditions, for example in cleanrooms, but this involves a certain amount of effort and is also costly.

[0030] Furthermore, a problem with sterilization is that the active ingredient content in the underlying aqueous composition or formulation sometimes cannot be maintained. It has also been assumed that degradation of the active substance in the form of oxybutynin or oxybutynin hydrochloride, accompanied by the formation of undesirable degradation products, occurs, for example, as a result of an undesirable interaction of the active substance with materials that are in direct contact with the underlying aqueous composition, such as materials used in storage or application devices, or the like. The reduction of the amount of active ingredient in an underlying composition or formulation...However, the formation of undesirable degradation products can negatively affect the effectiveness and safety of a corresponding composition, so that it may no longer be usable after sterilization, which also results in a corresponding economic loss.

[0031] In this context, it has been assumed that oxybutynin or oxybutynin hydrochloride in aqueous compositions is incompatible or instability, particularly when thermally sterilized, especially if the aqueous compositions containing oxybutynin or oxybutynin hydrochloride are in (disposable) syringes made of polypropylene (PP). It has also been assumed that this incompatibility or instability is sometimes exacerbated by the fact that the syringes generally use plunger stoppers or rubber stoppers and caps made of commonly used rubber materials.

[0032] With such systems, a sometimes significant reduction in the amount of active ingredient in the form of oxybutynin or oxybutynin hydrochloride has been observed during sterilization, particularly steam sterilization. Therefore, it has been assumed that such (disposable) syringes based on polypropylene, especially in combination with the use of plunger stoppers or rubber stoppers and caps made of commonly used rubber materials, are not suitable for aqueous compositions containing oxybutynin or oxybutynin hydrochloride as the active ingredient.With regard to the use of (disposable) syringes with a corresponding syringe cylinder and plunger rod made of polypropylene as primary packaging for corresponding aqueous compositions, it has thus far been assumed that an aqueous composition introduced therein using oxybutynin or oxybutynin hydrochloride as the active ingredient is not stable, particularly during sterilization, whereby it has been assumed primarily that the active ingredient in the form of oxybutynin or oxybutynin hydrochloride degrades, especially into its hydrolysis product, accompanied by a corresponding reduction in the amount or concentration of the active ingredient in the composition.

[0033] Against this background, the prior art pursues, for example, a concept whereby (disposable) syringes based on alternative materials are used as primary packaging or for the storage and sterilization of aqueous compositions containing oxybutynin or oxybutynin hydrochloride, such as syringes made of cycloolefin (co)polymer (COP or COC). The use of appropriate (disposable) syringes based on COP or COC, which are also designed as plunger syringes, is intended to stabilize the composition with regard to the active ingredient in the form of oxybutynin or oxybutynin hydrochloride, particularly during sterilization, in such a way as to reduce the loss of the active ingredient in the composition. This, in turn, allows for the provision of sterile and ready-to-use compositions with a constant or, as far as possible, unchanged active ingredient content and with improved product and storage properties.However, disposable syringes made of COP or COC can be relatively scratch-sensitive and, due to the material's relatively high rigidity, somewhat fragile and more susceptible to mechanical stress and extreme temperature fluctuations. This can affect their handling, even during (heat) sterilization. Furthermore, disposable syringes made of COP or COC are relatively expensive and therefore less economical.

[0034] Overall, disposable syringes made of COP or COC are a primary packaging material for aqueous compositions containing oxybutynin or oxybutynin hydrochloride as the active ingredient. While they generally ensure high (storage) stability of the sterilized compositions contained within, they are generally cost-intensive and sometimes involve increased requirements for (heat) sterilization.

[0035] Overall, there is a significant need in the current state of the art for suitable concepts that enable the effective sterilization of aqueous compositions containing oxybutynin or oxybutynin hydrochloride as the active ingredient in appropriate collection or application devices, while maintaining the stability of the compositions. This would allow for the development of ready-to-use products that are highly effective and safe for instillation into the bladder (i.e., with a high active ingredient content and low levels of degradation products, do not lead to infections or misuse). Furthermore, high (storage) stability of the compositions and consideration of cost-related aspects are essential.

[0036] Against this background, an object of the present invention is to provide an efficient method for the production of a sterile composition comprising oxybutynin or oxybutynin hydrochloride as an active ingredient and which is present in a preferably ready-to-use storage or application device, namely a piston syringe, wherein the disadvantages of the prior art described above are to be at least largely avoided or at least mitigated.

[0037] In this context, a particular object of the present invention is to provide a method for this purpose, which leads to a ready-to-use storage or application device containing an aqueous composition with oxybutynin or oxybutynin hydrochloride as the active ingredient in sterile form, wherein, even after sterilization, the composition exhibits not only a high degree of sterility but also a high or unchanged active ingredient content or, at most, a low content of corresponding degradation products. In particular, the present invention aims to minimize any potential loss of the active ingredient in the composition or the potential formation of degradation products of the active ingredient, or to reduce this to a pharmaceutically acceptable level.

[0038] In this regard, the present invention aims to provide a method that exhibits high cost-efficiency, particularly with respect to the materials and components used. Furthermore, the method aims to ensure the ease of handling of the materials and components used, especially with regard to sterilization treatments. Finally, the method according to the invention should be applicable and scalable on an industrial or large-scale production scale.

[0039] The present invention aims to provide, in particular, a method for producing a sterile composition containing oxybutynin or oxybutynin hydrochloride as the active ingredient, which, in addition to high sterility, also exhibits high efficacy and tolerability. Furthermore, it aims to ensure improved application safety and improved (storage) stability and shelf life. Specifically, this method aims to provide a ready-to-use product in which the composition is contained in a storage or application device, namely a disposable syringe or plunger syringe.

[0040] Furthermore, according to a further object of the present invention, an active ingredient-containing composition as such, or a storage or application device filled with the active ingredient-containing composition, specifically in the form of a (disposable) syringe or piston syringe, is to be provided. In this context, the (disposable) syringe or piston syringe is to be accessible to a sterilization process in an improved manner, whereby effective sterilization is to be ensured while maintaining the stability of the contents in the form of the active ingredient-containing composition.

[0041] To solve the problem described above, the present invention therefore proposes – according to a first aspect of the present invention – a method for producing a sterile oxybutynin-containing composition in a preferably ready-to-use piston syringe according to claim 1; advantageous further developments and embodiments of this aspect of the invention are the subject of the dependent claims relating to the method.

[0042] A further object of the present invention - according to a second aspect of the present invention - is also a sterile oxybutynin-containing composition, as it is intended to be used in particular for the prophylactic or therapeutic treatment of neurogenic bladder dysfunction, according to the independent patent claims relating to the composition according to the invention.

[0043] A further object of the present invention – according to a third aspect of the present invention – is also the piston syringe according to the invention, which has the sterile oxybutynin-containing composition according to the invention, according to the independent claims relating to the piston syringe according to the invention; advantageous further developments and embodiments of this aspect of the invention are the subject of the dependent claim relating to the piston syringe according to the invention.

[0044] The subject matter of the present invention – according to a fourth aspect of the present invention – is also the packaging unit according to the invention, which contains the piston syringe according to the invention with the composition, according to the independent patent claim relating to the packaging unit according to the invention.

[0045] Furthermore, the present invention also relates – according to a fifth aspect of the present invention – to the kits (kit-ofparts) according to the independent patent claims relating to the kits according to the invention.

[0046] Yet another subject matter of the present invention - according to a sixth aspect of the present invention - is the use of a special piston syringe in a method for producing a sterile oxybutynin-containing composition according to the related independent patent claim relating to the use according to the invention.

[0047] Finally, the subject matter of the present invention – according to a seventh aspect of the present invention – is the use according to the invention of heat sterilization, in particular steam sterilization, to provide a sterile oxybutynin-containing composition according to the independent claim relating to this use.

[0048] It goes without saying that any embodiments, designs, advantages and the like listed below for the purpose of avoiding repetition with regard to one aspect of the invention shall of course also apply to the other aspects of the invention without the need for separate mention.

[0049] Furthermore, with regard to the following description of the present invention, the features of the present invention cited in connection with the specific embodiments, configurations, advantages, examples, or the like are also considered disclosed in combination. Thus, higher-order combinations of individual or multiple features cited for specific embodiments, configurations, application examples, or the like are also considered disclosed.

[0050] With regard to all the relative or percentage weight-related information mentioned below, in particular quantity or concentration information, it should also be noted that, within the scope of the present invention, these must be selected by the person skilled in the art in such a way that, in sum, they add up to 100% or 100% by weight, taking into account all components or ingredients, in particular as defined below; however, this is self-evident to the person skilled in the art.

[0051] Furthermore, it is understood that the person skilled in the art may deviate from the concentration, weight, quantity and range specifications listed below, depending on the application or the specific case, without leaving the scope of the present invention.

[0052] Furthermore, all values ​​and parameters mentioned below can generally be determined using standardized or explicitly specified methods, or, failing that, using methods familiar to those skilled in the field. Unless otherwise stated, the underlying values ​​and parameters are determined under standard conditions (i.e., at a temperature of 20 °C and / or a pressure of 1013.25 hPa or 1.01325 bar) or atmospheric pressure.

[0053] Having said that, the present invention will now be explained in detail: Within the scope of the present invention, and as detailed below, the applicant has found that when using special (disposable) syringes or plunger syringes made of polypropylene (PP) as the syringe material, particularly during heat sterilization, especially steam sterilization, to obtain sterile oxybutynin-containing compositions, a migration or incorporation of oxybutynin into the syringe body also occurs. According to the invention, such migration or incorporation is controlled or compensated for, as is also the case for a possible degradation of oxybutynin in the composition to corresponding degradation products. Furthermore, the present invention also focuses on controlling the pH value and related changes in the composition.Within the scope of the present invention, ready-to-use products based on sterile oxybutynin-containing compositions can be provided using polypropylene-based piston syringes.

[0054] The subject matter of the present invention – according to a first aspect of the present invention – is thus a method for producing a sterile oxybutynin-containing composition in a preferably ready-to-use piston syringe, in particular a disposable piston syringe, and / or for producing a preferably ready-to-use, sterile piston syringe filled with an oxybutynin-containing composition, in particular a disposable piston syringe. wherein the piston syringe has a syringe body, in particular a syringe cylinder, on the one hand and a syringe piston with a piston stopper on the other hand, wherein the syringe body, in particular a syringe cylinder, is made of polypropylene (PP), and wherein the final oxybutynin-containing composition obtained after completion of the process, in particular after process step b), is formed as a sterile aqueous composition, in particular a terminally sterilized composition, and has the following specification requirements (i) and (ii) and / or (iii), preferably (i), (ii) and (iii): (i) specified concentration of oxybutynin, preferably in the form of the hydrochloride (oxybutynin hydrochloride, oxybutynin HCl), with a specified deviation of not more than ± 5%, based on the concentration of oxybutynin, (ii) specified specification pH value with a specified deviation of not more than ± 0.5 pH units, (iii) specified maximum amount of oxybutynin degradation product(s), in particular reactively generated oxybutynin degradation product(s), preferably hydrolytically and / or oxidatively generated oxybutynin degradation product(s), preferably phenylcyclohexylhydroxyacetic acid (impurity D); the procedure includes the following steps: a) Providing an oxybutynin-containing starting composition in the piston syringe and / or filling the piston syringe with an oxybutynin-containing starting composition and subsequently b) Heat sterilization, in particular steam sterilization, preferably steam sterilization, preferably terminal (heat, steam, steam) sterilization, of the oxybutynin-containing starting composition in the syringe and / or the syringe filled with the oxybutynin-containing starting composition to obtain the sterile oxybutynin-containing final composition in the preferably ready-to-use syringe and / or to obtain the preferably ready-to-use, sterile syringe filled with the oxybutynin-containing composition, wherein the migration and / or incorporation of the oxybutynin into the syringe body, in particular the syringe barrel, and / or into the plunger stopper, occurring in the process, in particular in process step b), and / or the degradation of the oxybutynin occurring in the process, in particular in process step b), in particular the reactive degradation of the oxybutynin, preferably the hydrolytically and / or oxidatively induced degradation, preferably the degradation to phenylcyclohexylhydroxyacetic acid (impurity D), is controlled and / or compensated in such a manner and with the proviso that that the sterile oxybutynin-containing final composition obtained after carrying out process step b) meets the previously mentioned specification requirements (i) and (ii) and / or (iii), preferably (i), (ii) and (iii), and that the sterile oxybutynin-containing final composition is obtained in the preferably ready-to-use piston syringe or the preferably ready-to-use, sterile piston syringe filled with the oxybutynin-containing final composition, wherein the migration and / or incorporation of the oxybutynin into the syringe body and / or the plunger stopper occurring in the process, in particular in process step b), and / or the degradation occurring in the process, in particular in process step b), in particular the reactive degradation of the oxybutynin, preferably the hydrolytically and / or oxidatively caused degradation of the oxybutynin, preferably the degradation to phenylcyclohexylhydroxyacetic acid, is controlled and / or monitored, in particular prevented and / or minimized and / or compensated for, by at least one of the following measures and / or steps (1), (2), (3) and / or (4): (1) Adjustment and / or use of an increased concentration and / or amount of oxybutynin, preferably in the form of the hydrochloride, in the initial composition compared to the specified concentration and / or amount of oxybutynin, preferably in the form of the hydrochloride; (2) Adjustment of the pH value of the initial composition to a value that differs from the specified pH value, in particular an increased pH value; (3) Setting and / or selecting the sterilization conditions, in particular selected from the group consisting of sterilization type, sterilization duration, sterilization temperature, sterilization pressure, sterilization atmosphere and combinations thereof, preferably setting and / or selecting the F0 value of the sterilization; (4) Equipment and / or treatment, in particular coating, of the syringe body, preferably the inner wall of the syringe body, and / or the plunger stopper with at least one migration- and / or degradation-reducing agent.

[0055] The following should be added to further the understanding of the aforementioned specifications (i) and (ii) and / or claim 1: Specifications (i) and (ii) each represent a single value (i.e., a point value) which is limited by the deviation specified for the respective specification. For example, if the specification concentration of oxybutynin according to (i) is 1 mg / ml, this results in a specified concentration regime of 1 mg / ml ± 5%, or of (1 ± 0.05) mg / ml, or of 0.95 to 1.05 mg / ml. The same applies to the specification pH value according to (ii): For example, if a specification pH value of 4.0 is specified according to (ii), this results in a specified specification pH regime of 4.0 ± 0.5 or of 3.5 to 4.5.

[0056] According to the present aspect, the invention also relates to a previously defined method for producing a sterile oxybutynin-containing composition in a preferably ready-to-use piston syringe, in particular a disposable piston syringe, and / or for producing a preferably ready-to-use, sterile piston syringe filled with an oxybutynin-containing composition, in particular a disposable piston syringe. wherein the piston syringe has a syringe body, in particular a syringe cylinder, on the one hand and a syringe piston with a piston stopper on the other hand, wherein the syringe body, in particular a syringe cylinder, is made of polypropylene (PP), and wherein the final oxybutynin-containing composition obtained after completion of the process, in particular after process step b), is formed as a sterile aqueous composition, in particular a terminally sterilized composition, and has the following specification requirements (i) and (ii) and / or (iii), preferably (i), (ii) and (iii): (i) specified concentration of oxybutynin, preferably in the form of the hydrochloride (oxybutynin hydrochloride, oxybutynin HCl): 0.5 mg / ml to 2 mg / ml with a maximum deviation of ± 5%, based on the concentration of oxybutynin, preferably 1 mg / ml with a maximum deviation of ± 0.05 mg / ml (i.e., the specified concentration of oxybutynin is to be selected or specified as a single value or point value from the aforementioned range of 0.5 mg / ml to 2 mg / ml, the maximum deviation of ± 5% relating to the single value or point value to be selected or specified). (ii) specified pH value: 2.8 to 5.2, in particular 3 to 5, preferably 3.2 to 4.8, preferably 3.5 to 4.5, particularly preferably 3.5 to 4.2, most preferably 3.8 to 4.2 (i.e., wherein the specified pH value is to be selected or specified as a single value or as a point value from the aforementioned ranges of 2.8 to 5.2, in particular 3 to 5, preferably 3.2 to 4.8, preferably 3.5 to 4.5, particularly preferably 3.5 to 4.2, most preferably 3.8 to 4.2, wherein the maximum deviation of ± 0.5 relates to the single value or point value to be selected or specified), (iii) specified quantity of oxybutynin degradation product(s), in particular reactively generated oxybutynin degradation product(s), preferably hydrolytically and / or oxidatively generated oxybutynin degradation product(s), preferably phenylcyclohexylhydroxyacetic acid (impurity D): at most 0.5 wt.%, in particular at most 0.2 wt.%, based on the total amount of oxybutynin used, preferably oxybutynin hydrochloride; the procedure includes the following steps: a) Providing an oxybutynin-containing starting composition in the piston syringe and / or filling the piston syringe with an oxybutynin-containing starting composition and subsequently b) Heat sterilization, in particular steam sterilization, preferably steam sterilization, preferably terminal (heat, steam, steam) sterilization, of the oxybutynin-containing starting composition in the syringe and / or the syringe filled with the oxybutynin-containing starting composition to obtain the sterile oxybutynin-containing final composition in the preferably ready-to-use syringe and / or to obtain the preferably ready-to-use, sterile syringe filled with the oxybutynin-containing composition, wherein the migration and / or incorporation of the oxybutynin into the syringe body, in particular the syringe barrel, and / or into the plunger stopper, occurring in the process, in particular in process step b), and / or the degradation of the oxybutynin occurring in the process, in particular in process step b), in particular the reactive degradation of the oxybutynin, preferably the hydrolytically and / or oxidatively induced degradation, preferably the degradation to phenylcyclohexylhydroxyacetic acid (impurity D), is controlled and / or compensated in such a manner and with the proviso that that the sterile oxybutynin-containing final composition obtained after carrying out process step b) meets the previously mentioned specification requirements (i) and (ii) and / or (iii), preferably (i), (ii) and (iii), and that the sterile oxybutynin-containing final composition is obtained in the preferably ready-to-use piston syringe or the preferably ready-to-use, sterile piston syringe filled with the oxybutynin-containing final composition.

[0057] The following should be added to further the understanding of the aforementioned specifications (i) and (ii) and the aforementioned embodiment: As already explained for the understanding of claim 1, specifications (i) and (ii) each represent a single value (i.e., a point value) which is limited by the deviation specified for the respective specification. For example, if the specification concentration of oxybutynin according to (i) is 1 mg / ml, this results in a specified specification concentration regime of 1 mg / ml ± 5% or of (1 ± 0.05) mg / ml or of 0.95 to 1.05 mg / ml. The same applies to the specification pH value according to (ii): For example, if a specification pH value of 4.0 is specified according to (ii), this results in a specified specification pH regime of 4.0 ± 0.5 or of 3.5 to 4.5.The same applies to the specification parameter (iv) described below.

[0058] With regard to the above information on the specification concentration of oxybutynin, the stated maximum deviation of ± 5% or ± 0.05 mg / ml should therefore be understood as a maximum deviation (meaning that all intermediate values ​​are included with respect to the stated deviations; i.e., the specification ± 5% covers the range from + 5% to - 5%, and the specification ± 0.05 mg / ml covers the range from + 0.05 mg / ml to - 0.05 mg / ml, so that, for example, a given specification concentration of oxybutynin or oxybutynin hydrochloride of 1 mg / ml results in a corresponding specification concentration range of 0.95 mg / ml to 1.05 mg / ml, including the corresponding intermediate values). The same applies to the specification pH value according to (ii) and the specification parameter described below (iv).

