GB2476494A - Formulation for the sublingual delivery of sufentanil - Google Patents
Formulation for the sublingual delivery of sufentanil Download PDFInfo
- Publication number
- GB2476494A GB2476494A GB0922537A GB0922537A GB2476494A GB 2476494 A GB2476494 A GB 2476494A GB 0922537 A GB0922537 A GB 0922537A GB 0922537 A GB0922537 A GB 0922537A GB 2476494 A GB2476494 A GB 2476494A
- Authority
- GB
- United Kingdom
- Prior art keywords
- sufentanil
- formulation
- pharmaceutical formulation
- spray
- citrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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- 239000000203 mixture Substances 0.000 title claims abstract description 102
- 238000009472 formulation Methods 0.000 title claims abstract description 100
- 229960004739 sufentanil Drugs 0.000 title claims abstract description 72
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 title claims abstract description 71
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 72
- 239000007921 spray Substances 0.000 claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 22
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims abstract description 21
- OJCZPLDERGDQRJ-UHFFFAOYSA-N Sufentanil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 OJCZPLDERGDQRJ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229960001204 sufentanil citrate Drugs 0.000 claims abstract description 17
- 229940081974 saccharin Drugs 0.000 claims abstract description 14
- 235000019204 saccharin Nutrition 0.000 claims abstract description 14
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 claims abstract description 14
- 229960002021 racementhol Drugs 0.000 claims abstract description 10
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims abstract description 7
- 235000003599 food sweetener Nutrition 0.000 claims abstract description 7
- 229940041616 menthol Drugs 0.000 claims abstract description 7
- 239000003765 sweetening agent Substances 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 6
- 229960004873 levomenthol Drugs 0.000 claims abstract description 6
- 239000012062 aqueous buffer Substances 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 24
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 239000000243 solution Substances 0.000 description 25
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 24
- 238000003860 storage Methods 0.000 description 19
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
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- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 3
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- 238000011156 evaluation Methods 0.000 description 2
- 229960002428 fentanyl Drugs 0.000 description 2
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 2
- 238000010579 first pass effect Methods 0.000 description 2
- 239000003517 fume Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 238000012487 in-house method Methods 0.000 description 2
- 239000012633 leachable Substances 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 231100001079 no serious adverse effect Toxicity 0.000 description 2
- 229940005483 opioid analgesics Drugs 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
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- 239000004033 plastic Substances 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
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- 239000001509 sodium citrate Substances 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
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- 210000001519 tissue Anatomy 0.000 description 2
- SUDBRAWXUGTELR-HPFNVAMJSA-N 5-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]-1h-pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OCC1=CNC(=O)NC1=O SUDBRAWXUGTELR-HPFNVAMJSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 101150085931 DSTN gene Proteins 0.000 description 1
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- 206010067482 No adverse event Diseases 0.000 description 1
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- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
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- XGZRAKBCYZIBKP-UHFFFAOYSA-L disodium;dihydroxide Chemical compound [OH-].[OH-].[Na+].[Na+] XGZRAKBCYZIBKP-UHFFFAOYSA-L 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
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- 239000013583 drug formulation Substances 0.000 description 1
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- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
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- 229940127240 opiate Drugs 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 102220013078 rs140245123 Human genes 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A pharmaceutical formulation for the sublingual delivery comprises sufentanil (e.g. sufentanil citrate 0.005-0.05%), an alcohol (e.g. ethanol (10-50%)) and water or an aqueous buffer (e.g. citrate). Preferably the formulation comprises the sweetener saccharin (0.3%), menthol (as levomenthol or racementhol at 1%) and is pH8.2. The formation may be loaded onto a canister for sublingual delivery, preferably the canister comprises a single dose delivered by one spray action.
Description
Pharmaceutical Preparation The present invention relates to a sublingually delivered formulation of sufentanil and to methods of delivering such a formulation.
The purpose of the present formulation is pain relief. Pain affects everyone and nobody gets through life without experiencing it; and is now recognised as a universal disorder, a serious and costly public health issue, and a challenge for family, friends, and health care providers who must give support to the individual suffering from the physical as well as the emotional consequences of pain.
