Abstract
Objectives
It is often difficult to relieve the pain from skin ulcers. In several patients, topical morphine, applied as a hydrogel, has been described as useful. There is no such product commercially available. We present a solution for compounding, packaging, sterilisation and chemical stability of a morphine containing hydrogel.
Methods
We developed a morphine containing poloxamer 407 thermoreversible hydrogel with a concentration of 5 mg/g (0.5% w/w) morphine hydrochloride. The hydrogel was packaged into a plastic prefillable syringe system: BD Sterifill SCF. This syringe can be steam sterilised after it has been filled.
Results
Sterility tests according to the European Pharmacopoeia showed the product to be sterile directly after production and sterilisation and after 20 months of storage. The stability of the morphine hydrochloride was assessed by monthly analysis of the concentration with a stability indicating HPLC-UV method. Morphine hydrochloride concentrations remained between 90% and 110% of the theoretical concentration for a period of 36 months, when stored at room temperature outside the influence of light.
Conclusion
With the described formulation, packaging, sterilisation and stability data, together with the previously reported biopharmaceutical dissolution profile, we present a complete solution for a morphine containing poloxamer 407 hydrogel that can be compounded in any pharmacy with a steam or hot water steriliser at their disposal. This might improve the availability of a sterile morphine hydrogel for the treatment of painful skin ulcers.
Keywords: development, sterile hydrogel, morphine, poloxamer 407, topical, painful skin ulcers
Introduction
It is commonly known that opioid analgesics relieve pain by acting on receptors in the central nervous system. Their systemic use is often accompanied by significant side effects such as constipation, sedation and euphoria.1 These side effects might result in suboptimal analgesia. Recent work by Annemans showed that the pharmacoeconomic impact of these side effects also warrant the reduction of the adverse-event profile of opioid analgesics.2 Research suggests that in contrast to the analgesia induced via the central nervous system, similar analgesia can be achieved through peripheral opioid receptors via a neuroimmune pathway.3 4 Opioid receptors have been detected on peripheral nociceptive nerve endings after peripheral injury and at the onset of inflammation. Under normal conditions, they are not detectable in healthy, intact tissue. Immune cells within inflamed subcutaneous tissue can release endogenous opioid peptides that interact with these receptors and produce pain relief. The experienced analgesia is reversible with an opioid antagonist, for example, naloxone.5 6
Similar pain relieving effects have been described in numerous reports for locally applied exogenous opioid agonists to painful skin ulcers.7 Most of these reports demonstrate an analgesic effect following this treatment, remarkably without the side-effects which are normally seen with systemic administration of opioids.
The exogenous opioids are most often applied in the form of a hydrogel.8–13 As hydrogels are often used to treat excoriating skin conditions and are easy to apply to and remove from an ulcer surface, this seems a logical choice.14 Currently, there are no commercially available morphine containing hydrogels.
Most of the reports of the use of topical opioids on painful skin ulcers only give limited information about the product used to apply the opioid to the ulcer. The most frequently used product was a bedside mixed combination of 10 mg morphine sulfate solution for injection with 8 g of Intrasite gel (Smith&Nephew).8 15 Choosing such a hydrogel for application to a skin ulcer is logical, in particular for necrotic or sloughy wounds. They show the capacity to donate fluid to a dry, necrotic wound and promote hydration and autolysis. Also, as the polymers are only partially hydrated, they have the ability to absorb a degree of wound exudate.16 17 The extent of this fluid absorption although differs from one hydrogel to another. Flanagan reported the positive effect of Intrasite gel in wounds of different origin and duration. Use of Intrasite gel showed a 75% reduction in non-viable tissue after 21 days of use.18 Hydrogels promote wound debridement by rehydration of non-viable tissue, thus facilitating the process of natural autolysis.
However our clinical experience is that with a moist wound surface, Intrasite gel does not adhere well. This results in leakage from the wound surface and because of that a limited contact time and a diminished duration of action. This is specifically the case with fistula, sacral pressure sores and is more pronounced when excessive wound fluid production is present.