[0059] The specific process according to the invention, including the heat sterilization provided according to the invention, in particular steam sterilization, leads to an effective sterilization of an oxybutynin-containing (final) composition in the underlying piston syringe, in particular a disposable piston syringe, wherein the resulting sterile oxybutynin-containing (final) composition can be specifically adjusted to concrete specifications, such as in particular the concentration of oxybutynin, the pH value and the amount of oxybutynin degradation products, as mentioned above.Based on the inventive method, sterile oxybutynin-containing compositions with defined properties, particularly with regard to a predetermined active ingredient concentration and a predetermined pH value, can be provided – and this with a simultaneously low content of degradation products, which are therefore safe to use due to the sterility and the small amount of degradation products, while exhibiting high efficacy with regard to the underlying indication.

[0060] Within the scope of the present invention, it is entirely surprising that a sterile oxybutynin-containing composition with defined properties with regard to the underlying specifications can be obtained in a piston syringe with a syringe body, in particular a syringe barrel, made of or based on polypropylene (PP), since it has been assumed in the prior art that polypropylene-based piston syringes exhibit a high degree of incompatibility with the active ingredient oxybutynin or oxybutynin hydrochloride, particularly with regard to the degradation or formation of oxybutynin degradation products, especially during sterilization. Furthermore, the applicant has – quite surprisingly – found within the scope of the present invention that, with regard to the active ingredient oxybutynin or oxybutynin hydrochloride, a particularly thermally induced orThe migration or deposition of oxybutynin, particularly in the form of the free amine base, occurs during heat sterilization, preferably steam sterilization, especially in the polypropylene (PP) syringe body and also in the plunger stopper. This migration or deposition of oxybutynin can be controlled or compensated for within the scope of the present invention by the targeted technical measures described in the inventive method, so that the previously mentioned specifications regarding the sterile oxybutynin-containing (final) composition can be achieved or maintained, and in particular, only a small loss of active substance occurs during sterilization.

[0061] The applicant was also able to demonstrate in a surprising way that, within the scope of the present invention, based on the very specific process according to the invention with the targeted sequence and design of the underlying process steps, a particularly thermally induced degradation of oxybutynin to corresponding oxybutynin degradation products, especially in the form of impurity D, can be reduced or prevented, or at most occurs only to a small or pharmaceutically acceptable extent.

[0062] In this context, the applicant was also able to demonstrate that, at least substantially, no degradation of oxybutynin occurs, or that its degradation is prevented or reduced to a pharmaceutically acceptable minimum, when the procedure according to the invention is followed, as described below. Furthermore, the applicant was able to show for the first time that, with regard to the use of polypropylene-based syringes, migration or incorporation of oxybutynin occurs, and that this can be surprisingly controlled, compensated for, or mitigated, so that an overall storage-stable, sterile oxybutynin-containing composition, or syringes filled therewith, can be provided in compliance with the specifications.

[0063] Based on the method according to the invention, corresponding (disposable) syringes or piston syringes based on polypropylene or with corresponding syringe bodies made of polypropylene can thus be used for the first time as storage or application devices for oxybutynin-containing compositions, also with regard to the provision of correspondingly sterile compositions using heat sterilization and in particular steam sterilization methods.

[0064] Thus, the disadvantages associated with polypropylene-based (disposable) syringes, particularly piston syringes, can be overcome within the framework of the method according to the invention, whereby both the degradation of the active substance to corresponding degradation products, in particular to impurity D, and the migration or incorporation of oxybutynin into the piston syringe or syringe body observed by the applicant can be controlled or compensated accordingly. As detailed below, the control or compensation can be achieved, for example, by specifying or adjusting the concentration or amount of oxybutynin or oxybutynin hydrochloride, by adjusting or specifying the pH value in the underlying starting composition, by adjusting or selecting the sterilization conditions, and by targeted treatment or modification of the piston syringe or syringe body.

[0065] Within the scope of the present invention, it has thus been possible to provide a sterile oxybutynin-containing composition (final composition) contained in a polypropylene-based piston syringe, which, even after heat sterilization, in particular steam sterilization, exhibits a defined or predetermined concentration of oxybutynin or oxybutynin hydrochloride at a similarly adjusted or predetermined pH value and a defined amount of impurities. According to the invention, particular emphasis is placed on minimizing the loss of oxybutynin that occurs during heat sterilization, in particular steam sterilization, which is primarily caused by migration or incorporation into the syringe material as well as by the degradation or formation of the corresponding hydrolysis product, especially in the form of impurity D, through targeted measures regarding the underlying starting composition.to control or compensate for the heat sterilization method used or the underlying syringe material, with the aim of minimizing the loss of active ingredient in the composition and maintaining a specific pH value.

[0066] As further stated below, the applicant has also found in this context that the loss of active substance occurring during sterilization also depends on the pH value as well as the amount or concentration of the active substance in the form of oxybutynin or oxybutynin hydrochloride in the initial composition, or can be controlled by these factors.

[0067] In particular, the process according to the invention also enables the provision of a specification-compliant oxybutynin-containing composition in sterile form.

[0068] Furthermore, within the framework of the inventive method, the migration or deposition of oxybutynin in the piston stopper used for the syringe can be controlled or compensated for, whereby the interaction in this regard can be further reduced by selecting special materials for the piston stopper, as explained below. Likewise, the degradation of oxybutynin associated with the piston stopper can also be further reduced.

[0069] The same applies to the closure element described below. Consequently, according to the invention, migration or incorporation of oxybutynin into the closure element can be controlled or compensated for, and / or degradation of oxybutynin associated with the closure element can be further reduced, as also described below.

[0070] A further advantage of the method according to the invention is that the use of polypropylene-based piston syringes allows for the use of a cost-effective storage and application device as primary packaging, which also leads to cost optimization of the underlying process as a whole and thus also of the resulting products. Furthermore, the polypropylene-based piston syringes used according to the invention also offer application-specific advantages with regard to high scratch resistance and high temperature resistance, combined with high mechanical strength and reduced material rigidity. For this reason, among others, the method according to the invention can be efficiently implemented in industrial and large-scale applications.

[0071] Without limiting ourselves to or relying on this theory, the migration or deposition of oxybutynin found and specifically controlled or compensated within the scope of the present invention, particularly in the syringe body or in the plunger stopper, or the degradation of oxybutynin occurring particularly during heat sterilization, is also related to the chemical-structural or physicochemical properties of oxybutynin.

[0072] Oxybutynin can react or be degraded in aqueous solutions via both acidic and basic hydrolysis to form the corresponding free acid, namely phenylcyclohexylhydroxyacetic acid (see structural formula (2) below), with this impurity being referred to as impurity D ("Impurity D" or "imp. D"). Generally, oxybutynin (see structural formula (1) below) is used in aqueous solutions as its hydrochloride due to its improved solubility in aqueous media. In this form, HCl coordinates to the free amine base, and in acidic solutions, the active substance is present particularly in its complexed form according to structural formula (3) (the same applies to the solid). The composition can reach an equilibrium of the active substance according to (1) and (3), also depending on the pH value.

[0073] The figure above shows the hydrolysis of oxybutynin (structural formula 1) to the impurity D in the form of phenylcyclohexylhydroxyacetic acid (structural formula 2).

[0074] The structural formula (3) above shows the water-soluble form of oxybutynin, namely in the form of oxybutynin hydrochloride.

[0075] Oxybutynin according to structural formula (1) and oxybutynin hydrochloride according to structural formula (3) differ—without limiting ourselves to or relying on this theory—also in their polarity, solubility, and affinity for nonpolar surfaces. In this context, the applicant has also surprisingly found that, particularly during heat sterilization, oxybutynin in the form of structural formula (1) is increasingly migrated into or significantly incorporated into the polypropylene-based syringe material, primarily due to its lower polarity compared to substance (3). This effect can generally be dominant over degradation, as the applicant has also observed.

[0076] In this context, the applicant also observed a decrease in the pH value of the oxybutynin-containing composition during migration, deposition, or loss of oxybutynin, which—without limiting or relying on this theory—may occur because oxybutynin, in particular in the form of the free amine base, is removed from the composition.

[0077] Furthermore, the applicant was able to show that at lower initial pH values ​​of the composition to be sterilized, there is a lower loss of oxybutynin or a reduced decrease in pH value during heat sterilization.

[0078] Within the scope of the present invention, the sterilization of the oxybutynin-containing composition is specifically and purposefully carried out using heat sterilization, preferably steam sterilization, which, according to the invention, allows for excellent sterilization results while maintaining high product stability. Heat sterilization, particularly steam sterilization, is a thermal sterilization method, whereby the use of heat energy ensures efficient sterilization. With regard to the steam sterilization method preferred according to the invention, the associated use of (water) steam is of great importance, as it ensures good energy and heat transfer to the components or material to be sterilized.In particular, during the condensation of the steam on the cooler item being sterilized, the heat energy or quantity is transferred to the syringe or the oxybutynin-containing composition being sterilized, thereby killing or irreversibly inactivating microorganisms or the like. Within the framework of the heat sterilization used according to the invention, especially steam sterilization, a virtually complete or simultaneous sterilization of the syringe and the oxybutynin-containing composition is thus ensured. This offers a further advantage over, for example, sterile filling or similar methods, since the terminal sterilization preferably provided according to the invention further increases sterilization reliability.

[0079] In general, the terms (heat) sterilization or (steam) sterilization, as used in the context of the present invention, are understood to mean, in particular, the killing or irreversible inactivation of microorganisms, germs, viruses, or the like that are located on or in an object to be sterilized, including their dormant stages or survival forms, such as endospores or the like. Since the complete elimination or inactivation of all pathogens on or in an object cannot be guaranteed with absolute certainty based purely on statistical probability, an object to be sterilized is generally considered sterile if the probability of contamination with viable pathogens does not exceed a certain value. In this regard, a value of at most 1 in 10 6 or 10 -6This means that, among 1 million units of a product to be sterilized, at most one unit may not be sterile (for example, if this unit is contaminated with a colony-forming unit (CFU) of a microorganism or pathogen, or if the residual pathogen count per unit of a product to be sterilized is at most 10). -6 The CFU is , which means that the probability of a non-sterile unit is 1 in 10 6 (lies). An object can therefore be considered sterile, in particular, if the theoretical value of no more than one living microorganism in 10 6 (1 million) sterilized units of the final product are present. This is generally also referred to as the Sterility Assurance Level (SAL). Reference can also be made to the following explanations.

[0080] Within the scope of the present invention, the procedure is therefore carried out in such a way as to perform terminal heat sterilization, in particular steam sterilization, of a syringe prefilled with the oxybutynin-containing composition, based on polypropylene or with a syringe body, in particular a syringe barrel, made of polypropylene in which the oxybutynin-containing composition is incorporated or present. This results in a high degree of sterilization safety and efficiency.

[0081] As previously stated, the present invention relates to the use of (disposable) syringes or piston syringes made of polypropylene. As previously stated, the invention provides that the piston syringe comprises a syringe body, in particular a syringe barrel, on the one hand, and a syringe piston with a piston stopper on the other, wherein the syringe body, in particular the syringe barrel, is made of and / or consists of polypropylene (PP). In this regard, corresponding piston syringes or syringe bodies or syringe barrels made of polypropylene with the product name ExxonMobil® PP 1013 H1 can be used.

[0082] According to the invention, the formulation in which the syringe body, in particular the syringe barrel, is formed from polypropylene (PP) is to be understood in particular as meaning that the syringe body, in particular the syringe barrel, comprises polypropylene in an amount of at least 90% by weight, in particular at least 95% by weight, preferably at least 99% by weight, preferably at least 99.5% by weight, based on the syringe body, in particular the syringe barrel, and preferably consists at least substantially of or entirely of this. In this regard, it may, in principle, be provided according to the invention that the syringe body, in particular the syringe barrel, contains small amounts of further ingredients, such as stabilizers, processing aids, dyes, plastic additives, or the like.According to the invention, it can be provided in particular that the syringe body, especially the syringe barrel, comprises or consists of polypropylene in an amount of at least substantially 100% by weight, based on the syringe body, especially the syringe barrel. It is therefore particularly preferred if the syringe body, especially the syringe barrel, consists at least substantially, preferably entirely, of polypropylene.

[0083] As regards the process according to the invention, the migration and / or incorporation of the oxybutynin into the syringe body, in particular the syringe barrel, and / or into the plunger stopper, occurring in the process, in particular in process step b), and / or the degradation occurring in the process, in particular in process step b), in particular the reactive degradation of the oxybutynin, preferably the hydrolytically and / or oxidatively caused degradation of the oxybutynin, preferably the degradation to phenylcyclohexylhydroxyacetic acid (impurity D), is controlled and / or monitored, in particular prevented and / or minimized or compensated for, by at least one of the following measures and / or steps (1), (2), (3) and / or (4): (1) Adjustment and / or use of an increased concentration and / or quantity (matching weight) of oxybutynin, preferably in the form of the hydrochloride, in the initial composition compared to the specified concentration and / or quantity of oxybutynin, preferably in the form of the hydrochloride; (2) Adjustment of the pH value in the initial composition to a value that differs from the specified pH value, in particular an increased pH value, (3) Setting and / or selecting the sterilization conditions, in particular selected from the group consisting of sterilization type, sterilization duration, sterilization temperature, sterilization pressure, sterilization atmosphere and combinations thereof, preferably setting and / or selecting the F0 value of the sterilization (lethality value); (4) Equipment and / or treatment, in particular coating, of the syringe body, in particular syringe cylinder, preferably of the inner wall of the syringe body, in particular syringe cylinder, and / or of the piston stopper with at least one migration- and / or degradation-reducing agent.

[0084] According to the invention, it is particularly preferred that at least measure or step (1) is carried out. According to the invention, it can therefore be provided that at least measure or step (1) and measure or step (2), optionally in combination with measure or step (3) and / or (4), are carried out.

[0085] According to the invention, it is equally advantageous if at least measure or step (1) and measure or step (2) are carried out.

[0086] Therefore, according to the invention, it is further preferred that at least measure or step (1) and measure or step (2) and measure or step (3), optionally in combination with measure or step (4), are carried out.

[0087] As regards measure or step (1), the following procedure can be taken in particular within the scope of the present invention: - Thus, according to the invention, in the case of measure and / or step (1), the concentration and / or amount of oxybutynin, preferably in the form of the hydrochloride, in the initial composition can be selected or adjusted by 1% to 20%, in particular 2% to 15%, preferably 2% to 15%, preferably 3% to 10%, particularly preferably 4% to 8%, and most preferably 4% to 6% above the specified concentration and / or specified amount of oxybutynin, preferably in the form of the hydrochloride, of the final composition. - Furthermore, in the case of measure and / or step (1), the concentration and / or amount of oxybutynin, preferably in the form of the hydrochloride, in the initial composition can be adjusted to a value in the range of 101% to 120%, particularly in the range of 102% to 115%, preferably in the range of 102% to 115%, preferably in the range of 103% to 110%, particularly preferably in the range of 104% to 108%, and most preferably in the range of 104% to 106% of the specification concentration and / or the specification amount of oxybutynin, preferably in the form of the hydrochloride, of the final composition. - Also, in the case of measure and / or step (1), the concentration and / or amount of oxybutynin, preferably in the form of the hydrochloride, in the initial composition can be adjusted to a value in the range of 0.51 mg / ml to 3.5 mg / ml, in particular in the range of 0.55 mg / ml to 3 mg / ml, preferably in the range of 0.6 mg / ml to 2.5 mg / ml, preferably in the range of 0.8 mg / ml to 2.2 mg / ml, particularly preferably in the range of 0.9 mg / ml to 1.8 mg / ml, even more preferably in the range of 1.05 mg / ml to 1.1 mg / ml, most preferably of about 1.05 mg / ml or of about 1.1 mg / ml.

[0088] According to the invention, it is therefore possible, in particular, to proceed by using an excess of oxybutynin, preferably in the form of the hydrochloride, in the starting composition, or in a higher quantity compared to the (final) composition (counted weight), in order to compensate for the migration, deposition, or degradation that occurs during heat sterilization, especially steam sterilization. It is also important to note that the measures according to the invention prevent excessive degradation and thus minimize the formation of undesirable degradation products despite the higher quantity of oxybutynin.

[0089] As regards measure or step (2), the following procedure can be taken in particular within the scope of the present invention: - According to the invention, in the case of measure and / or step (2), the pH value of the starting composition can be selected and / or adjusted by 0.02 pH units to 2.4 pH units, in particular 0.05 pH units to 2.2 pH units, preferably 0.1 pH units to 2 pH units, preferably 0.15 pH units to 1.8 pH units, particularly preferably 0.2 pH units to 1.6 pH units, and most preferably 0.25 pH units to 1.4 pH units above the specification pH value of the final composition. - In addition, in the case of measure and / or step (2), the pH value of the starting composition can be selected and / or adjusted by 5% to 90%, in particular 5% to 85%, preferably 10% to 80%, preferably 10% to 75%, particularly preferably 15% to 70%, and most preferably 20% to 60% above the specification pH value of the final composition. - In addition, in the case of measure and / or step (2), the pH value of the initial composition can be adjusted to a value in the range of 2.8 to 7.5, in particular in the range of 3.1 to 7, preferably in the range of 3.4 to 6.5, more preferably in the range of 3.5 to 6, particularly preferably in the range of 3.6 to 5.8, most preferably in the range of 3.9 to 5.

[0090] In general, in the case of measure and / or step (2), the pH of the initial composition can be adjusted using and / or hydrochloric acid (HCI).

[0091] Within the scope of the present invention, with regard to measure or step (2), it is therefore possible in particular to proceed such that a higher pH value is set or specified in the initial composition compared to the specification of the final composition. This compensates for the reduction in pH value associated with the migration or incorporation or degradation of oxybutynin.

[0092] As regards measure or step (3), the following procedure can be taken in particular within the scope of the present invention: - Thus, in the case of measure and / or step (3), heat sterilization, in particular steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization, with an FO value in the range of 6 min to 45 min, in particular in the range of 8 min to 40 min, preferably in the range of 10 min to 38 min, preferably in the range of 11 min to 35 min, particularly preferably in the range of 15 min to 32 min, most preferably in the range of 19 min to 30 min, can be carried out. - Furthermore, in the case of measure and / or step (3), the sterilization conditions can be set to or selected from a range of FO values ​​in the range of 6 min to 45 min, in particular in the range of 8 min to 40 min, preferably in the range of 10 min to 38 min, preferably in the range of 11 min to 35 min, particularly preferably in the range of 15 min to 32 min, and most preferably in the range of 19 min to 30 min.

[0093] In this regard, the applicant was able to demonstrate that by ensuring a high level of sterility, both migration and degradation can be further controlled or minimized.

[0094] The F0 value of heat sterilization, particularly steam sterilization, preferably water vapor sterilization, and more preferably terminal (heat, steam, water vapor) sterilization, serves in particular to determine the thermal stress on a sample. The F0 value represents the equivalent stress of the sterilization performed compared to sterilization at a reference temperature of approximately 121 °C and is expressed in minutes. With regard to the F0 value, all lethal effects of the heat sterilization performed are summed or integrated over the course of the sterilization process or the underlying sterilization program. An F0 value of one minute corresponds to a thermal stress equivalent to one minute at a sterilization temperature of approximately 121 °C. The definition and setting or specification of the F0 value are well known to those skilled in the art, so no further explanation is required in this respect.

[0095] As regards measure or step (4), the following procedure can be taken in particular within the scope of the present invention: - Thus, in the case of measure or step (4), the equipment and / or treatment, in particular coating, of the syringe body, in particular syringe cylinder, preferably the inner wall of the syringe body, in particular syringe cylinder, and / or the piston stopper can be carried out with a silicon-containing, in particular silicone- or silicate-based agent, preferably silicone oil or silicate, in particular by means of siliconization or silicateization. - In the case of measure and / or step (4), the migration and / or degradation-reducing agent may therefore be a silicon-containing, in particular silicone- or silicate-based, agent, preferably silicone oil or silicate.