There is increased interest in pain management throughout the healthcare industry, with treatment goals remaining focused on the achievement of decreased pain to a meaningful degree without causing harm, increasing both physical and cognitive functions that will in turn lead to is improved quality of life. Many of the treatments employed today use aspirin, opioids and local anaesthetics that have been around since early 20th century.
There is an urgent need to improve pain management in this patient segment as it may contribute to their disability and suffering later in life.
Similarly, persistent pain in elderly patients can interfere with physiological functions, increase suffering and decrease quality of life. Therefore, improvements in the detection, assessment and treatment can lead to care optimisation.
There is a strong need for drugs with improved efficacy, reduced side-effects and superior safety profile. Novel drugs in development are only few and development is heavily dependant on the reformulation of existing drugs, primarily opioids, targeting better drug delivery mechanisms, more convenient dosing schedules and specific patient populations. There is also a need for safer, non-abusable, non-addictive and non-tolerance producing oral and parenteral products.
In the past 20-years, advances in drug formulations and innovative routes of administration have been introduced thanks to the increased understanding of drug transport through the tissues. These advancements have often resulted in improved patient compliance to the therapeutic regime and pharmacologic response.
Misuse and abuse of a certain class of pain treatments is becoming a big problem. According to the FDA, the misuse and abuse of pain therapies has increased significantly in the past five years. And looking to reverse this trend, the US regulators are requiring manufacturers of opioid products to implement Risk Evaluation and Mitigation (REMS) strategies, which the agency is in the process of developing, possibly changing the commercial landscape for prescription painkillers.
Oral forms account for approximately 80% of all the drug dosage forms on the market. They are non-invasive, easily administered and have high patient compliance. Orally administered therapeutic agents, however, must be transported to the stomach and small intestine for absorption across the gastrointestinal (GI) mucosal membranes into the blood. The efficiency of such absorption can be low because of metabolism within the GI tract and first-pass metabolism within the liver. This results in relatively lengthy onset times and/or erratic absorption characteristics that are not well-suited to acute disorders such as pain.
The sublingual area of the oral cavity is characterised by a large quantity of blood vessels that allows a treatment to be rapidly absorbed. The anatomical characteristics (thin and non-keratinised) and the permeability characteristics of the sublingual mucosa (mucosal membranes lining the floor of the mouth) permit the avoidance of GI destruction of the drug and hepatic first-pass metabolism (destruction of drugs by liver enzymes). This permits a rapid absorption and on set of action of those drugs with short delivery period requirements and infrequent dosing, making it a conveniently accessible and generally well accepted systemic drug administration route. Furthermore, sublingual delivery is by far the most widely studied of the three different categories of drug delivery within the oral transmucosal cavity -i.e. sublingual, buccal (mucosal membranes lining the cheeks) and local drug delivery (into the oral cavity). The sublingual route of administration has been found to offer several potential advantages over other conventional means such as oral and intravenous (IV) routes. These make it particularly suitable in settings like A&E, paediatric wards and home-care facilities given its non-invasiveness, simplicity and ease of administration.
The most popular existing sublingual formulations consist of rapidly disintegrating tablets, lozenge, and soft gelatine capsules filled with liquid that are held under the tongue before swallowing. Glytrin and Nitrolingual (glyceryl trinitrate) are two sublingual sprays used in the cardiology setting for the relief of pain in an angina attack.
A spray delivery mechanism does not require the holding of the treatment under the tongue for an extended period of time, thus making it particularly suitable for fragile/debilitated patients, children and those requiring supervised drug administration. Further, it reduces the amount of medication that is swallowed and enters the blood stream through the gastrointestinal tract s compared to rapidly disintegrating tables, lozenges, and soft gelatine capsules. In addition spraying avoids the dispensation of sub-optimal drug concentrations in a relatively small part of the sublingual mucosa that can cause a slower and/or reduced rate and efficacy of absorption. Finally it has been shown that certain type of drug like lipophilic opiates need to be finely spread over the sublingual mucosa in order for them to be properly absorbed, and spraying can provide that coverage.