Macgregor et al 19 were the first to describe the positive effect of a P407 gel in excoriating skin conditions. Beynon et al 20 describe the advantages of P407 gels specifically in rectovaginal and vesicovaginal fistula. P407 gels show adequate bio adhesive properties and also have the ability to absorb serous secretion.21–23 At low temperatures, they are in a liquid state which enables easy application. As a water soluble gel, it is removable by any aqueous solution and easily rinsed from ulcers; on the other hand, the high viscosity of the gel at body temperature and the ability to absorb a degree of wound exudate reduces the rate at which it is removed, making it longer lasting following application than, for instance, Intrasite gel. Little has been published about the pharmaceutical aspects and compounding of opioid containing hydrogels for use in skin ulcers. In this article, we will describe the compounding, primary container, sterilisation and chemical stability of a morphine containing poloxamer 407 (P407) thermoreversible hydrogel. In an earlier publication, we presented the pharmaceutical dissolution profile of morphine from such a hydrogel.24
Materials and methods
Materials
The following approved pharmaceuticals were used for the formulation of the morphine containing P407 gel. All ingredients used were of Ph. Eur. (European Pharmacopoeia) quality: Poloxamer 407 (Lutrol F 127) (BUFA B.V., Uitgeest, The Netherlands), Morphine-HCL (hydrochloride 3 H2O) (Johnson-Matthey Macfarlan-Smith Ltd, London, UK), glycerol (BUFA B.V., Uitgeest, The Netherlands) and carmellosum sodium 2000 mPa s (sodium carboxymethylcellulosum high viscosity at 1% m/V 1500–2800 mPa s (BUFA B.V., Uitgeest, The Netherlands). (More information on the manufacturers of the different materials can be obtained through the corresponding author).
The following reagents and solvents were of analytical grade: Methanol HPLC grade (Boom B.V., Meppel, The Netherlands), potassium dihydrogen phosphate (BUFA B.V., Uitgeest, The Netherlands), phosphoric acid 85% (Merck) and heptane-1-sulfonic acid sodium salt (Merck).
Preparation of the morphine HCl 0.5% poloxamer hydrogel
Table 1 shows the morphine containing poloxamer gel formulation.
Table 1.
Formulation of 0.5% morphine-HCl poloxamer 407 hydrogel
| Morphine hydrochloride·3H2O | 0.5 g |
| Poloxamer 407 (Lutrol F 127) | 22 g |
| Glycerol | 20 g |
| Carmellose sodium (HPMC) (1% visc 2000 mPa s) | 0.075 g |
| Sterile water | Added until 100 g |
As described in the manufacturers (BASF) technical information leaflet, we used the so-called ‘hot process’ for preparation of the poloxamer gel. Distilled water was heated to 80°C. Morphine was dissolved in a portion of this water. The P407 was gently added to the water–morphine mixture in a melamine mortar and mixed with a pestle until homogenous (solution A). Carmellose sodium was mixed with the glycerol (solution B). Solution A was slowly added to B and mixed until homogenous. This mixture was left to cool to room temperature. Finally, sterile water was added to the desired total weight. Any remaining air bubbles were removed by cooling the gel in a refrigerator, making the gel liquid so air could escape.
The gel, in its cold, almost liquid state was manually poured into sterile syringe barrels in quantities of 5 g each. The syringe barrel was closed with a sterile rubber stopper. For research purposes, we produced 3 batches of 64 syringes, each containing 5 g of morphine P407 gel.
Container
As the primary container for our hydrogel, we chose the plastic prefillable syringe system from Beckton Dickinson: BD Sterifill SCF.25 This system can be used for a variety of pharmaceutical compounds and is also suitable for high viscosity liquids. The syringes are made from a crystal clear polymer that allows a clear view of the drug. They are delivered sterile and the front of the syringe is closed with a luer lock cap. The syringes can be easily filled from the back end and then closed with a rubber stopper. Thereafter, it can be sterilised by autoclaving. On use, a plunger rod can be screwed into the stopper to apply the gel.
Sterilisation
The morphine P407 gel filled syringes were sterilised for 15 min at 121°C in a rain system autoclave (Sanamij BV, The Netherlands). During the sterilisation process, the syringes were placed in an upright position. We used a validated sterilisation process that normally is used for polypropylene vials with a volume of 50–100 mL.
Storage
The product was stored in a conditioned environment outside the influence of light at room temperature (15°C–25°C).
Bioburden testing
After preparation of the morphine P407 gel, filling of the syringes and closing them with the stopper, but before sterilisation, we took two syringes from each batch (the first and last filled) and performed a bioburden test. This was done to examine the extent of microbial contamination before the sterilisation procedure.
For this bioburden test, the hydrogel was diluted with sterile NaCl 0.9% solution and this solution was filtered through a membrane with a pore size of less than 0.45 µm. The membrane was transferred to a soya-bean casein digest agar plate and incubated at 30°C–35°C for 5 days. The amount of CFU (colony-forming units) per sample item portion were determined. This method is based on Ph. Eur. 8th Ed. paragraph 2.6.12 microbiological examination of non-sterile products: microbial enumeration tests.26
Sterility testing
For the sterility test the membrane filtration method was used. (Ph. Eur. 8th Ed. paragraph 2.6.1). A sterility suitability test was performed for this method. From each batch, six samples were taken randomly, according to the guidelines for parenteral preparations in a batch not larger than 100 pieces.