[0096] For example, a coating can be applied using a silicone oil based on dimethicone, for example using silicone oil Ph. Eur. “Dimeticone” 1,000 mPas.

[0097] The necessary equipment or treatment is carried out in particular before the syringe body is filled with the initial composition.

[0098] The targeted or purposeful equipment of the syringe body, in particular the syringe cylinder, can further reduce the migration or deposition of oxybutynin in the syringe body or syringe cylinder, as the applicant surprisingly discovered.

[0099] In accordance with the present invention, the closure element described below can also be treated and / or coated accordingly, preferably with a silicon-containing, in particular silicone- or silicate-based agent, preferably silicone oil or silicate, in particular as a migration- and / or degradation-reducing agent.

[0100] According to the invention, piston syringes, in particular syringe bodies, and / or piston plugs and / or closure elements treated and / or coated with a silicon-containing, in particular silicone- or silicate-based agent, preferably silicone oil or silicate, can therefore be used for the method.

[0101] Within the scope of the present invention, it is particularly possible to proceed such that the migration and / or incorporation of the oxybutynin into the syringe body, in particular the syringe barrel, and / or into the plunger stopper, occurring in the process, particularly in process step b), and / or the degradation occurring in the process, in particular in process step b), in particular the reactive degradation of the oxybutynin, preferably the hydrolytically and / or oxidatively caused degradation of the oxybutynin, preferably the degradation to phenylcyclohexylhydroxyacetic acid (impurity D), is controlled and / or monitored, in particular prevented and / or minimized and / or compensated for, by at least one of the following measures and / or steps (1), (2), (3) and / or (4): (1) Adjustment and / or use of an increased concentration and / or quantity (matching weight) of oxybutynin, preferably in the form of the hydrochloride, in the initial composition compared to the specified concentration and / or quantity of oxybutynin, preferably in the form of the hydrochloride, in particular wherein the concentration and / or amount of oxybutynin, preferably in the form of the hydrochloride, in the starting composition is selected and / or adjusted by 1% to 20%, more preferably 2% to 15%, more preferably 2% to 15%, more preferably 3% to 10%, more preferably 4% to 8%, most preferably 4% to 6% above the specified concentration and / or amount of oxybutynin, preferably in the form of the hydrochloride; and / or in particular wherein the concentration and / or amount of oxybutynin, preferably in the form of the hydrochloride, in the starting composition is adjusted to a value in the range of 101% to 120%, particularly in the range of 102% to 115%, preferably in the range of 102% to 115%, more preferably in the range of 103% to 110%, particularly preferably in the range of 104% to 108%, and most preferably in the range of 104% to 106% of the specification concentration and / or the specification amount of oxybutynin, preferably in the form of the hydrochloride; and / or in particular wherein the concentration and / or amount of oxybutynin, preferably in the form of the hydrochloride, in the starting composition is adjusted to a value in the range of 0.51 mg / ml to 3.5 mg / ml, particularly in the range of 0.55 mg / ml to 3 mg / ml, preferably in the range of 0.6 mg / ml to 2.5 mg / ml, preferably in the range of 0.8 mg / ml to 2.2 mg / ml, particularly preferably in the range of 0.9 mg / ml to 1.8 mg / ml, even more preferably in the range of 1.05 mg / ml to 1.1 mg / ml, most preferably of about 1.05 mg / ml or of about 1.1 mg / ml; (2) Adjustment of the pH value of the initial composition to a value that differs from, in particular increases from, the specified pH value, in particular wherein the pH value of the starting composition is selected and / or adjusted by 0.02 pH units to 2.4 pH units, in particular 0.05 pH units to 2.2 pH units, preferably 0.1 pH units to 2 pH units, preferably 0.15 pH units to 1.8 pH units, particularly preferably 0.2 pH units to 1.6 pH units, most preferably 0.25 pH units to 1.4 pH units above the specification pH value of the final composition; and / or in particular wherein the pH value of the starting composition is selected and / or adjusted by 5% to 90%, in particular 5% to 85%, preferably 10% to 80%, preferably 10% to 75%, particularly preferably 15% to 70%, most preferably 20% to 60% above the specification pH value; and / or in particular wherein the pH value of the starting composition is adjusted to a value in the range of 2.8 to 7.5, in particular in the range of 3.1 to 7, preferably in the range of 3.4 to 6.5, preferably in the range of 3.5 to 6, particularly preferably in the range of 3.6 to 5.8, most preferably in the range of 3.9 to 5; the pH of the initial composition is adjusted using and / or hydrochloric acid (HCl); (3) Setting and / or selecting the sterilization conditions, in particular selected from the group consisting of sterilization type, sterilization duration, sterilization temperature, sterilization pressure, sterilization atmosphere and combinations thereof, preferably setting and / or selecting the F0 value of the sterilization (lethality value), in particular wherein the heat sterilization, in particular steam sterilization, preferably steam sterilization, preferably terminal (heat, steam, steam) sterilization with an FO value in the range of 6 min to 45 min, in particular in the range of 8 min to 40 min, preferably in the range of 10 min to 38 min, preferably in the range of 11 min to 35 min, particularly preferably in the range of 15 min to 32 min, most preferably in the range of 19 min to 30 min, is carried out; (4) Equipment and / or treatment, in particular coating, of the syringe body, in particular syringe cylinder, preferably the inner wall of the syringe body, in particular syringe cylinder, and / or of the plunger stopper with at least one migration and / or degradation-reducing agent, preferably a silicon-containing, in particular silicone- or silicate-based agent, preferably silicone oil or silicate, in particular by means of siliconization or silicateization, and / or wherein the migration and / or degradation-reducing agent is a silicon-containing, in particular silicone- or silicate-based agent, preferably silicone oil or silicate; in particular, where at least measure and / or step (1), possibly in combination with measure and / or step (2), (3) and / or (4), is carried out; and / or in particular, where at least measure and / or step (1) and measure and / or step (2), possibly in combination with measure and / or step (3) and / or (4), are carried out; and / or in particular, where at least measure and / or step (1) and measure and / or step (2) and measure and / or step (3), possibly in combination with measure and / or step (4), are carried out.

[0102] Within the scope of the present invention, it can be the case, in particular, that the migration and / or incorporation occurring in the process, especially in process step b), into the syringe body, in particular the syringe barrel, and / or into the plunger stopper, is caused by oxybutynin in the form of the free base, in particular oxybutynin in the form of the free amine base, and / or is caused by this. Reference can also be made to the above explanations in this regard.

[0103] In this context, it can be the case, in particular, that as a result of the migration and / or incorporation of oxybutynin in the form of the free base, especially oxybutynin in the form of the free amine base, into the syringe body, especially syringe cylinder, the pH value is lowered or reduced.

[0104] As previously stated, and without relying on or limiting ourselves to the relevant theory, oxybutynin in the form of the free base (see structural formula (1) above) exhibits lower polarity than oxybutynin in the form of the hydrochloride (see structural formula (3) above), which can result in preferential migration into the nonpolar syringe material. Removing or reducing the amount of oxybutynin in the form of the free base from the composition results in a corresponding decrease in the pH of the underlying composition. As previously stated, these effects can be compensated for or balanced by the measures mentioned above in order to achieve or ensure the previously stated specifications for the final composition obtainable by the process.

[0105] According to the invention, the migration and / or incorporation of oxybutynin into the syringe body, in particular the syringe barrel, and / or into the plunger stopper, occurring in the process, particularly in process step b), and / or the degradation occurring in the process, in particular in process step b), in particular the reactive degradation of oxybutynin, preferably the hydrolytically and / or oxidatively induced degradation of oxybutynin, preferably the degradation to phenylcyclohexylhydroxyacetic acid (impurity D), can be controlled by adjusting the ratio of (i) oxybutynin in the form of the free base, in particular oxybutynin in the form of the free amine base, on the one hand, and (ii) oxybutynin in the form of the complexed and / or coordinated and / or saline and / or protonated base, in particular oxybutynin in the form of the complexed and / or coordinated and / or saline and / or protonated amine base, preferably oxybutynin in the form of the hydrochloride, on the other hand.is controlled and / or monitored, in particular prevented and / or minimized and / or compensated for.

[0106] In this context, it may be such that the ratio is shifted in the direction of (ii) oxybutynin in the form of the complexed and / or coordinated and / or saline and / or protonated base, in particular oxybutynin in the form of the complexed and / or coordinated and / or saline and / or protonated amine base, preferably oxybutynin in the form of the hydrochloride, preferably by adjusting, in particular lowering and / or reducing, the pH value and / or by adjusting to a particularly low pH value, in particular to a pH value in the range of 2.8 to 5, preferably in the range of 3.1 to 4.5, preferably in the range of 3.2 to 4.2, in the initial composition and / or by adding an acid to the initial composition.

[0107] According to the invention, the migration or incorporation of (i) oxybutynin in the form of the free base into the syringe body or syringe barrel can be reduced by correspondingly low pH values ​​of the initial composition, insofar as there is a shift in the initial composition towards (ii) oxybutynin in the form of the complexed, coordinated, saline, or protonated base. This also results in a smaller decrease in pH value or a smaller pH loss during sterilization, especially steam sterilization.

[0108] Within the scope of the present invention, it can further be arranged in particular such that the migration and / or incorporation of the oxybutynin into the syringe body, in particular the syringe cylinder, and / or into the plunger stopper, occurring in the process, in particular in process step b), is limited and / or adjusted to a value of at most 20 wt.%, in particular at most 15 wt.%, preferably at most 10 wt.%, preferably at most 8 wt.%, particularly preferably at most 5 wt.%, of the concentration and / or amount of oxybutynin, preferably in the form of the hydrochloride, present in the initial solution or initial composition.

[0109] According to the invention, the final composition, or the final composition obtained according to the inventive process, particularly after process step (b), can have a lower pH value than the initial composition. This pH reduction can be caused by, or related to, the incorporation or migration of oxybutynin, particularly in the form of the free base, into the syringe body or syringe barrel—without limiting ourselves to or relying on this theory. In particular, within the scope of the present invention, the reduction in pH (pH loss) occurs during the process, especially in process step (b).

[0110] Within the framework of the inventive process, it may in particular be the case that the lowering or reduction of the pH value (pH loss) of the final composition compared to the initial composition is set and / or limited to a maximum of 2 pH units, in particular a maximum of 1.6 pH units, preferably a maximum of 1.2 pH units, preferably a maximum of 0.8 pH units, particularly preferably a maximum of 0.6 pH units, and most preferably a maximum of 0.4 pH units.

[0111] Similarly, according to the invention, it can be provided that the lowering or reduction of the pH value (pH loss) of the final composition compared to the initial composition is limited or adjusted to a maximum of 30%, in particular a maximum of 25%, preferably a maximum of 20%, more preferably a maximum of 15%, particularly preferably a maximum of 10%, and most preferably a maximum of 5% of the pH value of the initial composition.

[0112] Regarding the final oxybutynin-containing composition obtained after completion of the process, it may exhibit or fulfill further specification requirements: - In particular, the initial composition can be an aqueous composition. - Thus, the final oxybutynin-containing composition obtained after completion of the process, in particular after process step b), can, as a further specification requirement (iv), comprise at least one electrolyte, in particular an alkali metal salt, preferably an alkali metal chloride, preferably sodium chloride (NaCl), in particular in a specified quantity in the range of 0.1 wt.% to 2 wt.%, in particular in the range of 0.5 wt.% to 1.5 wt.%, preferably in the range of 0.7 wt.% to 1.2 wt.%, preferably of about 0.9 wt.%, based on the final composition. - In particular, the final oxybutynin-containing composition obtained after completion of the process, especially after process step b), may contain as a further specification (iv) sodium chloride, calculated as sodium, in a specified specification concentration of (3.5 ± 0.5) mg / ml, in particular (3.5 ± 0.3) mg / ml, preferably (3.5 ± 0.1) mg / ml, preferably about 3.5 mg / ml. - Furthermore, the final oxybutynin-containing composition obtained after completion of the process, in particular after process step b), may, as a further specification requirement (v), exhibit a specified quantity of total degradation products of not more than 1 wt.%, in particular not more than 0.5 wt.%, based on the total quantity of oxybutynin used, preferably oxybutynin hydrochloride. The total degradation products also include, in particular, the aforementioned impurity D.

[0113] With regard to the process according to the invention, the initial composition can be designed as follows, particularly with regard to the specified requirements for the final composition: - The starting composition can contain oxybutynin, preferably in the form of the hydrochloride, preferably in a concentration or amount in the range of 0.51 mg / ml to 3.5 mg / ml, particularly in the range of 0.55 mg / ml to 3 mg / ml, preferably in the range of 0.6 mg / ml to 2.5 mg / ml, preferably in the range of 0.8 mg / ml to 2.2 mg / ml, particularly preferably in the range of 0.9 mg / ml to 1.8 mg / ml, even more preferably in the range of 1.05 mg / ml to 1.1 mg / ml, and most preferably of about 1.05 mg / ml or of about 1.1 mg / ml. Furthermore, the initial composition can have a pH value in the range of 2.8 to 7.5, particularly in the range of 3.1 to 7, preferably in the range of 3.4 to 6.5, more preferably in the range of 3.5 to 6, most preferably in the range of 3.6 to 5.8, and most preferably in the range of 3.9 to 5. In this context, the pH value can be adjusted using hydrochloric acid (HCl). - Furthermore, the starting composition may optionally contain at least one electrolyte, in particular an alkali metal salt, preferably an alkali metal chloride, preferably sodium chloride (NaCl), in particular in an amount in the range of 0.1 wt.% to 2 wt.%, in particular in the range of 0.5 wt.% to 1.5 wt.%, preferably in the range of 0.7 wt.% to 1.2 wt.%, preferably of about 0.9 wt.%, based on the starting composition, and / or wherein the starting composition may optionally contain sodium chloride, calculated as sodium, in a predetermined specification concentration of (3.5 ± 0.5) mg / ml, in particular (3.5 ± 0.3) mg / ml, preferably (3.5 ± 0.1) mg / ml.

[0114] Furthermore, the initial composition can be formed as follows: The composition can thus be formed as an aqueous composition; wherein the starting composition contains oxybutynin, preferably in the form of the hydrochloride, preferably in an amount in the range of 0.02 wt% to 0.25 wt%, in particular in the range of 0.05 wt% to 0.2 wt%, preferably in the range of 0.08 wt% to 0.15 wt%, preferably of about 0.15 wt%, based on the starting composition; wherein the starting composition optionally contains at least one electrolyte, in particular an alkali metal salt, preferably an alkali metal chloride, preferably sodium chloride (NaCl), in particular in an amount in the range of 0.1 wt.% to 2 wt.%, in particular in the range of 0.5 wt.% to 1.5 wt.%, preferably in the range of 0.7 wt.% to 1.2 wt.%, preferably of about 0.9 wt.%, based on the starting composition; and wherein the starting composition may optionally include hydrochloric acid, in particular for adjusting the pH value, especially in the form of 10% hydrochloric acid and in an amount in the range of 0.001 wt.% to 0.01 wt.%, in particular 0.003 wt.% to 0.008 wt.%, based on the starting composition.

[0115] Furthermore, the piston syringe used in the inventive method can be designed as follows: - Thus, the piston syringe, preferably the syringe body, in particular the syringe cylinder, can have a volume, in particular a receiving volume for the oxybutynin-containing composition, in the range of 1 ml to 100 ml, in particular in the range of 2 ml to 50 ml, preferably in the range of 3 ml to 25 ml, preferably in the range of 4 ml to 25 ml, particularly preferably in the range of 6 ml to 20 ml, further preferably in the range of 8 ml to 15 ml, again more preferably in the range of 9 ml to 12 ml, most preferably of about 10 ml. - In particular, the piston syringe, preferably the syringe body, especially the syringe cylinder, can contain the oxybutynin-containing composition in an amount in the range of 1 ml to 100 ml, particularly in the range of 2 ml to 50 ml, preferably in the range of 3 ml to 25 ml, preferably in the range of 4 ml to 25 ml, particularly preferably in the range of 6 ml to 20 ml, further preferably in the range of 8 ml to 15 ml, again more preferably in the range of 9 ml to 12 ml, and most preferably in the range of about 10 ml.

[0116] As previously mentioned, the syringe body, in particular the syringe cylinder, serves especially to hold the underlying oxybutynin-containing composition.

[0117] Furthermore, the plunger of the piston syringe can also be made of polypropylene (PP). In this regard, a polypropylene based on or in the form of ExxonMobil® PP 1013 H1 can be used.

[0118] As regards the piston stopper of the piston syringe, it can generally be made of or consist of an elastomeric material, in particular a rubber material and / or a rubber material, preferably rubber material.

[0119] However, according to the invention, it is preferred if the piston stopper and / or the closure element described below is made of or consists of a halogenobutyl rubber, in particular a chlorobutyl rubber or a bromobutyl rubber, preferably a bromobutyl rubber. In this context, the applicant has found that, particularly during heat sterilization, there is a higher compatibility with oxybutynin or oxybutynin hydrochloride, so that the loss of oxybutynin or oxybutynin hydrochloride in the composition can be further reduced, especially due to lower migration into the piston stopper or the closure element.Furthermore, halogenobutyl rubber, in particular bromobutyl rubber, as preferably used for the piston plug in the present invention, offers further advantages, especially with regard to its high heat stability, improved aging properties, and low gas permeability. Commercially available products can be used for the piston plug (such as Dätwyler V9340FM257 / 2 bromobutyl compound).

[0120] According to the invention, the formulation in which the piston plug or the closure element is formed from a halogenated butyl rubber, in particular from a chlorobutyl rubber or from a bromobutyl rubber, preferably from a bromobutyl rubber, is to be understood in particular as meaning that the piston plug or the closure element comprises the halogenated butyl rubber, in particular the chlorobutyl rubber or the bromobutyl rubber, preferably the bromobutyl rubber, in an amount of at least 90 wt.%, in particular at least 95 wt.%, preferably at least 99 wt.%, preferably at least 99.5 wt.%, based on the piston plug or the closure element, and preferably consists at least substantially of or entirely of this. In this regard, it can, in principle, be provided according to the invention that the piston plug or the closure element is made of a halogenated butyl rubber, in particular the chlorobutyl rubber or the bromobutyl rubber, preferably the bromobutyl rubber, in an amount of at least 90 wt.%, in particular at least 95 wt.%, preferably at least 99 wt.%, based on the piston plug or the closure element, and preferably consists at least substantially of this or entirely of this.The closure element contains small amounts of other ingredients, such as stabilizers, processing aids, colorants, plastic additives, or the like. According to the invention, it can be provided, in particular, that the piston stopper or closure element comprises or consists of halobutyl rubber, especially chlorobutyl rubber or bromobutyl rubber, preferably bromobutyl rubber, in an amount of at least substantially 100% by weight, based on the piston stopper or closure element. It is therefore particularly preferred if the piston stopper or closure element consists at least substantially, preferably entirely, of halobutyl rubber, especially chlorobutyl rubber or bromobutyl rubber, preferably bromobutyl rubber.

[0121] According to an alternative embodiment, the invention also allows for the syringe plunger and plunger stopper to be formed integrally. In this context, the syringe plunger and plunger stopper can be made of or consist of polypropylene.

[0122] In general, the piston syringe, in particular the syringe body, preferably the syringe cylinder, has a receiving and / or filling opening, in particular for filling the syringe body, in particular the syringe cylinder, with the oxybutynin-containing composition and / or in particular for preferably sealing the syringe piston with the piston stopper and / or in particular wherein the receiving and / or filling opening with the syringe piston, in particular with the piston stopper, is closable and / or is designed to be closable or is closed.