Sufentanil is a powerful synthetic opioid analgesic drug, approximately 5-lOx more potent than fentanyl and is highly soluble with an immediate onset of action with relatively limited accumulation. It was first synthesised by Janssen Pharmaceutical in 1974 and marketed under different names.
Sufentanil has the following general formula: Sufentanil offers rapid elimination from tissue storage sites and so allows for relatively more rapid recovery as compared with equipotent dosages of fentanyl. The pharmacokinetics of IV Sufentanil can be described as a three compartment model with a distribution time of 1.4 minutes, redistribution of 17.1 minutes and an elimination half-life of 164 minutes in adults. The elimination half-life of Sufentanil is shorter (e.g. 97 ± 42 minutes) in infants and children, and longer in neonates (e.g. 434 ± 160 minutes) compared to that of adolescents and adults.
The liver and small intestine are the major sites of biotransformation.
Approximately 80% of the administered dose is excreted within 24 hours and only 2% of the dose is eliminated as unchanged drug. Whereas, after epidural administration of incremental doses of Sufentanil, totalling 5-40 pg during labour and delivery, maternal and neonatal Sufentanil plasma concentrations were at or near the 0.05-0.1 ng/ml limit of detection, and were slightly higher in mothers than in their infants. Sufentanil has also been used off-label' intra-nasally in adults and children for the treatment of minor painful injuries or procedures such as orthopaedic trauma not requiring an IV, burn dressing changes, re-packing wounds such as abscesses and in those procedures is where oral medication is considered to be too slow to act.
AcelRx Pharmaceuticals Inc. and Durect, are developing non-invasive sufentanil product candidates which are in trial. AcelRx is developing a sublingual drug/device combination product candidate designed for use in hospital settings to provide non-invasive patient-controlled analgesia (PCA) for the management of post-operative pain. This system requires a proprietary pre-programmed, hand-held dispenser. The dispenser is designed to be hospital compliant for administration of sublingual sufentanil NanoTabs, while providing features directed to patient safety and convenience. This is not applied by spray but is instead a dissolving tablet and it therefore uses a wholly different formulation to the present invention.
Durect/Endo Pharmaceuticals are developing a transdermal sufentanil patch intended for the continuous delivery of sufentanil for up to 7 days. This again is not spray applied and has a different formulation and delivery route as it is transdermal.
The aim of the present invention was to develop a novel formulation and mode of delivery for sufentanil for pain relief. It is a further preferred aim of the present invention to dosage form of sufentanil for sublingual spray in an aqueous ethanolic solution formulation. The applicant previously developed an improved form of dosage dispensing canister for the sublingual (under the tongue) spray of reformulated drugs. It is a yet further aim to provide for the systemically delivery of the new formulation through such a hand-held, dosage dispenser canister. It is a yet still further preferred aim to deliver the formulation for use in the treatment of procedural and trauma/incident pain or any action that is known to cause pain and needs to be repeated on several occasions as part of normal care, in both adults and children. Procedural and trauma/incident pain includes that which is caused by the moving of a patient onto a stretcher, changing of wound dressings, debridement, disimpaction, etc. Through extensive research for a solution to the primary aim the inventors of the present invention have found a new formulation of sufentanil that is highly effective, for sublingual delivery. Further they have developed the subsidiary aims and ways of achieving those aims.
According to a first aspect of the present invention there is provided a pharmaceutical formulation to be delivered sublingually by spray comprising: -sufentanil or a pharmaceutically acceptable salt thereof; -an alcohol; and -water and/or an aqueous buffer.
Sufentanil has a bitter taste which can become a problem in high enough doses. Therefore it is preferred that the formulation further comprises a sweetener. Any compatible sweetener may work, but it has been found that saccharin is particularly good with no adverse effects on the formulation. The use of a sweetener at low does to mask the taste of sufentanil may not be required.
The alcohol within the formulation is acting as a solvent and may also in sufficient concentration act as a preservative. To act as a preservative the concentration needs to be at least about 16% and preferably 18% w/w. Any alcohol which is a solvent for the sufentanil and it non-toxic can be used; however it has been found that ethanol is particularly well suited.