Each sample was aseptically split in half and transferred to two vials containing 100 mL sterile NaCl 0.9%. After dissolution of the hydrogel, these solutions were each filtered over a membrane with a pore size of less than 0.45 µm. Then, the membranes were washed with 100 mL 0.1% peptone in NaCl 0.9%. One of the membranes was transferred to a soya-bean casein digest medium and incubated at 20°C–25°C and the other was transferred to a fluid thioglycolate medium and incubated at 30°C–35°C both for 14 days.
Chemical stability testing
Morphine levels were determined using an HPLC system with a variable wavelength UV detector operating at 285 nm and an end-capped C18 reverse-phase column (Inertsil ODS 2, 250×4.6 mm, 5 µm). The aqueous mobile phase consisted of 10.2 g K2HPO2 in 750 mL demineralised water, brought to pH 3.0 with 85% phosphoric acid. This was mixed with 250 mL methanol. In this solution, 1762 mg heptane-1-sulfonic acid sodium salt was dissolved.
The flow was set to 0.6 mL/min at a pressure of around 82 bar and the volume of injection was 20 µL. The column had a constant temperature of 45°C during analysis.
Sample preparation: 1 g of morphine P407 gel 0.5% was dissolved in 100 mL of a mixture of demineralised water and methanol (3:1) resulting in a theoretical concentration of 50 mg/L morphine HCl. From this mixture, 20 µL was injected.
The method was validated and had a linear relationship between concentration and peak surface area for a concentration range of 12.5–100 mg/L with a correlation coefficient of 1.000. The lower limit of detection was 0.00025 mg/L and the lower limit of quantification was 0.00034 mg/L. For reproducibility, we found a coefficient ranging between 0.116 and 2997%. For accuracy, the measured bias was −0.17%. Forced stress tests in alkaline, heat and oxidative environment showed the method to be stability indicating. Figure 1A, B shows the chromatograms of 0.5 mL 1 mg/mL morphine solution mixed with 1 mL of a 30% hydrogen peroxide solution before and after 1 hour incubation with 30% at 100°C, respectively. The morphine peak is shown at 11.8 min. The peaks at 10.5 and 17.7 min in figure 1B are corresponding with morphine-N-oxide and pseudomorphine, respectively.
Figure 1.
(A) Chromatogram of morphine-HCl before forced oxidative degeneration (Morfine-HCl Rt=11.8 min). (B) Chromatogram of morphine-HCl after 1 hour forced oxidative degeneration (Morphine-HCl Rt=11.8 min; Morphine-N-oxide Rt=10.5; Pseudomorphine Rt=17.7).
Morphine concentrations were measured monthly in a randomly selected sample from each batch over a period of 3 years.
In the monograph Pharmaceutical Preparations of the Ph. Eur., there are no requirements for the content of the active substances. In the Netherlands, it is stated by law that the amount of an active substance of a preparation prepared in the pharmacy should not deviate more than 10% of the amount of that substance that is stated on the label. The limits of 90%–110% contain the total variation caused by preparation and analysis and counts for the entire shelf life.
Results
Bioburden test and sterility tests
The bioburden test revealed no growth in two batches and a limited growth of 3 CFU per sample item portion in the third batch. This was determined as being skin flora and Bacillus spp. Although there is no official guideline for the bioburden before sterilisation, in our hospital pharmacy, we use a limit of 20 CFU to assure no excessive contamination has taken place during compounding.
The sterility tests on six syringes per batch showed no microbial growth. We repeated the sterility tests for each batch after 20 months. Again, there was no growth in any of the samples.
Chemical stability test
Figure 2 shows the measured morphine-HCl concentrations, expressed as percentage of the theoretical concentration. The concentration remains between 90% and 110% throughout the 36-month period. These results show that morphine-HCl remains stable in the P407 hydrogel for a period of at least 36 months.
Figure 2.
Morphine-HCl concentration (percentage of theoretical concentration) over time (months). Every dot represents a randomly selected sample from the batch.
Discussion
Our study shows that a morphine P407 gel can be compounded and sterilised for 15 min at 121°C by hot water sterilisation, when packaged in BD Sterifill SCF syringes, providing us a sterile hydrogel in a ready to use unit dose package. Morphine-HCl remains stable in this hydrogel for at least 36 months when stored at room temperature outside the influence of light.
Poloxamer 407 is a triblock copolymer consisting, by weight, of approximately 70% ethylene oxide and 30% propylene oxide with an average total molecular weight of 12 500 Da.
The original Lutrol gel contains propylene glycol which is thought to be responsible for the occasional tendency for sensitisation and/or stinging sensation on application. One study examining propylene glycol use in patients with a history of contact dermatitis reported that 1.5% of enrolled patients, developed adverse reactions.27 28 For this risk of dermatological adverse reactions, we substituted propylene glycol for glycerol. Replacement with glycerol changed the sol-gel transition temperature making the formulation almost liquid with room and body temperature. Addition of carmellose sodium (1% viscosity 2000 mPa s) lowered the sol-gel temperature to approximately 6°C.