[0123] Furthermore, according to the invention, the syringe body may have an adapter, in particular for connecting an instillation device and / or for dispensing and / or applying the oxybutynin-containing composition (connection and / or dispensing adapter).

[0124] In this context, the syringe body can be formed in one piece, i.e., in particular, form a single, integral unit with the adapter. In particular, the adapter can form a connected unit with the syringe body, especially the syringe barrel, in particular a unit that is permanently and / or inseparably connected, preferably by a material bond. Within the scope of the present invention, it can also be the case that the adapter is connected to the syringe body, especially the syringe barrel, in particular permanently and / or inseparably connected, preferably by a material bond. In this context, according to the invention, for example, the adapter can be connected to the syringe body by means of casting, in particular injection molding, casting, extrusion, or the like, in particular permanently or inseparably connected, preferably by a material bond.

[0125] Within the scope of the present invention, the terms "one-piece" or "one-part" or "connected, in particular firmly and / or inseparably connected" are to be understood, with regard to the preferred embodiment of the syringe body or syringe cylinder on the one hand and the adapter on the other, in particular such that the syringe body exists as an inseparable or firmly connected unit based on the syringe cylinder and adapter as a part comprising or integrated with the syringe plunger and the adapter. In other words, within the scope of the present invention, the adapter on the one hand and the syringe cylinder on the other can form a coherent and firmly connected or permanent unit to form the syringe body. In particular, according to the invention, the adapter on the one hand and the syringe cylinder on the other are firmly connected to form the syringe body.The components cannot be permanently or inseparably connected. In particular, the aforementioned terms are to be understood as meaning that the syringe cylinder and the adapter are not separable or detachable from each other, or only separable by causing damage. Specifically, the syringe cylinder and the adapter can form a single structural or physical unit as the syringe body, without any possibility of non-destructive removal of the adapter or separation of these components.

[0126] In this respect, within the scope of the present invention, it can therefore be the case in particular that the syringe cylinder and the adapter are made of identical materials or that the syringe cylinder and the adapter consist of the same material, namely polypropylene, and in particular form a single, inseparably connected body.

[0127] As further explained below, within the scope of the present invention, it can be provided in particular that the adapter, which is formed integrally with the syringe cylinder, is shaped in a stepped cone form. Reference can also be made to the following descriptions.

[0128] Furthermore, the adapter for the piston syringe used in the inventive method can be designed as follows: The adapter may have an outlet opening, particularly at the free end of the adapter and / or specifically for dispensing and / or applying the oxybutynin-containing composition. In this context, the adapter may have an inlet opening, particularly in the transition area between the adapter and the syringe barrel and / or specifically for receiving the oxybutynin-containing composition from the syringe barrel. Furthermore, the adapter may be hollow. In addition, the adapter may have a cavity, particularly a passage channel, located between the outlet opening and the inlet opening of the adapter, specifically for the discharge of the oxybutynin-containing composition, wherein the cavity, particularly the passage channel, extends from the inlet opening to the outlet opening of the adapter and / or connects the inlet opening to the outlet opening.

[0129] The adapter may also be tapered or converging in the outlet direction and / or in the direction of the adapter's outlet opening. Furthermore, the adapter may have a decreasing and / or diminishing circumference, particularly its outer circumference, and / or a decreasing and / or diminishing diameter, particularly its outer diameter, in the outlet direction and / or in the direction of the adapter's outlet opening.

[0130] Within the scope of the present invention, the adapter can in particular be designed as follows: - According to the invention, the adapter can be designed in a nozzle-like shape, in particular as a conical or cylindrical nozzle, preferably without threads, preferably as a Luer-slip, or with threads, in particular screw threads, preferably as a Luer-lock. Reference can also be made in this regard to the relevant standards according to DIN EN 80369-7 and DIN EN 20594-1. Furthermore, the adapter can be conical or stepped-conical, preferably stepped-conical. In this context, the adapter can be designed such that the circumference, in particular the outer circumference, or the diameter, in particular the outer diameter, of the adapter decreases in the outlet direction or in the direction of the outlet opening of the adapter. - In particular, the adapter can be designed as a stepped cone adapter. In this context, the adapter can have a number of steps ranging from 2 to 40, particularly from 3 to 30, preferably from 5 to 25, more preferably from 8 to 20, and most preferably from 10 to 15. Furthermore, the circumference, in particular the outer circumference, and / or the diameter, in particular the outer diameter, of the steps of the adapter can decrease in the outlet direction and / or in the direction of the outlet opening of the adapter. - In addition, in this context, the ratio of the diameter, in particular the outer diameter, of the adapter at the inlet opening of the adapter to the diameter, in particular the outer diameter, of the adapter at the outlet opening of the adapter can be in a range of 1.1 to 15, in particular in a range of 1.25 to 10, preferably in a range of 1.5 to 5, preferably in a range of 2 to 4, particularly preferably in a range of 2.25 to 3.

[0131] According to the invention, the term "stepped cone" is understood to mean in particular a design of the adapter such that the circumference, in particular outer circumference, or the diameter, in particular outer diameter, of the adapter decreases in the discharge direction of the composition from the inlet opening towards the outlet opening by forming individual or successive steps or in a step-like manner.

[0132] According to the invention, the adapter can therefore be designed as a stepped cone adapter. As mentioned above, this can in particular be a stepped cone adapter formed integrally with the syringe body.

[0133] Furthermore, the circumference, in particular the outer circumference, and / or the diameter, in particular the outer diameter, of the adapter's steps may decrease in the outlet direction and / or in the direction of the adapter's outlet opening.

[0134] Within the scope of the present invention, a piston syringe with a versatile design with regard to the adapter can be used, whereby the specific configuration can be tailored, so to speak, particularly in light of the underlying application or range of uses. Furthermore, within the scope of the present invention, the possibility of connecting or attaching a variety of different application or instillation devices, especially in the form of installation hoses or (urinary) catheters, to the piston syringe used according to the invention can be combined. The optionally provided one-piece design of the syringe body or syringe cylinder and adapter according to the invention offers the advantage of improved handling of the piston syringe while simultaneously reducing the risk of contamination, particularly in the area of ​​the adapter.This is particularly advantageous with regard to the oxybutynin-containing composition in the piston syringe, as the step of attaching a separate adapter to the syringe barrel prior to application is eliminated, allowing the application or instillation device to be connected directly to the piston syringe. This also reduces the risk of user error. The stepped design of the adapter, which is equally preferred according to the invention, ensures secure attachment and fixation of the application or instillation device while simultaneously improving handling. The device can be guided over the adapter via a corresponding counterpart, or the adapter can be inserted into the application or instillation device, which is preferably tubular in design.

[0135] Furthermore, the piston syringe can have a closure element, in particular a detachable and / or removable and / or releasable closure element, in particular a closure cap (closure and / or sealing cap), preferably for sealing against the adapter and / or preferably for sealing on the adapter and / or preferably for sealing the outlet opening and / or the adapter.

[0136] The outlet opening or the adapter can be closed with the sealing element. In particular, it is provided within the scope of the present invention that the outlet opening or the adapter is closed at least during sterilization and preferably also during filling the piston syringe with the compositions or during the preparation of the compositions in the piston syringe.

[0137] Furthermore, the sealing element can completely and / or tightly enclose or cover the adapter, especially including the outlet opening.

[0138] In general, the sealing element can thus close the outlet opening or the adapter. In particular, according to the invention, the piston syringe or the outlet opening is closed by the sealing element within the framework of the method according to the invention.

[0139] As for the locking element, it can also be designed as follows: - In particular, the sealing element can be designed to preferably seal against the adapter and / or to be placed on the adapter in a particularly sealing manner and / or preferably to seal the outlet opening of the adapter and / or to substantially completely and / or sealingly enclose the adapter. - According to the invention, the closure element can in particular be designed in the shape of a cap or hat. - In general, the locking element can have a receiving space, in particular for at least substantially complete reception and / or at least substantially complete enclosure of the adapter. In particular, according to the invention, it can be configured such that the locking element at least substantially completely encloses the adapter, which is in particular shaped as a stepped cone. Furthermore, the locking element can be designed to fit against the adapter in a form-fit and / or force-fit manner, in particular by friction. Additionally, the locking element can enclose the adapter in a form-fit and / or force-fit manner, in particular by friction, or be designed to enclose it. - The locking element can generally be formed from an elastomeric material, in particular from a rubber material and / or a latex material, within the scope of the present invention. Preferably, the sealing element can be made of or consist of a halogenated butyl rubber, in particular a chlorobutyl rubber, or a bromobutyl rubber, preferably a bromobutyl rubber. Reference can also be made to the above descriptions of the piston stopper. - According to the invention, the locking element can further comprise a removal and / or disengagement device, in particular a pull-off device, preferably in the form of a particularly nipple-shaped extension and / or preferably for the particularly manual removal, in particular pulling off, of the locking element from the adapter. In this context, the removal and / or disengagement device can be arranged at and / or in the region of the closed end and / or at the tip of the locking element and / or in extension of the longitudinal axis of the locking element. - Furthermore, the locking element may have at least one recess on its outer surface, in particular a notch, indentation and / or material reduction. In this context, the recess may be longitudinal and / or linear and / or straight, and may also be arranged at least substantially in the longitudinal direction and / or at least substantially parallel to the longitudinal axis of the locking element (7). Furthermore, the locking element can have two, three, four, five or more, in particular two, three or four, preferably four, recesses. In this context, the recesses can be arranged on the outside of the locking element, at least substantially equidistant from each other and / or at least substantially parallel to each other.

[0140] According to the invention, it may in particular be provided that the piston syringe or the adapter or the closure element is physically designed (i.e. with the exception of the material from which the piston syringe is formed, i.e. not the material composition of the piston syringe) in accordance with DE 10 2020 130 032 A1 and / or in accordance with DE 20 2020 106 531 U1, wherein the respective disclosure content of the aforementioned documents is hereby fully included by reference.

[0141] As previously stated, according to the invention, the migration and / or incorporation of oxybutynin into the closure element occurring during the process, particularly in process step b), can also be controlled and / or compensated for, subject to the aforementioned provision and / or by means of the aforementioned measures and / or steps (1), (2), (3) and / or (4). However, this aspect is significantly less relevant, since the contact area with the composition is generally extremely small or minimal. This is also demonstrated by the applicant's investigations.

[0142] In summary, according to the invention, it can be such that the migration and / or incorporation of the oxybutynin into the syringe body, in particular the syringe cylinder, and / or into the plunger stopper and / or into the closure element, and / or the degradation of the oxybutynin occurring in the process, in particular in process step b), in particular the reactive degradation of the oxybutynin, preferably the hydrolytically and / or oxidatively caused degradation, preferably the degradation to phenylcyclohexylhydroxyacetic acid (impurity D), can be controlled and / or compensated, in the same way with the aforementioned provision and / or by means of the aforementioned measures and / or steps (1), (2), (3) and / or (4).

[0143] As regards the heat sterilization provided for in process step (b), this can be designed or carried out in particular as follows.

[0144] In general, heat sterilization, in particular steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization, can be carried out according to the invention under temperature exposure (heating).

[0145] According to the invention, heat sterilization, in particular steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization, can be carried out at temperatures of at least 105 °C, in particular at least 110 °C, preferably at least 115 °C, preferably at least 120 °C.

[0146] In particular, heat sterilization, especially steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization, can be carried out at temperatures of at most 160 °C, especially at most 150 °C, preferably at most 140 °C, preferably at most 130 °C.

[0147] According to the invention, heat sterilization, in particular steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization, can be carried out at temperatures in the range of 105 °C to 160 °C, in particular in the range of 110 °C to 150 °C, preferably in the range of 115 °C to 140 °C, preferably in the range of 120 °C to 130 °C, and particularly preferably at about 121 °C.

[0148] As previously stated, according to the invention, heat sterilization can be carried out with an F0 value in the range of 6 min to 45 min, particularly in the range of 8 min to 40 min, preferably in the range of 10 min to 38 min, more preferably in the range of 11 min to 35 min, most preferably in the range of 15 min to 32 min, and most preferably in the range of 19 min to 30 min. Reference can also be made to the above explanations.

[0149] In particular, heat sterilization, especially steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization, can be carried out for a (total) period of at least 1 min, especially at least 2 min, preferably at least 3 min, preferably at least 4 min, particularly preferably at least 5 min, most preferably at least 6 min.

[0150] Furthermore, heat sterilization, in particular steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization, can be carried out for a (total) period of at most 600 min, in particular at most 500 min, preferably at most 400 min, preferably at most 350 min, particularly preferably at most 300 min, most preferably at most 250 min.

[0151] Likewise, heat sterilization, in particular steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization, can be carried out for a (total) period in the range of 1 min to 600 min, in particular in the range of 2 min to 500 min, preferably in the range of 3 min to 400 min, preferably in the range of 4 min to 350 min, particularly preferably in the range of 5 min to 300 min, most preferably in the range of 6 min to 240 min.

[0152] According to the invention, heat sterilization, in particular steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization, can be carried out under pressure.

[0153] According to the invention, it can also be provided that the heat sterilization, in particular steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization, is carried out at a relative pressure in the range of 0.1 bar to 10 bar, in particular in the range of 0.5 bar to 5 bar, preferably in the range of 1 bar to 3.5 bar, preferably in the range of 1.5 bar to 3 bar.

[0154] In particular, heat sterilization, especially steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization, can be carried out at an absolute pressure in the range of 1.1 bar to 10 bar, especially in the range of 1.5 bar to 6 bar, preferably in the range of 2 bar to 4.5 bar.

[0155] Likewise, heat sterilization can be carried out in the presence of an atmosphere containing, in particular, pure water vapor and / or as a saturated steam process, or steam sterilization can be carried out in the presence of a water vapor / gas mixture, in particular a mixture of water vapor with inert gas, in particular nitrogen, and / or oxygen, preferably a water vapor / air mixture.

[0156] Furthermore, heat sterilization, in particular steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization, can be carried out in a preferably closed sterilization device, in particular in a gas-tight sealed pressure vessel, preferably in an autoclave device (autoclave).

[0157] In this context, the sterilization atmosphere can be generated by injecting water vapor and / or water vapor / compressed air mixtures, preferably water vapor / compressed air mixtures, into the sterilization device.

[0158] Furthermore, the sterilization atmosphere can be created in this context by injecting premixed steam / compressed air mixtures and / or by separate injections of steam and compressed air into the sterilization device.

[0159] According to the invention, it can also be provided that in heat sterilization, in particular steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization, the water vapor is generated from distilled and / or fully demineralized water.

[0160] Furthermore, according to the invention, it can be provided that in heat sterilization, in particular steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization, the compressed air is generated from sterile air, in particular wherein the air is cleaned and / or sterilized by passing it through filters.

[0161] According to the invention, heat sterilization, in particular steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization, can be carried out under overkill conditions and / or at about 121 °C and / or for a period of at least 6 min, preferably about 6 min, or at least 20 min, preferably about 20 min.

[0162] Furthermore, heat sterilization, in particular steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization, can be carried out in accordance with Pharmacopoea Europaea (Ph. Eur.), Chapter 5.1.1 (07 / 2017:50101), in particular under overkill conditions and / or at about 121 °C and / or for a period of at least 15 min, in particular at least 20 min, preferably about 20 min.

[0163] According to the invention, it has also proven advantageous if the heat sterilization, in particular steam sterilization, preferably steam sterilization, preferably terminal (heat, steam, steam) sterilization, is carried out in multiple cycles, particularly wherein at least the final and / or terminal cycle is carried out under at least one of the aforementioned conditions. In this regard, it can be provided in particular that the final and / or terminal cycle is carried out under overkill conditions and / or at approximately 121 °C and / or for a period of at least 6 min, preferably approximately 6 min, or at least 20 min, preferably approximately 20 min.

[0164] According to the invention, it can also be provided that the piston syringe filled with the oxybutynin-containing composition is placed in a packaging, particularly a ready-to-use package, which is sealed and / or closed in a watertight and / or germ-proof manner, especially before heat sterilization, particularly steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization. In this regard, a part of the packaging can be designed to be at least permeable to water vapor, and in particular to water vapor and / or gas. According to the invention, it can be arranged such that the packaging is sterilized in the same way during steam sterilization.

[0165] Particularly with regard to large-scale industrial application, the invention provides for the simultaneous sterilization of a large number of piston syringes filled with the oxybutynin-containing composition. In this context, it is particularly possible that several piston syringes are preferably brought together on a (syringe) carrier during steam sterilization.

[0166] The sterile oxybutynin-containing composition (final composition) obtained after completion of the process, in particular after process step b), and / or the sterile plunger syringe filled with the oxybutynin-containing composition (final composition) obtained after completion of the process, in particular after process step b), can in particular have a SAL value (Sterility Assurance Level) of at least 10 -5 , in particular at least 10 -6 , preferably at least 10 -7 exhibit.

[0167] In particular, according to the invention, it can be provided that the sterilized or sterile oxybutynin-containing composition (final composition) or the piston syringe obtained within the framework of the process according to the invention and filled with the oxybutynin-containing composition is sterile in accordance with DIN EN 566-1.

[0168] For further details regarding the heat sterilization, in particular steam sterilization, underlying the method according to the invention, reference may be made in particular to DE 10 2017 104 931 A1 and to WO 2018 / 145799 A1, which belongs to the same patent family, the full disclosure of which is hereby included by reference. Reference may also be made to DE 10 2011 105 840 A1 and to WO 2012 / 136313 A2, which belongs to the same patent family, and to US 2014 / 093422 A1, the full disclosure of which is hereby included by reference.

[0169] As previously mentioned, the process according to the invention provides a sterile, highly stable oxybutynin-containing composition. In particular, the sterile oxybutynin-containing composition has a low content of impurities and degradation products.

[0170] In particular, the sterile oxybutynin-containing composition (final composition) meets the previously defined specification requirements, even after prolonged storage.