Menthol in various forms can be added to the formulation. This acts as is both as fragrance/taste modifier and may also act as an adjunct to analgesic effect of the sufentanil. The menthol may be in any pure or mixed stereo-form such as levomenthol or racementhol.
The sufentanil may preferably be in the form of sufentanil citrate. The general formulae of sufentanil citrate is shown below:
COH
) 1 " ./
COH
N S K
I "OH
HC
I. CO?H It may be advantageous to deliver the formulation at a controlled pH.
This can aid the uptake of the active by matching the optimum dissociation conditions of the sufentanil citrate. To achieve this, a buffer may be present, in place of some or all of the water content. It has been found that citrate buffer is particularly effective, but others are also suitable. Preferably the pH of the formulation is approximately 8.2.
Clearly variation in the relative quantities of the components is possible within the scope of the invention whilst retaining efficacy. The level of the active ingredient can vary according to the dose required and flavourings/sweeteners may alter dependent on the need to cover other unpleasant tastes and the preferences of the target users.
A pharmaceutical formulation as claimed in any of claims 1 to 10, which comprises: -0.005 -0.05%w/w sufentanil or salt thereof; -0-0.30 %w/wsodium saccharin; -0 -1 %w/w menthol -10-50 %w/w ethanol; and -the balance water and/or a buffer.
A particularly preferred formulation of the present invention comprises: -0.01 %w/w sufentanil citrate; -0.1 %w/wsodium saccharin; -17.99 %w/w ethanol; and -81.90 %w/wwater.
According to a second aspect of the present invention there is also provided a method of drug delivery comprising -providing a dose dispensing spray canister loaded with a pharmaceutical formulation as claimed in any of the preceding claims; and -manual operation of the spray canister to delivering the pharmaceutical formulation as a spray to the sublingual mucosa.
Preferably the canister is as described in the applicant's co-pending patent applications (EP 2,054,162 and others) the details of which are incorporated herein by reference. Preferably the canister holds only a single dose and this is all dispensed in a single action -such as the depression of a plunger. The canister may be a single use item that is disposed of after drug delivery.
According to a third aspect of the present invention there is also provided a disposable single dose dispensing canister loaded with a pharmaceutical formulation as claimed in any of the preceding claims and adapted to deliver that dose by a single sublingually spray.
is The present invention also provides the use of sufentanil in the preparation of a med icament for sublingual spray delivery for the treatment of pain.
EXAMPLES
Various examples of the preparation and testing of the formulation according to the invention and the use in human pain relieve are discussed below.
Formulation A batch of formulation (NOROO1 PDO1/007) was prepared with the following composition.
i'heoretiia Aftliu1 %ighis Weights (g) (gI' StLiianil citrate Ph iur 001 35 OO1 36 054)0111 Ethanc, anhvdmus Pb Eu 32O58 32)9O5 05/(65 A3 Racementhol Ph Er O974 O7(.i i 033: :2CC-4$5 PittcdVatc Ph Ui - ---3 Liot 64163 64J92$ *Equivalent to 9mg sufentanil base.
The sufentanil citrate was weighed in a weighing boat and transferred to a 1 OOml stoppered volumetric flask. The ethanol was added and the flask shaken to dissolve the sufentanil. The racementhol was added and dissolved with shaking. Both materials dissolved quickly to give a clear colourless solution. On addition of the water the mixture appeared cloudy for a brief moment and then cleared to give a clear colourless solution with some fibrous particulates present. The solution was passed through a GF/A filter paper in a filter funnel under gravity. This removed the particulates. It should be noted that these particulates were the only ones observed during the development programme. It was therefore concluded that they were from contaminated laboratory apparatus and were not present in the active, the excipients or the solvents.
400 p1 aliquots of the solution were filled into polypropylene HPLC vials with screw caps to mimic the filling of the delivery device. These samples were placed on storage at 4, 25 and 40°C and examined at regular intervals.
The results obtained for these samples are detailed in the Stability Results Section below.