As a wound can be classified as severely injured skin, on application to the wound, hydrogels need to be sterile as described in the European Pharmacopoeia 8th Ed. paragraph Liquid preparations for cutaneous use.26 The previously described bedside mixing of morphine solution for injection and a sterile unit of Intrasite gel can be considered sterile if used immediately after preparation. However, a ready to use, sterile product would be favourable. Commercially available sterile hydrogels are often sterilised by ionising radiation (gamma radiation). Due to its strict safety provisions, gamma sterilisation is restricted to specialised companies. The market for a ready to use morphine containing hydrogel is small, therefore it is not to be expected that a large scale production is economically feasible. In the Netherlands, pharmaceutical compounding facilities, especially in hospitals, still produce sterile injections and infusions. These products are steam or hot water sterilised. However, the containers for the fluids are either glass or polypropylene ampoules or vials, none of which are suitable for packaging a high viscosity hydrogel. Filling these kinds of packages with a hydrogel is already challenging, retrieving the content for use is even more troublesome. The BD Sterifill SCF syringe system proved to be an easy to use primary package. Filling the syringe barrel with the morphine P407 gel in its liquid state was easily done by pouring the gel at low temperature into the back end. The syringes could be sterilised in a rain system autoclave. Finally, the hydrogel could be easily removed from the syringe for easy application to for instance a skin ulcer even in its gel state.
The stability of morphine-HCl in aqueous solution is well known. Storage at room temperature outside the influence of light shows adequate stability in a range of concentrations and in different containers, where storage between 2°C and 8°C and freezing at −20°C sometimes results in precipitation. The rate of degradation of morphine to its major degradation products pseudomorphine and morphine-N-oxide was not influenced by temperature. On the other hand, light results in a higher rate of degradation.29–31 Zeppetella showed morphine sulfate in a concentration of 0.125% (w/w) in Intrasite gel to be stable for a period of 28 days at 4°C and room temperature both in the absence and presence of light.15
Own previous research already showed that storage in a glass jar at room temperature under the influence of light shows degradation within 3 months to a concentration below 90% of the theoretical concentration. After 8 months, only 75% of the theoretical concentration was left. Storage at room temperature outside the influence of light showed no degradation during the period of 8 months (data on file). Therefore, we chose to examine the current product in the BD Sterifill SCF syringe only at room temperature outside the influence of light.
Even though the currently described product is suitable, one can still improve the validation of the package, for instance, by looking into extractable and leachable substances from the syringe system. Furthermore, the closure integrity of the luer-lock closure both at the syringe tip and at the rubber stopper at the rear end is worth further investigation. The manufacturer BD has done initial work on the closure integrity of their syringe. We did a 14-day test where 10 syringes were submerged in a methylene blue solution. During this test, no blue discoloration of the content of the syringe was seen nor was there any blue discoloration in the luer-lock part of the syringe or around the rubber stopper. Another potential improvement might be a higher sol-gel temperature. A sol-gel temperature of around 20°C makes it easier to apply the hydrogel in its liquid state by pouring it on the painful skin ulcer after which it will gel to a solid hydrogel in situ.
Conclusion
A morphine containing poloxamer 407 thermoreversible hydrogel, intended for use in painful skin ulcers, can be compounded and sterilised after packaging it in the BD Sterifill SCF syringe system. This results in a sterile, ready to use product with a chemical stability of morphine for at least 36 months when stored at room temperature outside the influence of light.
With the described formulation, packaging and sterilisation, together with the previously reported biopharmaceutical dissolution profile, we present a complete solution for a morphine P407 gel that can be compounded in any pharmacy that have a steam or hot water steriliser at their disposal. This might improve the availability of a sterile morphine hydrogel for the treatment of painful skin ulcers.
What this paper adds.
What is already known on this subject
Treatment with morphine hydrogel can give analgesia in painful skin ulcers.
Little has been published about the pharmaceutical aspects and compounding of opioid containing hydrogels for use in skin ulcers.
In most publications, (dia-)morphine was mixed bedside with Intrasite gel or no or very little information given about the preparation.
What this study adds
Morphine HCl 0.5 g/g in a poloxamer 407 hydrogel is chemically stable for a period of at least 36 months.
Morphine HCl 0.5 g/g poloxamer 407 hydrogel can be packaged in the plastic prefillable syringe system from Beckton Dickinson: BD Sterifill SCF and sterilised for 15 min at 121°C in a rain system autoclave, resulting in a sterile, ready to use product.
Acknowledgments
We thank Professor Dr Yechiel A. Hekster for his role in setting up this research and advice until he died in November 2015.
Footnotes
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication
Not required.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data relevant to the study are included in the article or uploaded as supplementary information.