[0171] In this context, according to the invention, it can behave in particular as follows: - According to the invention, the sterile oxybutynin-containing final composition obtained after completion of the process, particularly after process step b), exhibits and / or fulfills the specified requirements (i) and (ii) and / or (iii), in particular (i), (ii) and (iii), even after storage of the sterile syringe filled with the oxybutynin-containing final composition at temperatures in the range of 25 °C to 40 °C, at a relative humidity in the range of 60 % to 75 % and at a pressure of 1,013.25 mbar for at least 10 days, in particular at least 30 days, preferably at least 3 months, preferably at least 6 months, particularly preferably at least 12 months. - Furthermore, the sterile oxybutynin-containing final composition obtained after completion of the process, in particular after process step b), can meet the following specification requirements. (i) and (ii) and / or (iii), in particular (i), (ii) and (iii), even after storage of the sterile syringe filled with the oxybutynin-containing final composition at temperatures in the range of 25 °C to 40 °C, at a relative humidity in the range of 60% to 75% and at a pressure of 1,013.25 mbar for at least 10 days, in particular at least 30 days, preferably at least 3 months, preferably at least 6 months, particularly preferably at least 12 months, exhibit or fulfill: (i) specified concentration of oxybutynin, preferably in the form of the hydrochloride (oxybutynin hydrochloride, oxybutynin HCl): 0.5 mg / ml to 2 mg / ml with a maximum deviation of ± 5%, based on the concentration of oxybutynin, preferably 1 mg / ml with a maximum deviation of ± 0.05 mg / ml, (ii) specified pH value: 2.8 to 5.2, in particular 3 to 5, preferably 3.2 to 4.8, preferably 3.5 to 4.5, particularly preferably 3.5 to 4.2, most particularly preferably 3.8 to 4.2, (iii) specified quantity of oxybutynin degradation product(s), in particular reactively generated oxybutynin degradation product(s), preferably hydrolytically and / or oxidatively generated oxybutynin degradation product(s), preferably phenylcyclohexylhydroxyacetic acid (impurity D): at most 0.5 wt.%, in particular at most 0.2 wt.%, based on the total amount of oxybutynin used, preferably oxybutynin hydrochloride. - Furthermore, the sterile oxybutynin-containing final composition obtained after completion of the process, in particular after process step b), can meet the specified specification (iv), in particular the specified quantity (iv) of electrolytes, in particular alkali metal salt, preferably alkali metal chloride, preferably sodium chloride (NaCl), in the range of 0.1 wt.% to 2 wt.%, in particular in the range of 0.5 wt.% to 1.5 wt.%, preferably in the range of 0.7 wt.% to 1.2 wt.%, preferably of about 0.9 wt.%.-%, based on the final composition, and / or the specified concentration (iv) of sodium chloride, calculated as sodium, of (3.5 ± 0.5) mg / ml, in particular (3.5 ± 0.3) mg / ml, preferably (3.5 ± 0.1) mg / ml, preferably about 3.5 mg / ml, even after storage of the sterile syringe filled with the oxybutynin-containing final composition at temperatures in the range of 25 °C to 40 °C, at a relative humidity in the range of 60 % to 75 % and at a pressure of 1,013.25 mbar for at least 10 days, in particular at least 30 days, preferably at least 3 months, preferably at least 6 months, particularly preferably at least 12 months. - Furthermore, according to the invention, the sterile oxybutynin-containing final composition obtained after completion of the process, in particular after process step b), exhibits or fulfills the specified specification (v), in particular the specified quantity of total degradation products of at most 1 wt.%, in particular at most 0.5 wt.%, based on the total quantity of oxybutynin used, preferably oxybutynin hydrochloride, even after storage of the sterile syringe filled with the oxybutynin-containing final composition at temperatures in the range of 25 °C to 40 °C, at a relative humidity in the range of 60 % to 75 % and at a pressure of 1,013.25 mbar for at least 10 days, in particular at least 30 days, preferably at least 3 months, preferably at least 6 months, particularly preferably at least 12 months.

[0172] With regard to the design of the method according to the present aspect, reference can also be made to the following explanations concerning the further aspects of the invention, which apply accordingly.

[0173] Furthermore, the present invention relates – according to a further aspect of the present invention – to the sterile oxybutynin-containing composition (final composition), in particular for use in the prophylactic and / or therapeutic treatment of neurogenic bladder dysfunction, especially neurogenic bladder emptying disorders, preferably neurogenic bladder dysfunction associated with detrusor overactivity and / or detrusor-sphincter dyssynergia. wherein the oxybutynin-containing composition is obtainable or obtained according to the inventive process; and / or wherein the oxybutynin-containing composition is or has been heat-sterilized according to the inventive method, in particular steam-sterilized, preferably steam-sterilized, preferably terminally (heat-, steam-, steam-)sterilized.

[0174] According to this aspect, the present invention further relates to the sterile oxybutynin-containing composition (final composition), in particular for use in the prophylactic and / or therapeutic treatment of neurogenic bladder dysfunction, especially neurogenic bladder emptying disorders, preferably neurogenic bladder dysfunction associated with detrusor overactivity and / or detrusor-sphincter dyssynergia, in particular the composition defined above, wherein the oxybutynin-containing composition is present in a preferably ready-to-use piston syringe, in particular a disposable piston syringe. wherein the piston syringe has a syringe body, in particular a syringe cylinder, on the one hand and a syringe piston with a piston stopper on the other hand, wherein the syringe body, in particular a syringe cylinder, is made of polypropylene (PP), and wherein the oxybutynin-containing composition is formed as a sterile aqueous composition, in particular a terminally sterilized composition, and has the following specification requirements (i) and (ii) and / or (iii), preferably (i), (ii) and (iii), wherein the oxybutynin-containing composition exhibits and / or fulfills the following specifications (i) and (ii) and / or (iii), in particular (i), (ii) and (iii), even after storage of the sterile syringe filled with the oxybutynin-containing composition at temperatures in the range of 25 °C to 40 °C, at a relative humidity in the range of 60% to 75% and at a pressure of 1013.25 mbar for at least 30 days: (i) specified concentration of oxybutynin, preferably in the form of the hydrochloride (oxybutynin hydrochloride, oxybutynin HCl): 0.5 mg / ml to 2 mg / ml with a maximum deviation of ± 5%, based on the concentration of oxybutynin, preferably 1 mg / ml with a maximum deviation of ± 0.05 mg / ml, (ii) specified pH value: 2.8 to 5.2, in particular 3 to 5, preferably 3.2 to 4.8, preferably 3.5 to 4.5, particularly preferably 3.5 to 4.2, most particularly preferably 3.8 to 4.2, (iii) specified quantity of oxybutynin degradation product(s), in particular reactively generated oxybutynin degradation product(s), preferably hydrolytically and / or oxidatively generated oxybutynin degradation product(s), preferably phenylcyclohexylhydroxyacetic acid (impurity D): at most 0.5 wt.%, in particular at most 0.2 wt.%, based on the total amount of oxybutynin used, preferably oxybutynin hydrochloride; and wherein the oxybutynin-containing composition and / or the sterile syringe filled with the oxybutynin-containing composition has a SAL (Sterility Assurance) value of at least 10 -6 exhibits; wherein the oxybutynin-containing composition contained in the piston syringe, including the piston syringe, has been heat-sterilized, in particular steam-sterilized, preferably steam-sterilized, preferably terminally (heat-, steam-, steam-)sterilized.

[0175] The oxybutynin-containing composition according to the invention can also, as a further specification (iv), comprise at least one electrolyte, in particular an alkali metal salt, preferably an alkali metal chloride, preferably sodium chloride (NaCl), in particular in a specified quantity in the range of 0.1 wt.% to 2 wt.%, in particular in the range of 0.5 wt.% to 1.5 wt.%, preferably in the range of 0.7 wt.% to 1.2 wt.%, preferably of about 0.9 wt.%, based on the final composition.

[0176] In particular, the oxybutynin composition may, as a further specification requirement (iv), contain sodium chloride, calculated as sodium, at a specified concentration of (3.5 ± 0.5) mg / ml, in particular (3.5 ± 0.3) mg / ml, preferably (3.5 ± 0.1) mg / ml, preferably about 3.5 mg / ml.

[0177] Furthermore, the oxybutynin-containing composition may, as a further specification requirement (v), have a specified quantity of total degradation products of not more than 1 wt.%, in particular not more than 0.5 wt.%, based on the total quantity of oxybutynin used, preferably oxybutynin hydrochloride. As stated above, the specified quantity of total degradation products also includes impurity D.

[0178] According to the invention, it is particularly provided that the piston plug is made of an elastomeric material, in particular a rubber material and / or a rubber material, preferably a rubber material. According to the invention, it is preferred that the piston plug is made of or consists of a halogenated butyl rubber, in particular a chlorobutyl rubber, or a bromobutyl rubber, preferably a bromobutyl rubber.

[0179] As regards the composition according to the invention, it can be heat-sterilized, in particular steam-sterilized, preferably steam-sterilized, preferably terminally (heat-, steam-, steam-) sterilized, under at least one of the conditions previously defined for the process according to the invention.

[0180] According to the invention, it can be provided in particular that the oxybutynin-containing composition with an F0 value in the range of 6 min to 45 min, in particular in the range of 8 min to 40 min, preferably in the range of 10 min to 38 min, more preferably in the range of 11 min to 35 min, particularly preferably in the range of 15 min to 32 min, most preferably in the range of 19 min to 30 min, is or has been heat-sterilized, in particular steam-sterilized, preferably steam-sterilized, preferably terminally (heat-, steam-, steam-)sterilized.

[0181] In particular, the composition may be heat-sterilized, in particular steam-sterilized, preferably steam-sterilized, preferably terminally (heat-, steam-, steam-)sterilized, or may have been heat-sterilized, in particular by steam sterilization, preferably by water vapor sterilization, preferably by terminal sterilization, under overkill conditions and / or at about 121 °C and / or for a period of at least 6 min, preferably about 6 min, or at least 20 min, preferably about 20 min.

[0182] According to the invention, it may in particular be provided that the composition is heat-sterilised, in particular steam-sterilised, preferably steam-sterilised, preferably terminally (heat-, steam-, steam-)sterilised, in accordance with Pharmacopoea Europaea (Ph. Eur.), Chapter 5.1.1 (07 / 2017:50101), in particular under overkill conditions and / or at about 121 °C and / or for a period of at least 15 min, in particular at least 20 min, preferably about 20 min.

[0183] With regard to the composition according to the invention, it is particularly such that it, including the corresponding piston syringe, is or has been heat sterilized, in particular steam sterilized, preferably steam sterilized, preferably terminally (heat-, steam-, steam-) sterilized.

[0184] The composition according to the invention is characterized overall by defined specification requirements and their establishment or maintenance (even for longer storage periods), particularly as a result of the inventive method for its production, so that the inventive method is directly reflected in the composition according to the invention.

[0185] In particular, the composition is also characterized by high (storage) stability: According to the invention, the oxybutynin-containing composition can, in particular, exhibit or fulfill the specified requirements (i) and (ii) and / or (iii), especially (i), (ii) and (iii), even after storage of the sterile piston syringe filled with the oxybutynin-containing composition at temperatures in the range of 25 °C to 40 °C, at a relative humidity in the range of 60% to 75% and at a pressure of 1,013.25 mbar for at least 10 days, in particular at least 30 days, preferably at least 3 months, preferably at least 6 months, particularly preferably at least 12 months.

[0186] Furthermore, according to the invention, the oxybutynin-containing composition can also exhibit or fulfill the following specifications (i) and (ii) and / or (iii), in particular (i), (ii) and (iii), even after storage of the sterile syringe filled with the oxybutynin-containing composition at temperatures in the range of 25 °C to 40 °C, at a relative humidity in the range of 60% to 75% and at a pressure of 1,013.25 mbar for at least 10 days, in particular at least 30 days, preferably at least 3 months, preferably at least 6 months, particularly preferably at least 12 months: (i) specified concentration of oxybutynin, preferably in the form of the hydrochloride (oxybutynin hydrochloride, oxybutynin HCl): 0.5 mg / ml to 2 mg / ml with a maximum deviation of ± 5%, based on the concentration of oxybutynin, preferably 1 mg / ml with a maximum deviation of ± 0.05 mg / ml, (ii) specified pH value: 2.8 to 5.2, in particular 3 to 5, preferably 3.2 to 4.8, preferably 3.5 to 4.5, particularly preferably 3.5 to 4.2, most particularly preferably 3.8 to 4.2, (iii) specified quantity of oxybutynin degradation product(s), in particular reactively generated oxybutynin degradation product(s), preferably hydrolytically and / or oxidatively generated oxybutynin degradation product(s), preferably phenylcyclohexylhydroxyacetic acid (impurity D): at most 0.5 wt.%, in particular at most 0.2 wt.%, based on the total amount of oxybutynin used, preferably oxybutynin hydrochloride.

[0187] In particular, the oxybutynin-containing composition can meet the specified specification (iv), in particular the specified quantity (iv) of electrolytes, in particular alkali metal salt, preferably alkali metal chloride, preferably sodium chloride (NaCl), in the range of 0.1 wt.% to 2 wt.%, in particular in the range of 0.5 wt.% to 1.5 wt.%, preferably in the range of 0.7 wt.% to 1.2 wt.%, preferably of about 0.9 wt.%, based on the final composition, and / or the specified concentration (iv) of sodium chloride, calculated as sodium, of (3.5 ± 0.5) mg / ml, in particular (3.5 ± 0.3) mg / ml, preferably (3.5 ± 0.1) mg / ml, preferably about 3.5 mg / ml, even after storage of the sterile syringe filled with the oxybutynin-containing composition at temperatures in the range of 25 °C to 40 °C, at a relative humidity in the range of 60% to 75% and at a pressure of 1.013.25 mbar of at least 10 days, in particular at least 30 days, preferably at least 3 months, preferably at least 6 months, especially preferably at least 12 months, exhibit or meet.

[0188] Likewise, the oxybutynin-containing composition can exhibit or fulfill the specified specification (v), in particular the specified quantity of total degradation products of at most 1 wt.%, in particular at most 0.5 wt.%, based on the total quantity of oxybutynin used, preferably oxybutynin hydrochloride, even after storage of the sterile syringe filled with the oxybutynin-containing composition at temperatures in the range of 25 °C to 40 °C, at a relative humidity in the range of 60 % to 75 % and at a pressure of 1,013.25 mbar for at least 10 days, in particular at least 30 days, preferably at least 3 months, preferably at least 6 months, particularly preferably at least 12 months.

[0189] Furthermore, the oxybutynin-containing composition and / or the sterile syringe filled with the oxybutynin-containing composition can have a SAL (Sterility Assurance) value of at least 10. -5 , in particular at least 10 -6 , preferably at least 10 -7 exhibit.

[0190] According to the invention, the neurogenic bladder dysfunction is generally characterized by or associated with detrusor overactivity and / or detrusor-sphincter dyssynergia, in particular with an overactive detrusor.

[0191] In particular, neurogenic bladder dysfunction may be associated with or caused by spinal cord injury, especially paraplegia, spina bifida, diabetes, multiple sclerosis, stroke or Parkinson's disease.

[0192] The present invention also relates to the sterile oxybutynin-containing composition according to the invention for use in the prophylactic and / or therapeutic treatment of neurogenic bladder dysfunction, in particular neurogenic bladder emptying disorders, preferably neurogenic bladder dysfunction associated with detrusor overactivity and / or detrusor-sphincter dyssynergia, in particular wherein the neurogenic bladder dysfunction is associated with detrusor overactivity and / or detrusor-sphincter dyssynergia, in particular with an overactive detrusor, and / or is characterized by this, and / or in particular wherein the neurogenic bladder dysfunction is associated with or caused by a spinal cord injury, in particular paraplegia, spina bifida, diabetes, multiple sclerosis, stroke or Parkinson's disease.

[0193] In particular, the composition according to the invention can be provided or prepared for instillation or preferably topical application into the urogenital area, especially into the bladder.

[0194] Furthermore, the oxybutynin-containing composition according to the invention can be provided or prepared for administration, instillation, or preferably topical application into the urogenital tract, particularly into the bladder. In particular, the oxybutynin-containing composition can be administered by instillation or topical application into the urogenital tract, particularly into the bladder.

[0195] With regard to further embodiments of the composition according to the invention, reference can also be made to the explanations concerning the further aspects of the invention, which apply accordingly in the present case.

[0196] Furthermore, the present invention relates – according to a further aspect of the present invention – to the piston syringe according to the invention, in particular a disposable piston syringe, wherein the piston syringe has a syringe body, in particular a syringe cylinder, on the one hand and a syringe piston with a piston stopper on the other hand, wherein the syringe body, in particular the syringe cylinder, is made of polypropylene (PP). wherein the piston syringe is filled with a sterile oxybutynin-containing composition (final composition), in particular for use in the prophylactic and / or therapeutic treatment of neurogenic bladder dysfunction, especially neurogenic bladder emptying disorders, preferably of neurogenic bladder dysfunction associated with detrusor overactivity and / or detrusor-sphincter dyssynergia, in particular as defined above, wherein the piston syringe is obtainable or obtained by a process according to a process as previously defined; and / or wherein the oxybutynin-containing composition including the piston syringe is or has been heat-sterilized, in particular steam-sterilized, preferably steam-sterilized, preferably terminally (heat-, steam-, steam-)sterilized, according to the previously defined method.

[0197] In particular, according to this aspect, the present invention also relates to the piston syringe according to the invention, in particular a disposable piston syringe, wherein the piston syringe has a syringe body, in particular a syringe cylinder, on the one hand and a syringe piston with a piston stopper on the other hand, wherein the syringe body, in particular the syringe cylinder, is made of polypropylene (PP), in particular a piston syringe as defined above. wherein the piston syringe is filled with a sterile oxybutynin-containing composition (final composition), in particular for use in the prophylactic and / or therapeutic treatment of neurogenic bladder dysfunction, especially neurogenic bladder emptying disorders, preferably neurogenic bladder dysfunction associated with detrusor overactivity and / or detrusor-sphincter dyssynergia, wherein the oxybutynin-containing composition is formed as a sterile aqueous composition, in particular a terminally sterilized composition, and has the following specification requirements (i) and (ii) and / or (iii), preferably (i), (ii) and (iii), wherein the oxybutynin-containing composition exhibits and / or fulfills the following specifications (i) and (ii) and / or (iii), in particular (i), (ii) and (iii), even after storage of the sterile syringe filled with the oxybutynin-containing composition at temperatures in the range of 25 °C to 40 °C, at a relative humidity in the range of 60% to 75% and at a pressure of 1013.25 mbar for at least 30 days: (i) specified concentration of oxybutynin, preferably in the form of the hydrochloride (oxybutynin hydrochloride, oxybutynin HCl): 0.5 mg / ml to 2 mg / ml with a maximum deviation of ± 5%, based on the concentration of oxybutynin, preferably 1 mg / ml with a maximum deviation of ± 0.05 mg / ml, (ii) specified pH value: 2.8 to 5.2, in particular 3 to 5, preferably 3.2 to 4.8, preferably 3.5 to 4.5, particularly preferably 3.5 to 4.2, most particularly preferably 3.8 to 4.2, (iii) specified quantity of oxybutynin degradation product(s), in particular reactively generated oxybutynin degradation product(s), preferably hydrolytically and / or oxidatively generated oxybutynin degradation product(s), preferably phenylcyclohexylhydroxyacetic acid (impurity D): at most 0.5 wt.%, in particular at most 0.2 wt.%, based on the total amount of oxybutynin used, preferably oxybutynin hydrochloride; and wherein the oxybutynin-containing composition and / or the sterile syringe filled with the oxybutynin-containing composition has a SAL (Sterility Assurance) value of at least 10 -6 exhibits; wherein the oxybutynin-containing composition contained in the piston syringe, including the piston syringe, is or has been heat-sterilized, in particular steam-sterilized, preferably steam-sterilized, preferably terminally (heat-, steam-, steam-)sterilized.

[0198] The oxybutynin-containing composition may also exhibit or fulfill the following specifications: - The oxybutynin-containing composition may, as a further specification requirement (iv), comprise at least one electrolyte, in particular an alkali metal salt, preferably an alkali metal chloride, preferably sodium chloride (NaCl), in particular in a specified quantity in the range of 0.1 wt.% to 2 wt.%, in particular in the range of 0.5 wt.% to 1.5 wt.%, preferably in the range of 0.7 wt.% to 1.2 wt.%, preferably of about 0.9 wt.%, based on the final composition, in particular in a specified quantity. - In addition, the oxybutynin-containing composition may, as a further specification requirement (iv), contain sodium chloride, calculated as sodium, in a specified concentration of (3.5 ± 0.5) mg / ml, in particular (3.5 ± 0.3) mg / ml, preferably (3.5 ± 0.1) mg / ml, preferably about 3.5 mg / ml. - In addition, the oxybutynin-containing composition may, as a further specification requirement (v), have a specified quantity of total degradation products of at most 1 wt.%, in particular at most 0.5 wt.%, based on the total quantity of oxybutynin used, preferably oxybutynin hydrochloride.