The above batch proved to be reasonably stable but it was considered useful to prepare a batch containing a buffer in order to control the formulation pH at 8.2, the pKa for sufentanil, to aid bioavailability and stability. Saccharin was also added to improve the acceptability to the patient of the formulation taste. The following batch (NOROO1 PD011029) was therefore prepared which delivers 5Opg sufentanil as base: Theoretical tt w/w Batch Citrate un 11cr; (it R. ( id CH1I1 p 0 ñS7 12 1 Ear Sodium Citrate2H70 Ph L5 I. M067 Fur Sodiuni Hydroxide Ph FLu: 2.5 tO 3005 $d km -----Lilor Theoretical % w/w Batch tM citric Acid; C'tnau PhlThr ---06 &87l2 t)tritc_,j \\ fu P I in _1 t 0i il i ihuiaun> »= 5:j sodium hydroxide Sodium Flydroxide Ph Fur 20.0 3005 PunPA Wm i Ph tim To lOOmI I abu'utor.'uppIy Formulation; Suttran I citiatt. Ph 1 or 0 0Gb 0 02 0 ii) 111 Ethanol. rmhydrous Ph Fur 9.006 40,26 06/546 A2 R t.unentho1 Ph but 1 0 4 (R i22 SaoeharinPh Fur 0.0558 0.25 537918 316 (ni alt. But1u 1 3 1 lS S 71 1 ibm atm sitppl 22.3677 100MG Method of manufacture; 1. The citric acid and sodium hydroxide solutions were prepared using standard laboratory techniques.
Buffer; 2. The citrate buffer was prepared by adding the citric acid, tn-sodium citrate, and sodium hydroxide into a beaker and transferred to a 250m1 volumetric flask.
3. 200m1 water was added and mixed until all materials were completely dissolved and allowed to cool to room temperature.
4. The pH was then adjusted to 8.2 using the sodium hydroxide or citric acid solutions.
5. The buffer was then made up to weight with water.
Formulation; 6. The sufentanil citrate was weighed into a 50m1 volumetric flask and the ethanol added. The flask was shaken until the sufentanil dissolved (readily soluble).
7. The racementhol was added to the flask and shaken until dissolved (readily soluble).
8. The saccharin was added to the flask and shaken until dissolved (readily soluble).
9. 1 0.Og of citrate buffer was added and mixed.
10. The pH of the solution was measured and found to be 8.1 and hence no adjustment of the pH was made.
is 11. The solution was made up to weight with citrate buffer and the pH checked.
12. 50 HPLC polypropylene vials were filled with 400pl each of the formulation using an autopipette and the caps fitted.
13. These samples were placed on storage at 4, 25 and 40°C and examined at regular intervals.
The results obtained for these samples are detailed in the Stability Results Section but can be summarised as showing some extra peaks in HPLC profile, increasing with both time and temperature. These are thought to be leached material from the device as shown by the work also detailed in the Stability Results Section for NOROOI/PDOO1/001 when a similar formulation was stored in glass at 40°C for 6 months without any extra peaks being found by HPLC.
The solubility of sufentanil citrate in formulations of 5Opg per 400pl dose (as base) using buffered aqueous systems with and without propylene glycol was investigated. The following formulations were prepared; OROO1 P1)OLt5 NOitOO PD(l/5h Batth % wlw % wIw Sntntan 0M094 0.0187 0.0094 OW 84 0500 111 ejOate.
C)0O00 09 1 25 0000 4 70[ Propylene 259000 5477 05 1558 odmw 0 0 0 saccharin S03387 1{)0.0 5L2.87 Q0.O * 2% citric acid, 1 % sodium hydroxide & 1 % sodium citrate adjusted to pH 8.2.
In each case the sufentanil citrate was added to a lOOmI volumetric flask, the citrate buffer added and shaken to dissolve the sufentanil. The sodium saccharin was then added and shaken to dissolve. For NOROOI PDOI/65b the propylene glycol was added and shaken in. Both formulations were clear, colourless solutions. The above lots were each split into two 25m1 volumetric flasks and one flask placed at 4°C and the other at 40°C. After 24hours, four and five week's storage no change was observed. The pH was is found to be 7.8 for both lots and no degradation was found after one week's storage tor both formulations at both temperatures.
Samples of both formulations were examined for sufentanil content after one and six month's storage at 4 and 40°C. At one month the samples store at 40°C appeared hazy with a residue coating the glass. The 4°C samples were clear and colourless. The sufentanil content of the 40°C -14-samples is lower than the 4°C samples. At six months formulation a showed small white/clear crystals with the sufentanil content decreased. Formulation b was satisfactory.
Based on the above the following formulation was prepared, filled into delivery devices and autoclaved; NOROO1 /PDO1 /107 Weight (mg) % w/w Volume (ml) Sufeitani eitate 0.075 0.02 Levomenthol 2.700 0.74 Sudum Sachuli 700 14 Ethanol 150 It)0 4 U6 U 9 101 41 65 5'S 100 00 40 Adjusted to target pH 8.2 with sodium hydroxide Many of the prepared units leaked following autoclaving on examination it appeared that the loss was via the cap not the plug.
Consequently modifications to the cap were made before further studies were conducted.
Bulk samples stored in glass serum bottles were placed on stability storage. Results are shown in the Stability Results Section.
is Following the modifications to the cap a further batch of 100 units (NOROO1/PDOI/1 18) was filled with a formulation similar to NOROO1/PDO1/107. These were filled, sealed and autoclaved successfully (12 failures).
Work showed the benefits of the formulation being at pH 8.2 to aid absorption, so the following formulations were prepared to investigate both citrate and phosphate buffers: i\1OROO1/ NORJJ JN()R1 PDl11/12h Pfllflhl2& PPO1f2$d -V W fl1 umt' V-. \V m uxuL. . -TJ, 0.038 0.01 (;.038 001. L038 001 0.038 0.01 ciirat Ph Fur Levorncnthol 2.700 Q,74 2.700 0.74 2.700 0.74 2.00 0.74 Ph Fur P)Qo 1 3 -) u1() ) 2 E. ur..-...--7,-, 7 Etbinol KO 10 4127 -Ulo 4 cOin 41 27 1H I anhvdrous Ph 0 0 0 0 Phsohate 000 7 ifl(0 783.
I hflkr -I - . hut 2( 303 H t Phosphate hitifer Sodiwn 1.3 d i1rugeu Sodiuni hydi'o uSe 1urilied water 3 o 250Il 0.05 M Citrate!1fr j Chne aukl 2,5 Trodiuni.25 c.itrat.2HO Sodium [25 hydrodc Pur1 bed Waver Fe v---The buffers were prepared in 200m1 water, adjusted to pH 8.2 with 1 M NaOH and made up to volume. Similarly the formulations were prepared and adjusted to approximately pH 8.2 with 1M NaOH or 1M citric acid. The formulations were transferred to serum bottles and placed on storage at 4, 25 and 4000. The formulations were checked visually after storage for 24 hours and found to have remained clear, colourless solutions at 25 and 40°C.
Formulations C and D at 4°C also remained as clear, colourless solutions.
Formulations A and B were found to contain a fine white precipitate at 4°C. It was concluded from this that the phosphate buffer is not ideally suitable for this formulation.
Previous stability lots have contained relatively high amounts of ethanol which is thought to have leached material from the device into the formulation.
Therefore further formulations were be prepared for stability testing in the device with reduced or no ethanol. The formulations were; T10(1 tl)OFa NOR91 PI)llu1 b NORO1 PJ)1ie %OROO11 DOVltd
_______________
Sn nhi 0)OI TOI 1�) i'e Ph Ei Soum / 4O1 0. C) ft400 0,1) 0$O( 0.10 S]-win, 1 --1 ____ t / / hyous / / / Purfied 400.OO() i)99 4Q)) S) -
-
C t -I b I ir 4 -j -I t units were prepared for each formulation. The citrate buffer was the same as used in the previous formulations. 16 placebo units to match each of the above formulations were also prepared (NOROO1/PDO1/139a -d). All the units were autoclaved for 15 minutes at 121°C and placed on stability storage at 4, 25 and 40°C. Initial analysis of the formulations showed a reduced sufentanil content for a, b and d.