[0199] According to the invention, the piston syringe, preferably the syringe body, in particular the syringe cylinder, can have a volume, in particular a receiving volume for the oxybutynin-containing composition, in the range of 1 ml to 100 ml, in particular in the range of 2 ml to 50 ml, preferably in the range of 3 ml to 25 ml, preferably in the range of 4 ml to 25 ml, particularly preferably in the range of 6 ml to 20 ml, further preferably in the range of 8 ml to 15 ml, and even more preferably in the range of 9 ml to 12 ml, most preferably of about 10 ml.Likewise, the piston syringe, preferably the syringe body, in particular the syringe cylinder, can contain the oxybutynin-containing composition in an amount in the range of 1 ml to 100 ml, particularly in the range of 2 ml to 50 ml, preferably in the range of 3 ml to 25 ml, preferably in the range of 4 ml to 25 ml, particularly preferably in the range of 6 ml to 20 ml, further preferably in the range of 8 ml to 15 ml, again more preferably in the range of 9 ml to 12 ml, and most preferably in the range of about 10 ml.

[0200] As regards the piston syringe according to the invention, the syringe piston in question can in particular be made of or consist of polypropylene.

[0201] Furthermore, the piston plug can be made of or consist of an elastomeric material, in particular a rubber material and / or a rubber material, preferably a rubber material. According to a preferred embodiment of the invention, the piston plug can be made of or consist of a halogenated butyl rubber, in particular a chlorobutyl rubber, or a bromobutyl rubber, preferably a bromobutyl rubber.

[0202] According to the invention, it can be such that the piston syringe, in particular the syringe body, preferably the syringe cylinder, has a receiving and / or filling opening, in particular for filling the syringe body, in particular the syringe cylinder, with the oxybutynin-containing composition and / or in particular for preferably sealing the receiving of the syringe piston with the piston stopper and / or in particular wherein the receiving and / or filling opening with the syringe piston, in particular with the piston stopper, is closable and / or is designed to be closable and / or is closed.

[0203] Furthermore, according to the invention, the syringe body may have an adapter, in particular for connecting an instillation device and / or for dispensing and / or applying the oxybutynin-containing composition.

[0204] In this context, it may be provided that the syringe body is formed in one piece. It may also be provided that the adapter forms a connected unit with the syringe body, in particular the syringe barrel, in particular a fixed and / or inseparable connection, preferably a material-bonded unit. It may also be provided that the adapter is connected to the syringe body, in particular the syringe barrel, in particular a fixed and / or inseparable connection, preferably a material-bonded unit.

[0205] According to the invention, the adapter may have an outlet opening, particularly at the free end of the adapter and / or specifically for dispensing and / or applying the oxybutynin-containing composition. Furthermore, the adapter may have an inlet opening, particularly in the transition area between the adapter and the syringe barrel and / or specifically for receiving the oxybutynin-containing composition from the syringe barrel.

[0206] In particular, according to the invention, the adapter is designed to be hollow.

[0207] In particular, the adapter may have a cavity, especially a passage channel, located between the adapter's outlet and inlet openings, specifically for the outlet of the oxybutynin-containing composition. In this context, the cavity, especially the passage channel, may extend from the adapter's inlet to its outlet or connect the inlet to the outlet.

[0208] According to the invention, it can also be provided that the adapter is tapered or converging in the outlet direction and / or in the direction of the outlet opening of the adapter.

[0209] Furthermore, the adapter may have a decreasing and / or diminishing circumference, in particular outer circumference, and / or a decreasing and / or diminishing diameter, in particular outer diameter, in the outlet direction and / or in the direction of the outlet opening of the adapter.

[0210] According to the invention, the adapter can also be designed in particular as follows: - The adapter can be designed in a nozzle shape, in particular as a conical or cylindrical nozzle, preferably without threads, preferably as a Luer-Slip, or with threads, in particular screw threads, preferably as a Luer-Lock. - Furthermore, the adapter can be conical or stepped-conical, preferably stepped-conical. - According to a preferred embodiment of the invention, the adapter can be designed as a stepped cone adapter. In this context, the adapter can have a number of steps ranging from 2 to 40, particularly from 3 to 30, preferably from 5 to 25, preferably from 8 to 20, and most preferably from 10 to 15. Furthermore, the circumference, particularly the outer circumference, and / or the diameter, particularly the outer diameter, of the steps of the adapter can decrease in the outlet direction and / or in the direction of the outlet opening of the adapter.It may also be provided in this context that the ratio of the diameter, in particular the outer diameter, of the adapter at the inlet opening of the adapter to the diameter, in particular the outer diameter, of the adapter at the outlet opening of the adapter is in a range of 1.1 to 15, in particular in a range of 1.25 to 10, preferably in a range of 1.5 to 5, preferably in a range of 2 to 4, particularly preferably in a range of 2.25 to 3.

[0211] According to the invention, it can be such that the piston syringe has a stepped cone-shaped adapter or a stepped cone adapter, wherein the stepped cone-shaped adapter or stepped cone adapter forms a connected, in particular firmly or inseparably connected, preferably materially bonded, unit with the syringe body, in particular syringe cylinder, or wherein the adapter is formed integrally with the syringe body, in particular syringe cylinder.

[0212] Furthermore, the piston syringe according to the invention can be designed as follows: - The piston syringe can thus have a closure element that is in particular removable and / or detachable and / or releasable, in particular a closure cap (closure and / or sealing cap), preferably for sealing against the adapter and / or preferably for sealing on the adapter and / or preferably for sealing the outlet opening and / or the adapter. - In particular, according to the invention, the outlet opening and / or the adapter is closed with the closure element. Specifically, the piston syringe or the outlet opening and / or the adapter is closed with the closure element during the execution of the method according to the invention, particularly in process step b). - In particular, the sealing element can at least substantially completely and / or sealingly enclose or cover the adapter, especially including the outlet opening, particularly at least substantially over the entire outer surface and / or (outer) wall of the adapter and / or particularly at least substantially over the entire outlet opening of the adapter. In particular, the sealing element can at least substantially completely and sealingly enclose or cover the adapter, preferably designed as a stepped cone adapter, particularly at least substantially over the entire outer surface or (outer) wall of the adapter designed as a stepped cone adapter.

[0213] According to the invention, it is therefore particularly provided that the closure element is designed to be positioned against the adapter in a sealing manner and / or to be placed on the adapter in a sealing manner and / or preferably to seal the outlet opening of the adapter and / or to essentially completely and / or sealingly enclose the adapter.

[0214] In general, the closure element within the scope of the present invention can be designed in the shape of a cap or hat.

[0215] Furthermore, the locking element may have a receiving space, in particular for the at least substantially complete reception and / or the at least substantially complete enclosure of the adapter.

[0216] In particular, according to the invention, it can be provided that the locking element is designed to be form-fit and / or force-fit, in particular friction-fit, to the adapter and / or is designed to be fit and / or is designed to be fit and / or to be fit and / or to be fit and fit around the adapter in a form-fit and / or force-fit, in particular friction-fit, manner.

[0217] According to the invention, the closure element can generally be made of an elastomeric material, in particular a rubber material and / or a latex material. According to a preferred embodiment of the invention, the closure element can be made of or consist of a halogenated butyl rubber, in particular a chlorobutyl rubber, or a bromobutyl rubber, preferably a bromobutyl rubber.

[0218] According to a preferred embodiment of the invention, the locking element may also have a removal and / or detachment device, in particular a pull-off device, preferably in the form of a particularly nipple-shaped extension and / or preferably for the particularly manual removal, in particular pulling off, of the locking element from the adapter. In this context, the removal and / or detachment device may be arranged at and / or in the region of the closed end and / or at the tip of the locking element and / or in extension of the longitudinal axis of the locking element.This can make the operation of the closure element easier overall, especially with regard to gripping the closure element with the hand and in particular removing the closure element from the adapter, especially with regard to the use of the piston syringe according to the invention when administering the sterile oxybutynin-containing composition.

[0219] Furthermore, the locking element can have at least one recess, in particular a notch, indentation, and / or material taper, on its outer surface. In this context, the recess can be longitudinal and / or linear and / or straight. Moreover, the recess can be arranged at least substantially longitudinally and / or at least substantially parallel to the longitudinal axis of the locking element. In particular, the locking element can have two, three, four, five, or more, preferably four, recesses. The recesses can be arranged at least substantially equidistant from each other and / or at least substantially parallel to each other on the outer surface of the locking element.

[0220] According to the invention, the piston syringe, in particular the adapter or the closure element, can be physically designed in accordance with DE 10 2020 130 032 A1 and / or DE 20 2020 106 531 U1, as previously stated. The advantages of the respective embodiments mentioned in the respective documents also apply accordingly in the present case.

[0221] As regards the piston syringe according to the invention, it can be heat-sterilized, in particular steam-sterilized, preferably steam-sterilized, preferably terminally (heat-, steam-, steam-)sterilized, under at least one of the conditions defined above, particularly with regard to the method according to the invention.

[0222] In particular, the piston syringe can be heat-sterilized, in particular steam-sterilized, preferably steam-sterilized, preferably terminally (heat-, steam-, steam-) sterilized, with an F0 value in the range of 6 min to 45 min, in particular in the range of 8 min to 40 min, preferably in the range of 10 min to 38 min, preferably in the range of 11 min to 35 min, particularly preferably in the range of 15 min to 32 min, most preferably in the range of 19 min to 30 min.

[0223] Furthermore, the piston syringe can be heat-sterilized, in particular steam-sterilized, preferably steam-sterilized, preferably terminally (heat-, steam-, steam-)sterilized, under overkill conditions and / or at about 121 °C and / or for a period of at least 6 min, preferably about 6 min, or at least 20 min, preferably about 20 min.

[0224] Furthermore, it may be provided that the syringe is heat-sterilized, in particular by steam sterilization, preferably by steam sterilization, preferably by water vapor sterilization, preferably terminally (heat-, steam-, or water vapor) sterilization, in accordance with Pharmacopoea Europaea (Ph. Eur.), Chapter 5.1.1 (07 / 2017:50101), in particular under overkill conditions and / or at approximately 121 °C and / or for a period of at least 15 min, in particular at least 20 min, preferably approximately 20 min. The heat sterilization, in particular steam sterilization, refers to the composition including the syringe containing the composition.

[0225] In particular, the composition can also have the following properties with regard to the piston syringe according to the invention or the piston syringe with the sterile composition included therein: The sterile oxybutynin-containing composition can thus exhibit or fulfill the specified requirements (i) and (ii) and / or (iii), in particular (i), (ii) and (iii), even after storage of the sterile syringe filled with the oxybutynin-containing composition at temperatures in the range of 25 °C to 40 °C, at a relative humidity in the range of 60% to 75% and at a pressure of 1,013.25 mbar for at least 10 days, in particular at least 30 days, preferably at least 3 months, preferably at least 6 months, particularly preferably at least 12 months.

[0226] Furthermore, the sterile oxybutynin-containing composition can exhibit and / or meet the following specifications (i), (ii), and / or (iii), in particular (i), (ii), and (iii), even after storage of the sterile syringe filled with the oxybutynin-containing composition at temperatures in the range of 25 °C to 40 °C, at a relative humidity in the range of 60% to 75%, and at a pressure of 1,013.25 mbar for at least 10 days, in particular at least 30 days, preferably at least 3 months, preferably at least 6 months, and particularly preferably at least 12 months: (i) specified concentration of oxybutynin, preferably in the form of the hydrochloride (oxybutynin hydrochloride, oxybutynin HCl): 0.5 mg / ml to 2 mg / ml with a maximum deviation of ± 5%, based on the concentration of oxybutynin, preferably 1 mg / ml with a maximum deviation of ± 0.05 mg / ml, (ii) specified pH value: 2.8 to 5.2, in particular 3 to 5, preferably 3.2 to 4.8, preferably 3.5 to 4.5, particularly preferably 3.5 to 4.2, most particularly preferably 3.8 to 4.2, (iii) specified quantity of oxybutynin degradation product(s), in particular reactively generated oxybutynin degradation product(s), preferably hydrolytically and / or oxidatively generated oxybutynin degradation product(s), preferably phenylcyclohexylhydroxyacetic acid (impurity D): at most 0.5 wt.%, in particular at most 0.2 wt.%, based on the total amount of oxybutynin used, preferably oxybutynin hydrochloride.

[0227] In particular, the sterile composition can meet the specified specification (iv), especially the specified quantity (iv) of electrolytes, especially alkali metal salts, preferably alkali metal chloride, preferably sodium chloride (NaCl), in the range of 0.1 wt.% to 2 wt.%, particularly in the range of 0.5 wt.% to 1.5 wt.%, preferably in the range of 0.7 wt.% to 1.2 wt.%, preferably of about 0.9 wt.%, based on the final composition, and / or the specified concentration (iv) of sodium chloride, calculated as sodium, of (3.5 ± 0.5) mg / ml, particularly (3.5 ± 0.3) mg / ml, preferably (3.5 ± 0.1) mg / ml, preferably about 3.5 mg / ml, even after storage of the sterile syringe filled with the oxybutynin-containing composition at temperatures in the range of 25 °C to 40 °C, at a relative humidity in the range from 60% to 75% and at a pressure of 1.013.25 mbar of at least 10 days, in particular at least 30 days, preferably at least 3 months, preferably at least 6 months, especially preferably at least 12 months, exhibit or meet.

[0228] Furthermore, the sterile oxybutynin-containing composition can exhibit or fulfill the specified specification (v), in particular the specified quantity of total degradation products of at most 1 wt.%, in particular at most 0.5 wt.%, based on the total quantity of oxybutynin used, preferably oxybutynin hydrochloride, even after storage of the sterile syringe filled with the oxybutynin-containing composition at temperatures in the range of 25 °C to 40 °C, at a relative humidity in the range of 60 % to 75 % and at a pressure of 1,013.25 mbar for at least 10 days, in particular at least 30 days, preferably at least 3 months, preferably at least 6 months, particularly preferably at least 12 months.

[0229] Furthermore, the oxybutynin-containing composition and / or the sterile syringe filled with the oxybutynin-containing composition can have a SAL (Sterility Assurance) value of at least 10.-5 , in particular at least 10 -6 , preferably at least 10 -7 exhibit.

[0230] The piston syringe according to the invention is particularly suitable for instillation or preferably topical application of the oxybutynin-containing composition into the urogenital area, especially into the bladder, particularly using a suitable application or instillation device, especially in the form of an instillation tube or the like, or in the form of a (bladder) catheter.

[0231] With regard to further embodiments of the piston syringe according to the invention, reference can also be made to the explanations concerning the further aspects of the invention, which apply accordingly in the present case.

[0232] The present invention further relates – according to yet another aspect of the present invention – to the packaging unit according to the invention, comprising at least one packaging and at least one piston syringe, in particular a disposable piston syringe, as defined above, wherein the piston syringe is incorporated into the packaging or is present in the packaging.

[0233] In this context, according to the invention, the packaging unit or the packaging in question, together with the piston syringe and the oxybutynin-containing composition, can be heat-sterilized, in particular steam-sterilized, according to the method defined above. Furthermore, the packaging unit according to the invention can generally be designed as a ready-to-use package. In particular, the packaging unit according to the invention can be sealed or closed in a watertight and / or germ-proof manner. Furthermore, at least part of the packaging can be designed to be at least permeable to water vapor, in particular permeable to water vapor and / or gas.

[0234] For further details or embodiments of the packaging unit according to the invention, reference can also be made to the further details concerning the other aspects of the present invention, which apply accordingly.

[0235] A further object of the present invention – according to a further aspect of the present invention – is the kit according to the invention, in particular the application and / or instillation system, comprising (i) at least one oxybutynin-containing composition, as defined above, in a piston syringe, in particular a disposable piston syringe; (ii) (a) at least one application and / or instillation device, in particular in the form of an instillation tube or the like, preferably in the form of a urinary catheter, which can be connected to the piston syringe; and / or (b) at least one connection device, which can be connected to the piston syringe, for connecting to an application and / or instillation device, in particular in the form of an instillation tube or the like, preferably in the form of a urinary catheter; and optionally (iii) at least one application and / or instillation instruction.

[0236] According to this aspect, the present invention also relates to the further kit according to the invention, in particular an application and / or instillation system, comprising (i) at least one oxybutynin-containing composition, as defined above, in a piston syringe, in particular a disposable piston syringe; (ii) (a) at least one application and / or instillation device, in particular in the form of an instillation tube or the like, preferably in the form of a urinary catheter, which can be connected to the piston syringe, in particular to the adapter of the piston syringe; optionally (iii) an adapter counterpart for connecting the application and / or instillation device to the piston syringe, in particular to the adapter of the piston syringe; and optionally (iv) at least one application and / or instillation instruction.

[0237] The piston syringe according to the invention, with the sterile oxybutynin-containing composition as defined above, can also be used in the form of the packaging unit described above.

[0238] Regarding further embodiments in this respect, reference can also be made to the explanations concerning the other aspects of the invention, which apply accordingly.

[0239] A further aspect of the present invention is the use of a piston syringe, in particular a disposable piston syringe, in a process for producing a sterile oxybutynin-containing composition, as defined above. Regarding the physical design of the piston syringe, reference can be made to the above descriptions, which apply accordingly. The piston syringe used according to the invention comprises a syringe body, in particular a syringe cylinder, on the one hand, and a syringe plunger with a plunger stopper on the other, wherein the syringe body, in particular the syringe cylinder, is made of polypropylene (PP).

[0240] In this regard, reference can also be made to the explanations concerning the other aspects of the invention, which apply accordingly in the present case.

[0241] Furthermore, another object of the present invention – according to a further aspect of the present invention – is the use according to the invention of heat sterilization, in particular steam sterilization, preferably water vapor sterilization, preferably terminal (heat, steam, water vapor) sterilization, in a process for producing a sterile oxybutynin-containing composition, as defined above, in a preferably ready-to-use piston syringe, in particular a disposable piston syringe, and / or for producing a preferably ready-to-use, sterile piston syringe, in particular a disposable piston syringe, filled with an oxybutynin-containing composition, as defined above.

[0242] Regarding the physical design of the piston syringe, reference can be made to the above statements, which apply accordingly. The piston syringe used according to the invention comprises a syringe body, in particular a syringe cylinder, on the one hand, and a syringe piston with a piston stopper on the other, wherein the syringe body, in particular the syringe cylinder, is made of polypropylene (PP).

[0243] For further details regarding the use according to the invention in this respect, reference can also be made to the details regarding the other aspects of the invention, which apply accordingly in the present case.

[0244] The present invention is described below with reference to figures illustrating preferred embodiments and configurations. In connection with the explanation of these preferred embodiments and configurations of the present invention, which are by no means limiting in relation to the present invention, further advantages, properties, aspects, and features of the present invention are also presented. Furthermore, for the illustrations in Fig. 1 and Fig. Reference numerals shown in section 2 refer to the following list of reference numerals.

[0245] The depictions of figures show: Fig. 1 a schematic sectional view of a piston syringe obtained within the framework of the inventive method or of a piston syringe filled with the sterile oxybutynin-containing composition according to the invention; Fig.2 a schematic sectional view of a further piston syringe usable or obtained within the framework of the inventive method or a piston syringe filled with the sterile oxybutynin-containing composition according to the invention; Fig. Figure 2 shows a preferred embodiment of the present invention, wherein the piston syringe has a stepped cone-shaped adapter or a stepped cone adapter, wherein the syringe body is formed integrally with the adapter or wherein the adapter is connected to the syringe cylinder, in particular firmly or inseparably connected, preferably by a material bond; Fig. Figure 2 also shows another embodiment according to the invention, in which the adapter including the outlet opening is closed or at least substantially completely covered with a closing element in the form of a closure cap; Fig.3 a graphical representation of the dependence of the reduction in pH value (pH loss) present for sterile oxybutynin-containing compositions (final compositions) after carrying out the process according to the invention or after heat sterilization on the initial pH value (starting pH value) of the initial composition before heat sterilization; Fig. 4 a graphical representation of the dependence of the migration or storage rate of oxybutynin (loss of oxybutynin after heat sterilization) on the pH value of the initial composition (composition or solution before heat sterilization).