The samples were examined at 10 days, 3 weeks and 5 weeks after storage at 25 and 40°C. At 3 and 5 weeks a loss of sufentanil was observed at 40°C but no degradation was found.
Five units were filled with NOROO1/PDO1/136b and fitted with plugs but not sealed. They were left inverted in a fume cupboard for 72 hours at room temperature. An additional four units were similarly prepared and stored but sealed by ultrasonic welding. The five unsealed units were tested and found to have an average of 95.8pg/ml sufentanil.
A repeat of the above lot (4 units -NOROO1IPDO1I147) was prepared using the same formulation but sealing the units and storing them upright in a fume cupboard. These when tested were found to have a sufentanil content of 82.6 pg/mI. It would thus appear that sealing of the aqueous based formulations with the ultrasonic welder reduces the sufentanil content.
After review it became apparent that there were several issues with the formulations to date; * The levels of ethanol used either gave greater than expected levels of leachables (ie 40% ethanol or more) or gave loss of sufentanil either on autoclaving or after storage at higher temperature (ie 10% ethanol).
* The device can give problems when autoclaving either with leakage or dilution of the product.
Therefore it was decided that a formulation should be tried with a level of ethanol which would give sufficient antimicrobial activity but which would not generate excessive leachables. This would enable manufacture of the product without sterilisation. The current edition of Remington's Pharmaceutical Sciences (21st Edition, 2006) gives the minimum level of ethanol to give good antimicrobial activity as 18% w/w. Therefore a batch was prepared to evaluate this formulation (NOROO1/PDOO1/148b). As the ethanol will now be a preservative in a regulatory sense limits for its concentration will have to be applied. These will be set at ± 10% as this is the appropriate level.
Given this it will be necessary to perform the Ph Eur Preservative Efficacy challenge study on the formulation at both the theoretical ethanol concentration and at the lower limit allowed in the specification ie 16.2%. A lot (NOROOI/PDO1/148a) at this lower level of ethanol and one at 18% (NOROOIIPDO1I148b) were prepared. The details are; NORO{J1 N)OJ/ i$a NO1UDi P1)01 /14$b ig %S1S rng Sufcan1 citrate 19.0 001 1 9.0 0.01 Na. Sacearin 200.0 0.1 0 200.0 0.10 EthanoL anhydmus $ 1086,5 16.19 343950 7.98 iU. I \ I 3 90 0 8)0 -- i. 01O1 0 Y) Method; 1. The sufentanil citrate was weighed into a 200m1 volumetric flask.
2. The ethanol was added to the flask and shaken until the sufentanil citrate dissolved.
3. The sodium saccharin and most of the water were added to the flask and shaken until the saccharin had dissolved.
4. The remaining water was added to the flask and shaken to mix.
The solids dissolved readily producing a clear, colourless solution.
Samples of the solutions subjected to a Ph Eur Preservative Efficacy testing.
is The remaining solutions were placed at 4°C in the flasks. Both formulations passed the test showing the formulation is still well preserved when the preservative (ethanol) is at its lowest specification.
22 devices were filled with NOROOIIPDOIII48b using 400pl per unit and ultrasonically sealed. Units were placed on storage at 25 and 4000.
Delivery device The formulation according to the present invention may be delivered using a device such as is covered by the applicant's earlier patents (including EP 2,054,162). Such a device may be entirely made of non-metal material and is a single dose, non-reusable dispensing canister which has been designed for the safe administration of 400 p1 of non-pressurised formulation.
The canister incorporates one-way ratchet mechanism that makes them tamper and disassembly resistant. The canisters include a system that automatically prevents further dispensing movement once the required dose has been dispensed. The fluid is contained in a chamber located in the top part of the device and is sprayed through an orifice via a nozzle when the canister is activated. Both the orifice and the nozzle are protected by a sealing removable cap that has a protective function to prevent dirt and moisture entering the nozzle and a safety feature should contents leak is through the nozzle.
A device in the form of a single dose spray pump type system filled with 400pl of formulation and having negligible retention of product after use.