[0246] For further details regarding the embodiments and exemplary embodiments illustrated in the figures, reference may be made to the above explanations, as well as to the following supplementary explanations of the present invention and to the explanations of the exemplary embodiments, which apply accordingly to the figures, in order to avoid unnecessary repetition. Furthermore, for the [unclear] in Fig. 1 and Fig. Reference numerals shown in section 2 refer to the following list of reference numerals.

[0247] Further embodiments, modifications and variations as well as advantages of the present invention are readily apparent and achievable for the person skilled in the art when reading the description, without leaving the scope of the present invention.

[0248] The following embodiments serve only to illustrate the present invention, without limiting the present invention to them. Examples and further details of the present invention: Objective of the following series of experiments

[0249] The aim here is to produce or provide a sterile oxybutynin-containing composition that meets the specifications listed in Table 1.

[0250] In this context, a 0.1% oxybutynin solution is used. The sterile oxybutynin-containing composition is to be provided in a ready-to-use, disposable polypropylene syringe, whereby both the disposable syringe and the oxybutynin-containing composition are to be thermally sterilized simultaneously. Due to its solubility, the active ingredient oxybutynin is used in the following aqueous composition as its hydrochloride (oxybutynin hydrochloride or oxybutynin HCl, structural formula (3)). Table 1: Specification requirements of the sterile oxybutynin-containing composition after sterilization in the piston syringe (impurity D = phenylcyclohexylhydroxyacetic acid) parameter specification Oxybutynin content 95 - 105 % Contamination D ≤ 0.2 wt.% further impurities ≤ 0.2 wt.% Total impurities ≤ 0.5 wt.% PH value 3,5 - 4,2 background

[0251] The applicant's preliminary tests, which are not based on the inventive method, indicate that a non-sterile oxybutynin-containing solution in a cylinder treated by terminal thermal sterilization does not fall within the specified parameters, whereas the values ​​mentioned are generally achieved for primary packaging materials or cylinders made of cycloolefin copolymer (COC) (see Table 1).

[0252] Preliminary tests show a loss of approximately 10% of the oxybutynin after sterilization in a polypropylene (PP) syringe, as well as the formation of the hydrolysis product phenylcyclohexylhydroxyacetic acid (impurity D, structural formula 2) at a concentration of 0.7%. Consequently, the specifications defined in Table 1 are not met. In contrast, the solution shows a lower loss after sterilization in COC. Oxybutynin in polypropylene storage devices (piston syringes)

[0253] The above preliminary tests can be used as background or basis for the following experiments and questions according to the invention.

[0254] Three aspects are particularly relevant: understanding the loss of oxybutynin concentration after sterilization, the dependence of the formation of the hydrolysis product (impurity D), the influence of the magnitude of the thermal stress on the aforementioned points depending on the sterilization conditions, and the influence of the pH value on the parameters listed in Table 1.

[0255] The standard composition used is an oxybutynin-containing composition with the amounts specified in Table 2. Table 2: Oxybutynin-containing composition raw material Crowd Sodium chloride 0.9 wt.% 10% hydrochloric acid 0.0052 wt.% Oxybutynin HCl 0.1 wt.% Water 98.9948 wt.% Behavior of specification parameters under different storage conditions without sterilization

[0256] The specification parameters of oxybutynin-containing compositions in polypropylene piston syringes are documented under two different storage conditions. Changes in the specification parameters over time are determined for oxybutynin-containing compositions with an initial pH of 3.8 and an initial pH of 4.2 (the initial pH values ​​represent values ​​at the upper and lower end of the specification ranges). The oxybutynin-containing compositions with the different initial pH values ​​are stored at 25 °C and 60% relative humidity (RH) and at 40 °C and 75% RH. The specification parameters are determined after 10 days, 30 days, and 3 months and are listed in Table 3.

[0257] Table 3 below shows the behavior of the specification parameters under different storage conditions without sterilization of oxybutynin-containing compositions in polypropylene piston syringes. Table 3: Specifications Condition Length of time pH Oxybutynin[%] Oxybutynin loss [%] Contamination D [%] global pollution[%] Total impurities [%] lower pH value limit t0 0 3,92 100,9 nb n / a n / a 25 / 60 10 days 3,93 100,6 0,3 nb 0,03 0,03 40 / 75 10 days 3,91 100,6 0,3 nb 0,03 0,03 25 / 60 30 days 4 100,3 0,6 nb 0,03 0,03 40 / 75 30 days 4,01 100 0,9 nb 0,03 0,03 40 / 75 3 months - 99,9 1 0,01 0,08 0,09 upper pH limit t0 0 4,21 99,7 nb n / a n / a 25 / 60 10 days - 99,8 -0,1 nb 0,03 0,03 40 / 75 10 days - 99,8 -0,1 nb 0,03 0,03 25 / 60 30 days - 99,2 0,5 nb n / a n / a 40 / 75 30 days - 97,1 2,6 0,01 6 0,025 0,041 nb = not determined

[0258] It has been shown that when the non-sterile oxybutynin-containing composition is stored in a polypropylene piston syringe without prior sterilization, the specification requirements are met over the entire period.

[0259] Furthermore, the data listed in Table 3 indicate that at higher pH values ​​and more intensive storage conditions (upper pH limit, 40 °C, 75% relative humidity, 30 days) a certain loss of oxybutynin can be observed, which, however, is not accompanied by an increase in the degradation product D. Behavior of specification parameters under different storage conditions after sterilization

[0260] Furthermore, the changes in the specification parameters after thermal sterilization of an oxybutynin-containing composition with an initial pH of 3.8 (initial pH in the lower range of the specification requirements) are also determined.

[0261] The specification parameters are determined after 10 days, 30 days and 3 months and are listed in Table 4.

[0262] Table 4 below shows the behavior of the specification parameters under different storage conditions of oxybutynin-containing compositions in polypropylene piston syringes after sterilization (compared to the initial values ​​before sterilization). Table 4: Specifications Condition Length of time pH Oxybutynin[%] Oxybutynin loss [%] Contamination D [%] further pollution agreements [%] Total impurities [%] non-sterile t0 0 3,92 100,9 - nb nb nb t0 0 3,73 91,1 9,8 nb nb nb 25 / 60 10 days 3,69 94,4 6,5 0,018 0,028 0,046 40 / 75 10 days 3,7 93,7 7,2 nb 0,02 0,02 sterile 25 / 60 30 days 3,76 92,6 8,3 0,015 0,028 0,043 40 / 75 30 days 3,8 93,8 7,1 0,008 0,023 0,031 25 / 60 3 months 3,75 92,3 8,6 0,01 0,028 0,038 40 / 75 3 months 3,8 94 6,9 0,014 0,111 0,125 nb = not determined

[0263] Table 4 shows that with an initial pH value at the lower end of the specification range (approx. 3.8), a reduction or loss of 9.8% of oxybutynin is observed after sterilization. A corresponding drop in the solution's pH value of 0.19 units occurs immediately after sterilization at time t0. The solution is therefore not in compliance with specifications. However, after storage for three months under stressed conditions (40 °C, 75% relative humidity), the oxybutynin concentration stabilizes at approximately 7%. This results in a return to a pH value of 3.8, which meets the specifications.

[0264] Compared to the non-sterile formulations, an increase of 0.018% in the hydrolysis product impurity D is observed after 10 days of storage at 25 °C and 60% relative humidity. However, the same order of magnitude is also observed in a non-sterile solution after 30 days at 40 °C and 75% relative humidity (see Table 3). This suggests that hydrolysis is a thermally induced process, but one of minor significance overall. As also shown in Table 3, the unknown impurities are at levels between those found in the sterile and non-sterile solutions. Mechanism of oxybutynin loss after sterilization

[0265] As previously described and shown in Table 4, sterilization of an aqueous oxybutynin solution at a pH of 3.92 results in an oxybutynin loss of 9.8%. However, this loss does not directly correlate with the simultaneous increase in impurity D (hydrolysis product of oxybutynin) or other unknown impurities.

[0266] As subsequently confirmed, oxybutynin could migrate from the aqueous solution into the PP packaging (i.e., into the polypropylene syringe), particularly during sterilization. This would mean that the reduction or loss of oxybutynin is thermally induced. Such a previously undescribed effect would be completely surprising to someone skilled in the art.

[0267] The above assumption of the migration of oxybutynin into the packaging material can be confirmed, especially in the case where (i) migration of the contaminant D into the packaging material and a consequent loss in the solution can be ruled out; and (ii) the reduction of oxybutynin is based on an unknown thermally induced degradation reaction whose degradation products cannot be detected by the validated HPLC method can be ruled out.

[0268] To rule out the possibility of a thermally induced degradation reaction of oxybutynin HCl forming an unknown byproduct that cannot be detected using a validated HPLC method, or of migration of the hydrolysis product D, the packaging material used (polypropylene cylinder and rubber stopper) is subjected to extraction with THF after sterilization, and the resulting extract is examined both qualitatively by thin-layer chromatography and quantitatively by HPLC.

[0269] Furthermore, the extract is subjected to aqueous microprocessing with diethyl ether at pH 4 to demonstrate that oxybutynin exists at pH 4 as a free amine base (structural formula (1)) in the organic phase (diethyl ether) or as a hydrochloride in the aqueous phase.

[0270] The assay results after sterilization show a decrease in oxybutynin content in the solution of up to 9% at pH 3.8. It can be assumed that at pH 4, the majority of the oxybutynin is present in the diethyl ether phase as a free amine base.

[0271] The extracts of the packaging materials are analyzed with the respective analytical reference substances of oxybutynin and impurity D on the thin-layer chromatography or TLC plate using the mobile phase cyclohexane / ethyl acetate 1:6.

[0272] Further experiments show that the extract of the rubber parts does not contain oxybutynin, while the extract of the polypropylene cylinder does contain oxybutynin.

[0273] By acidic, aqueous processing of the polypropylene cylinder extract, it can be qualitatively demonstrated that oxybutynin is present in the organic diethyl ether phase, but not in the aqueous phase.

[0274] In this context, the microprocessing samples are also analyzed using HPLC analysis, which allows the following qualitative evidence to be obtained: • Migration of oxybutynin into the packaging material • Affinity of migration into the polypropylene cylinder compared to the butyl rubber of the rubber parts • Comparison with a blank material (not migrated) • Exclusion of the migration of contaminant D into the polypropylene cylinder and the rubber parts Calculation of the maximum detectable concentration of oxybutynin in the samples

[0275] As previously stated, immediately after sterilization 9.8% of the oxybutynin is no longer detectable or recognizable in the oxybutynin-containing composition, whereby an average migration rate of 7.8% can be calculated across all packaging materials used.

[0276] At an oxybutynin concentration of 0.1%, 0.78 mg / syringe migrates into the packaging. With four packaging materials used, this corresponds to a mass of approximately 3.1 mg, which can be recovered through quantitative analysis (see Table 5). Table 5: Calculation of the theoretically migrated amount of oxybutynin based on the remaining concentration in the solution after sterilization Concentration of the solution 0,1 % volume of the solution 10 ml Oxybutynin / injection 10 mg average migration rate 7,84 % migrated quantity / syringe 0.78 mg Amount in 4 syringes for quantitative detection 3.1 mg

[0277] The following samples will be analyzed using HPLC: - Rubber parts (aqueous, organic phase) - Polypropylene cylinder (aqueous, organic phase) - Blank rubber parts (aqueous, organic phase) - Blank polypropylene cylinders (aqueous, organic phase)

[0278] Table 6 lists the amount of oxybutynin in the measured samples (no impurity D was found in each case). Table 6: HPLC results of the extraction tests of the rubber parts and polypropylene cylinders Oxybutynin [µg / ml] other values Rubber part organic phase blank nb Rubber part organic phase 8,71 Rubber part, aqueous phase, blank nb Rubber part aqueous phase 2,71 Cylinder organic phase blank nb Cylinder organic phase 71,78 Blank cylinder, aqueous phase nb Cylinder aqueous phase 13,39 Total rubber part 11,43 Total cylinders 85,17 Total packaging materials 96,59 Quantity / Rubber part 2,86 Quantity / cylinder 21,29 Quantity / syringe 24,15 Ratio of oxybutynin cylinder / oxybutynin gum part (aqueous phase) 4,94 Ratio of oxybutynin cylinder / oxybutynin gum part (organic phase) 8,24 Ratio of oxybutynin cylinder / oxybutynin gum part (total) 7,45 Oxybutynin in HPLC sample 96,59 Sample dilution factor 10 Oxybutynin in extraction sample 965,92 µg Oxybutynin / injection 0.24 mg Migration rubber part 11,83 % Migration Cylinder 88,17 % Migration of aqueous cylinders 15,72 % Migration organic cylinder 84,28 %

[0279] Impurity D could not be detected in either the aqueous or the organic phase, indicating that the substance did not migrate into the cylinder or the rubber parts, as confirmed by thin-layer chromatography. This finding further supports the assumption that the hydrolysis of oxybutynin and the subsequent migration of phenylcyclohexylhydroxyacetic acid (impurity D or the hydrolysis product of oxybutynin) are not responsible for the decrease in the oxybutynin concentration.

[0280] Comparison of the aqueous and organic samples from the microprocessing confirms the qualitative findings of the thin-layer chromatography, which show that oxybutynin is primarily (84%) detectable in the organic samples. The value for the aqueous processing of the cylinders is 13.4 µg / ml compared to 71.8 µg / ml for the organic processing. This supports the conclusion that oxybutynin exists largely as a neutral amine base at pH 4 and is therefore soluble in diethyl ether (84%). The amounts of oxybutynin from the aqueous and organic samples are added to determine the total amount of oxybutynin after solid-phase extraction. 88% of the oxybutynin migrates into the cylinder material, while only 12% migrates into the rubber parts.

[0281] Since the experiments were not performed with precise amounts of solvent and without the use of an external standard, only 30% of the migrated oxybutynin was recovered. Similarly, the low recovery rate can be explained by a potentially incomplete solid-phase extraction with THF. The results of the HPLC measurements are within the range expected from the stability storage tests. Table 6 shows that 965.92 µg were detected from four packaging materials after sample preparation, corresponding to 0.24 mg / syringe.

[0282] The solubility of oxybutynin in aqueous environments is limited, so the substance is used in aqueous systems in the form of its hydrochloride. Both qualitative results from thin-layer chromatography and quantitative values ​​from HPLC show that oxybutynin migrates into polypropylene after thermal stress. Oxybutynin migrates into the packaging material in its nonpolar form and can be detected again as a free amine base by extraction with THF.

[0283] Consequently, it is assumed that at increasing pH values ​​in the aqueous solution, oxybutynin exists in its free, uncomplexed form, which migrates into the packaging material. At lower, strongly acidic pH values, oxybutynin is complexed by the hydrochloride and is then inhibited from migrating into polypropylene due to its polarity. Thus, the migration rate of oxybutynin increases after sterilization with increasing pH of the initial solution and decreases after sterilization with decreasing pH. Furthermore, if the uncomplexed free amine base migrates, a decrease in the pH of the solution can be observed after sterilization, since the hydrochloride is present as a free acid.

[0284] These assumptions are phenomenologically supported by a decrease in oxybutynin concentration of 9.8% and a pH reduction of 0.19 (see Table 4). Effects of initial pH value on oxybutynin loss

[0285] To verify the previously described pH-dependent migration, the amount of HCl in the oxybutynin-containing composition (see Table 2) is adjusted to achieve pH values ​​of 3 and 5. To compensate for the oxybutynin loss after sterilization at pH 5, oxybutynin at a concentration of 105% is used. The solutions are sterilized in a polypropylene piston syringe, and specification parameters are determined after thermal treatment (see Table 7).

[0286] Table 7 below shows the behavior of the specification parameters of oxybutynin-containing compositions in polypropylene piston syringes for different initial pH values ​​(pH 3 and pH 5) after sterilization (compared to the initial values ​​before sterilization). Table 7: Specification parameters at pH 3 and pH 5 before and after sterilization Condition Length of time pH Oxybutynin[%] Oxybutynin loss [%] Contamination D[%] other impurities[%] Total impurities [%] 100% oxybutynin, pH 3, non-sterile t0 0 2,86 99,5 - 0,008 0 0,084 100% oxybutynin, pH 3, sterile t0 0 2,82 100,3 -0,8 0,03 0 0,034 25 / 60 10 days 2,84 98,9 0,6 0,05 0 0,089 40 / 75 10 days 2,86 98,9 0,6 0,058 0 0,094 25 / 60 30 days 2,82 98 1,5 0,023 0 0,023 40 / 75 30 days 2,81 98,8 0,7 0,063 0 0,063 25 / 60 3 months 2,84 99 0,5 0,025 0 0,031 40 / 75 3 months 2,86 99,2 0,3 0,029 0,16 0,189 105% oxybutynin, pH 5, non-sterile t0 0 5,2 103,9 - 0,01 0 0,01 105% oxybutynin, pH 5, sterile t0 0 3,8 95,9 8 0,06 0 0,06

[0287] Table 7 shows that a starting pH of 3 leads to specifications-compliant results after sterilization, and the migration rate can be reduced from 9.8% (see Table 4) to 0%. Furthermore, the pH decrease after sterilization is only 0.04 (i.e., 0.15 compared to the results at a starting pH of 3.92; see Table 4). These results also support the assumption that at lower pH values, oxybutynin is mainly present in its polar form, thus surprisingly reducing migration into polypropylene and consequently resulting in only a slight reduction in pH after sterilization. After three months of storage under harsh conditions (40 / 75), a maximum migration rate of 0.3% and a stable pH of approximately 2.8 are observed.

[0288] Furthermore, it is shown that while increasing the initial pH to pH 5 results in an increased loss of oxybutynin (8%), this loss can surprisingly be compensated for by increasing the oxybutynin concentration to 105%. Here, after sterilization, specification-compliant values ​​of up to 95.9% oxybutynin and a pH of 3.8 can be achieved.

[0289] The experiments are repeated with further variations in initial pH values ​​(adjusting the pH by modifying the HCl concentration). In this context, pH values ​​in the range of 2.86 to 5.2 are considered, and the relationship to the pH drop after sterilization is documented (see [reference]). Fig. 3) This dependency can be represented by a nonlinear correlation, which can be expressed using a second-degree polynomial and a coefficient of determination of R. 2 = 0.9799 (y = 0.2898x 2- 1.7344x + 2.6217). Based on this function, further pH losses can be interpolated, and example pH values ​​can be extrapolated. The graph shows a quadratically increasing pH loss with increasing initial pH. From this, it can be deduced that for a pH specification range of 3.5 to 4.2, a maximum initial pH of 5.2 and a minimum initial pH of 4.2 should be used.

[0290] In Fig. Figure 4 visualizes the dependence of oxybutynin loss after sterilization on the initial pH of the solution. It also shows that the observed migration rate exhibits a linear trend in the pH range from 2.86 to 5.2. The resulting linear correlation yields a coefficient of determination of R. 2= 0.8078 (y = 3.4196x - 8.1923) and illustrates that in the pH range of 3.8 to 4.2, an average oxybutynin loss of 5% can be expected after thermal input. Migration can be essentially suppressed at pH values ​​of 3 and increases to a migration loss of approximately 8% at pH values ​​above 5. Effect of oxybutynin concentration on other specification parameters

[0291] By adjusting the pH of the oxybutynin-containing composition to acidic conditions (pH of approximately 3) before sterilization, the specification requirements can be met by suppressing or reducing migration (see [reference]). Fig.4) However, the physiological applicability of such acidic solutions (pH approx. 3) is sometimes not given. The loss of oxybutynin after sterilization within the specified pH range can surprisingly be compensated for by using higher initial concentrations of oxybutynin.

[0292] Furthermore, the experimental series show that an increase in the initial pH value results in an increase in the migration rate (see [reference]). Fig.4) At an initial pH of 5, migration is 8%, whereas highly acidic solutions inhibit migration. In the pH range between 3.8 and 4.2, an average migration of 5.5% occurs. Using linear correlation, threshold values ​​for defining a possible overdose or weight match can be derived depending on the initial pH. Starting from a lower pH of 2.86, it is possible to maintain the oxybutynin content in accordance with specifications (100% to 105% oxybutynin) up to a pH of 3.8 without overdosing. From a pH of 3.8 onwards, an overdose of at least 5% is permissible (threshold value). Here, an oxybutynin concentration of 105% to 110% can be used. Consequently, by adjusting the pH, a specification-compliant oxybutynin content can be obtained after sterilization.

[0293] Further tests using 105% and 110% oxybutynin (see Table 8) show that the oxybutynin content can be achieved within the specified range after sterilization, but the pH value is outside the specified range, between 3.8 and 4.2. Increasing the oxybutynin content to 105% without adjusting the amount of HCl results in an initial pH of 3.63 for the unsterilized solution, which drops to 3.45 after sterilization. The migration of 4.6% can be compensated for by the overdose. By increasing the oxybutynin content to 110% and adjusting the pH value with HCl, a starting pH of 3.99 can be achieved. After sterilization, the oxybutynin content drops to 99.9%, and the pH value simultaneously decreases to 3.6.Increasing the oxybutynin content to 115% while simultaneously adjusting the pH to 4.2 results in a migration rate of 6.6% and a drop in pH to 3.7.

[0294] Table 8 below shows the behavior of the specification parameters of oxybutynin-containing compositions in polypropylene piston syringes for different initial oxybutynin concentrations (at an initial pH of pH 3) after sterilization (compared to the initial values ​​before sterilization). Table 8: Specification parameters at pH 3 and different initial oxybutynin levels Description Condition Length of time pH Oxybutynin[%] Oxybutynin loss [%] Contamination D[%] other impurities[%] Total impurities [%] pH 3, non-sterile t0 0 2,86 99,5 - 0,008 0 0,084 pH 3, sterile t0 0 2,82 100,3 -0,8 0,03 0 0,034 25 / 60 10 days 2,84 98,9 0,6 0,05 0 0,089 40 / 75 10 days 2,86 98,9 0,6 0,058 0 0,094 25 / 60 30 days 2,82 98 1,5 0,023 0 0,023 40 / 75 30 days 2,81 98,8 0,7 0,063 0 0,063 25 / 60 3 months 2,84 99 0,5 0,025 0 0,031 40 / 75 3 months 2,86 99,2 0,3 0,029 0,16 0,189 105% oxybutynin, non-sterile t0 0 3,63 104,4 - 0,008 0 0,103 105% oxybutynin, sterile t0 0 3,45 99,8 4,6 0,028 0 0,036 25 / 60 10 days 3,49 100,4 4 0,054 0 0,09 40 / 75 10 days 3,5 100,6 3,8 0,039 0 0,004 25 / 60 30 days 3,42 100,1 4,3 0,024 0 0,024 40 / 75 30 days 3,47 99,2 5,2 0,016 0 0,016 25 / 60 3 months 3,54 99,8 4,6 0,016 0 0,021 40 / 75 3 months 3,51 99,2 5,2 0,024 0,17 0,2 110% oxybutynin, non-sterile t0 0 3,99 110 - 0,008 0 0,093 110% oxybutynin, sterile t0 0 3,6 99,9 10,1 0,028 0 0,034 25 / 60 10 days 3,62 103,2 6,8 0,05 0 0,075 40 / 75 10 days 3,61 103,5 6,5 0,043 0 0,068 25 / 60 30 days 3,6 102,1 7,9 0,032 0 0,032 40 / 75 30 days 3,59 102,8 7,2 0,024 0 0,024 25 / 60 3 months 3,61 104 6 0,015 0 0,02 40 / 75 3 months 3,72 102,3 7,7 0,015 0,167 0,181 115% oxybutynin, non-sterile t0 0 4,2 115 - 0,02 - 0,045 115% oxybutynin, sterile t0 0 3,7 108,4 6,6 0,0055 - 0,078

[0295] The experiments show that the percentage of surprisingly migrated oxybutynin can be compensated for in an equally surprising way by higher initial concentrations, whereby the drop in pH is also a critical process parameter which - equally surprisingly - can be controlled or compensated for by a combination of pH adjustments and increasing the concentration of oxybutynin. Adjustment of pH and oxybutynin concentration

[0296] As previously explained, the migration of oxybutynin into the polypropylene packaging material after sterilization can surprisingly be compensated for by increasing the oxybutynin concentration; however, this may prevent compliance with the pH limits (see Table 8).

[0297] As previously stated and in Fig.As shown in Figure 3, a surprisingly observed correlation exists between the initial pH of the oxybutynin-containing composition and the pH reduction after sterilization. With an initial pH of 4.5, the pH reduction is 0.75, resulting in a post-sterilization pH of approximately 3.75. Consequently, a post-sterilization pH of 3.7 can be achieved by combining an increased oxybutynin concentration with an adjustment of the initial pH. In particular, the initial pre-sterilization pH can be set to 4.5 (especially with an oxybutynin concentration of 105%). This can prevent pH values ​​that sometimes do not meet specifications, for example, on an industrial scale, and also leads to optimized process control.

[0298] Table 9 below shows the behavior of the specification parameters of oxybutynin-containing compositions in polypropylene piston syringes for an initial oxybutynin content of 105% (at an initial pH of 4.5) after sterilization (compared to the initial values ​​before sterilization). Table 9: Specification parameters at pH 4.5 and 105% oxybutynin Description Condition Length of time pH Oxybutynin[%] Oxybutynin loss [%] Contamination D[%] other impurities[%] Total impurities [%] 105% oxybutynin, pH 4.5, non-sterile t0 0 4,5 104,2 - 0,01 0 0,01 105% oxybutynin, pH 4.5, sterile t0 0 3,7 96,9 7,3 0,05 0 0,05 25 / 60 10 days 3,8 99,5 4,7 0,04 0 0,05 40 / 75 10 days 3,84 | 97,6 6,6 0,04 0 0,04

[0299] When using 105% oxybutynin at an initial pH of 4.5, a migration of 7.3% occurs, and consequently both the oxybutynin content after sterilization and the pH value are within the specification limits. Influence of sterilization parameters

[0300] As previously described, the migration of oxybutynin into the packaging material polypropylene is primarily thermally induced. The average migration rate after thermal stress from autoclaving is 5%. This correlation is also evident from the stability data of non-sterile compositions (see Table 3): a migration rate of 2.6% occurs over a period of 3 months at 40 °C and 75% relative humidity.

[0301] To determine the influence of the selected sterilization parameters on the migration rate, two different sterilization programs (A and B) are tested and the relevant specification parameters are determined after thermal input (see Table 10).

[0302] Sterilization programs A and B differ in the thermal stress applied to the sample. The F0 value serves as a measure of this thermal stress. It represents the equivalent stress of the sterilization program compared to sterilization at a reference temperature (121.1 °C) and is expressed in minutes. It serves to sum all lethal effects of a sterilization program (heating, sterilizing, cooling) over the course of the program, thus enabling comparability. An F0 value of 1 minute therefore corresponds to a thermal stress equivalent to 1 minute at 121.1 °C.

[0303] Sterilization program A achieves FO values ​​in the range of 19 to 23 minutes, with an effective sterilization holding time of at least 6 minutes at 121.5 °C. Sterilization program B additionally features an adaptation to comply with EP 5.1.1 (European Pharmacopoeia) with typical FO values ​​of 28 to 31 minutes and a sterilization holding time of at least 20 minutes at 121.5 °C.

[0304] The sterilization programs show a significant difference in the length of their plateau phase (sterilization time), which corresponds to the thermal stress at < 121 °C. A higher loss of oxybutynin is expected after sterilization with program B.

[0305] Table 10 shows the reduction of pH and oxybutynin content in three different experimental series, where the three experimental series differ in oxybutynin concentration (standard formulation or 105%) and initial pH (3.9 to 4.5). Table 10: Comparison of specification parameters according to sterilization programs A and B Description Sterilization program pH Oxybutynin[%] Oxybutynin loss [%] Standard formula non-sterile 3,92 100,9 - Standard formula A 3,73 91,1 9,8 Standard formula B 3,68 94,1 6,8 Standard formula non-sterile 4,21 99,7 Standard formula A 3,8 92,3 7,4 Standard formula B 3,8 93,5 6,2 105% oxybutynin, pH 4.5 non-sterile 4,5 104,2 - 105% oxybutynin, pH 4.5 A 3,8 97 7,2 105% oxybutynin, pH 4.5 B 3,7 96,9 7,3

[0306] The table shows that all compositions with 105% oxybutynin and a pH of 4.5 achieve specifications-compliant values. In this context, both sterilization programs enable effective sterilization, resulting in specifications-compliant compositions, as previously mentioned. Furthermore, no significant influence of the increased FO values ​​and the longer sterilization holding time on the reduction of the oxybutynin content can be observed. There are no significant differences between the two sterilization programs with regard to either the pH value or the loss of oxybutynin (see Table 10). Only the composition with an initial pH of 3.92 shows a slightly higher deviation in oxybutynin loss (9.8%), which is even lower (6.8%) with the more demanding sterilization (sterilization program B), so no conclusion can be drawn about an increased product contamination.At an initial concentration of 105% and a pH of 4.5, the migration values ​​are 7.3% and 7.2%, respectively. These results suggest that FO values ​​in the range of 19 to 31 minutes can be used without significantly affecting the oxybutynin migration rate or pH loss. Summary of the preceding results

[0307] The oxybutynin content in an aqueous 0.1% oxybutynin solution decreases after terminal steam sterilization in a polypropylene syringe. Furthermore, the pH of the solution drops after thermal stress. Extraction tests of the polypropylene packaging material, followed by qualitative analysis using thin-layer chromatography and quantitative analysis using HPLC, demonstrate that the decrease in oxybutynin concentration is not primarily due to hydrolysis of the oxybutynin or the formation of an unknown impurity, but rather to the migration of oxybutynin in its uncomplexed form (i.e., as a free amine base). This process is primarily thermally induced.

[0308] Furthermore, terminal steam sterilization with F0 values ​​in the range of 19 min to 31 min results in comparable migration rates of oxybutynin and pH losses, so they can be used equally.

[0309] Furthermore, the migration of oxybutynin can be controlled via the pH of the solution prior to sterilization – lower pH values ​​lead to reduced migration. The migration rate at higher pH values ​​can be compensated for by increasing the oxybutynin concentration in the solution prior to sterilization.

[0310] The observed relationship between initial pH and post-sterilization pH can be described by a second-degree polynomial function. In combination with overdosing, pH values ​​can be determined that yield specifications-compliant results.

[0311] The pH and oxybutynin concentration ranges listed in Table 11 (AE) can thus be identified from the experiments conducted. The specified oxybutynin content of 95 to 105% is met in all combinations (AE). For combinations A and B at acidic pH values, the sterilized solution can achieve a pH specification as low as 2.8 (physiological aspects are not considered in this case). Combinations C and D meet the specifications and exhibit final pH values ​​of 3.5 to 4.2.

[0312] Combination E, considered an optimal combination, is based on an overdose of oxybutynin of 105% and an initial pH value of 4.5, resulting in a final pH specification achievable in production technology within the range of 3.5 to 4.2.

[0313] Table 11 below summarizes the pH and oxybutynin concentration ranges shown. Table 11: Corridors for pH values ​​and oxybutynin concentrations combination pH value before sterilization Oxybutynin concentration before sterilization [%] pH loss after sterilization Oxybutynin loss after sterilization [%] pH value after sterilization Oxybuynin concentration after sterilization [%] pH value specification after sterilization A 2,9 - 3,8 100 0,02 - 0,22 1,7 - 4,8 2,88 - 3,58 95,2 - 98,3 2,8 - 4,2 B 2,9 - 3,8 105 0,02 - 0,22 1,7 - 4,8 2,88 - 3,58 100,2 - 103,2 2,8 - 4,2 C 3,8 - 5,2 105 0,22 - 1,44 4,8 - 9,6 3,58 - 3,76 95,4 - 100,2 3,5 - 4,2 D 3,9 - 5 2 110 0,27 - 1,44 5,1 - 9,6 3,53 - 3,76 100,4 - 104,9 3,5 - 4,2 E 4,5 105 0,69 7,2 3,81 97,8 3,5 - 4,2

[0314] The surprising correlations summarized above were determined by the applicant during the aforementioned series of experiments. In this regard, the present invention has surprisingly succeeded in demonstrating an efficient concept for the production of sterile oxybutynin-containing compositions, which in particular allows for the production of compositions with a defined active ingredient content and pH value while simultaneously minimizing impurities. Based on this, an efficient and economical process can thus be provided. Experimental procedure; Materials used; Thin-layer chromatograms

[0315] Thin-layer chromatograms are performed on aluminum plates coated with silica gel 60 F254. Detection is carried out using KMNO4 solution followed by heating on a hot plate. HPLC release analysis and stability studies Device HPLC system (pump, sampler, DAD detector, column oven) Detection 210 nmDAD spectrum (200-350 nm) Stationary phase C18 column (e.g., Kinetex) Length: 50 mm; Inner diameter: 4.6 mm; Particle size: 2.6 µm Mobile Phase (Gradient) Time / [min] Eluent A[%] Eluent B[%] 0,0 65 35 0,7 65 35 6,7 20 80 7,7 20 80 8,0 65 35 12,0 65 35 Column temperature 25 °C Flow rate 1.3 ml / min Injection volume / 5 µl test solution for content determination, 40 µl test solution for impurity determination, 40 µl calibration solution Duration / 12 minutes HPLC for evaluating migration experiments Device Ultmate 3000 from thermo fisherscientific Column: Kinetex C18 Evo 150x4.6mm, 2.6µm EluentA: 0.5% aqueous TFA solution EluentB: Acetonitril Gradient: Time %B -5 22 0 22 0,7 22 6,7 78 10 78 Flow: 1 ml / min Detection: 215 nm Temperature: 30°C Duration: 10 min Injection volume: 20µl Packaging material rubber sealing cap Material: Bromobutyl rubber Silicone oil: Ph. Eur. 1,000 mPas Amount of silicone: 0.005 - 0.010 mg / cm 2 rubber stopper Material: Bromobutyl rubber Silicone oil: Ph. Eur. 1,000 mPas Amount of silicone: 0.040 - 0.080 mg / cm2 cylinder Material: ExxonMobil PP 1013 H1 natural Silicone oil: Ph. Eur. “Dimeticone” 1,000 mPas Production of laboratory batches

[0316] 50% of the water is weighed directly into a suitable beaker. The sodium chloride and the oxybutynin HCl are weighed into suitable glass containers. The components are then transferred to the beaker while stirring. The weighing containers are rinsed.

[0317] A large portion of the remaining water is then weighed into the beaker while stirring. The pH value is then measured and recorded. For formulations where the pH is adjusted (3, 4.5, 5), hydrochloric acid (0.001%) is added until the target pH value is reached. The solution is then stirred for 30 minutes at 250 rpm using a magnetic stirrer.

[0318] The obtained solution is drawn manually into the PP syringe cylinder, fitted with the rubber sealing cap, and the filled syringe cylinders are first blister-packed and then subjected to steam sterilization. Sterilization process

[0319] For steam sterilization, the SBM / Bosch SDR-12.12.60 / 2 large-capacity steam-air autoclave is used. However, for the present experiments, only empty chamber runs are performed to optimize the process. In these runs, the test syringes are placed on a pallet and moved to the center of the chamber, where they are autoclaved without any contents, and the other pallets are also autoclaved.

[0320] The blister-packed syringes, packed in folding boxes, are placed on an empty pallet in quantities of 5 to 25 folding boxes (depending on the size of the experiment) and equipped with sensors for temperature measurement and program control.

[0321] Therefore, all the experiments whose results are discussed here are not full-chamber experiments. Sterilization program A

[0322] Sterilization program A begins with a deaeration phase to reduce air contamination in the blisters and folding cartons, alternating with steam bursts for slow pressure build-up. Once these steps are complete, sterilization under pressure follows for a minimum of 6 minutes at approximately 121 °C. Finally, controlled and multi-stage cooling is performed while maintaining constant pressure. After cooling, multi-stage drying takes place via the internal heat exchangers. This is achieved through purging and deaeration phases at temperatures between 60 and 70 °C, ensuring a dry product can be removed after successful sterilization. On average, FO (Finishing Time) values ​​of 19 to 23 minutes are achieved. Sterilization program B

[0323] Sterilization program B is an extension of sterilization program A, ensuring a minimum sterilization time of 20 minutes at approximately 121 °C. The rest of the program's phases are equivalent to those of sterilization program A. The extended plateau phase of the sterilization process results in FO values ​​ranging from 28 to 31 minutes, representing an increase in the sterilization load of approximately 50% to 60%. stability

[0324] After sterilization, the test batches are stored in stability chambers under conditions of 25 °C / 60 % RH and 40 °C / 75 % RH for up to 3 months. Extraction experiments

[0325] The 0.1% oxybutynin solution, analogous to Table 2, is prepared on a laboratory scale as described in the chapter "Preparation of Laboratory Batches," and the filled syringes are steam sterilized. The syringes are then stored for 10 days at both 25 °C / 60% RH and 40 °C / 75% RH.

[0326] Four of the collected, isolated samples are subjected to extraction tests together with untreated reference packaging (blank). The contents of oxybutynin solution from four filled syringes are discarded, and the cylinders and rubber parts are rinsed with distilled water. The plunger rods of all four syringes are unscrewed and discarded, and the rubber sealing caps and stoppers are removed and separated from the PP cylinder material. The empty syringe bodies and rubber parts are crushed into uniform pieces (average size of PP cylinder: 1 cm). 2 , average size GT: 9 mm 2 ).

[0327] The four crushed syringes and the crushed rubber parts are separately heated under reflux with 150 ml of THF for 1.5 hours. After 1.5 hours, the mixtures are cooled to room temperature, the packing material is filtered off, and washed with approximately 30 ml of THF. The filtrate is then concentrated to dryness.

[0328] The filtrate from the rubber parts is a yellowish oil (1.993 g). The filtrate from the cylinders is a violet oil (0.1951 g). Qualitative verification using DC

[0329] The obtained extracts from rubber parts and cylinders, as well as the reference substances oxybutynin hydrochloride and impurity D, are dissolved in acetone. A 1:6 cyclohexane / ethyl acetate solution is used as the mobile phase. Acidic aqueous microprocessing of the extracts

[0330] The extracts from the rubber parts and the cylinder undergo non-volume-precise microprocessing. The dry extract is dissolved in approximately 3 ml of buffer solution (pH 4, citric acid, sodium hydroxide, hydrochloric acid) and 3 ml of diethyl ether, then extracted. The organic phase is separated. Both phases are filtered through a PTFE syringe filter. Quantitative detection with HPLC: Sample preparation for HPLC

[0331] The aqueous and organic samples from the cylinders and rubber parts are evaporated in an argon stream until dry. The residue is dissolved in 1 ml of THF (tetrahydrofuran) and quantitatively transferred with another ml to a 10 ml volumetric flask. The solution is then made up to the desired volume with 0.1% TFA water. The resulting turbidity is removed via a PTFE syringe filter. Reference symbol list: 1 piston syringe 2 syringe bodies 3 syringe cylinders 4 adapters 4a Outlet opening 4b Inlet opening 5 syringe plungers 5a Intake and / or filling opening 6 piston plugs 7 Locking element 8 Weight loss and / or removal device Z Oxybutynin-containing composition AR outlet direction

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