Hydraulic pressure is generated by the patient depressing the plunger; the formulation is delivered under pressure to the outlet nozzle which has been designed to spray the formulation in a fine, uniform plume to the patient's sublingual area. The particle size generated is significantly greater than that required for respiratory deposition although the patient will be directed to hold their breath whist taking a dose from the device. Any attempt to reuse the device by withdrawing the plunger results in the disengagement of the piston which renders the device safe and hence ensures reuse is impossible.
-20 -prototype devices were filled with the following placebo formulation (NOROO1/PDO1/134) using an auto pipette; Theoretical Mg Per Batch W'eIohts (cs) 400u.1 F thailifi dUlA ±2' cHL ?-(jQft i LL I 06 S46 \ 2 Levo menthol Ph Eur 0. 1 65 2.77 0000019302 achai in Ph Fur 0 062 0)$ os I Curate Buflër (as 111488 218.9 P.1)0W 129) The filling was performed through the filling port which was then sealed with a plug which was ultrasonically welded in place (Wolfcroft US welder 0.5 sec at 60% amplitude).
----\leanmg --14811% [Ovenfl 3852 112 Lrn IC 3X E]2iI11I1iIIII The results were considered good especially for a prototype process.
The filled units were weighed and placed at 40°C in upright and inverted positions. After storage for one day the units were reweighed. Eight out of the ten units stored had excessive leakage, range 32.5 to 68.8mg. Of these units all but one was stored upright, that is with the actuator at the top, ready for dosage. This result appeared to be due to incorrect sealing of the filling plug. The units initially showing little leakage were re-examined after another day's storage and found to still have good seals, leakage -0.2 to 3.6mg.
Further testing was then undertaken. The full results are shown below; -21 -Time at Unit loss in mg 4000 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 1 day 0.3 32.5 0.9 1.0 1.2 0.8 60.5 68.8 49.9 0.7 2.5 0.9 1.0 0.9 0.5 59.3 55.8 50.8 57.9 56.8 2 days 0.4 1.1 0.7 0.6 0.4 -0.2 3.6 1.11.0 1.5 0.7 3 days 0.3 0.9 0.6 1.3 0.4 0.0 3.9 1.0 0.8 1.1 0.8 4days 0.8 0.9 1.0 0.8 0.7 -0.1 5.4 1.1 1.2 1.8 1.7 7days 0.8 1.6 1.4 1.3 1.1 0.4 7.0 1.4 1.5 2.9 3.2 11 days 1.3 1.7 1.6 1.3 1.5 0.8 9.9 1.8 1.6 2.7 4.3 weeks 3.9 3.7 3.6 4.6 2.6 4.5 4.0 5.7 6.9 An additional 20 placebo units were filled (N0R001 PDOI/42) and sealed with the amplitude of the US welder increased to 65%.
Meanmg RSD% Overall 382.8 2.2 Units 1-l0OperatorJH 383.8 3.1 Units 11-20 Operator MS 381.7 0.8 Again for a manual prototype filling process these results were considered good and showed little operator dependence. These units were then stored at 40°C in an upright position and re-examined see below for the results and ongoing weight monitoring; C) Time Unit loss in mg Q at 40°C 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 (\J 3 1.4 146.1 1.3 2.6 0.9 1.9 1.0 1.2 0.9 1.7 0.3 0.4 135.6 83.5 0.0 1.4 0.0 0.0 0.9 1.1 6 1.5 2.0 3.3 1.9 3.3 1.8 2.2 1.8 2.9 0.8 0.9 142.0 89.6 0.5 2.0 0.6 0.6 1.7 1.6 1.7 1.9 3.4 1.7 3.5 1.8 1.6 1.6 2.7 1.1 0.6 182.3 98.8 0.4 3.1 1.1 0.9 1.6 2.0 3.8 4.7 7.0 5.5 9.2 4.6 4.5 4.8 7.4 3.7 3.2 2.8 6.9 4.2 3.8 4.7 4.2 weeks These results show that the seal was improved using the new process but further work was required to improve the consistency of the seal. A further batch (NOROO1 PD01156) was prepared using the same placebo formulation as NOROOI PD01134 which was filled, sealed at two different settings for the ultrasonic welder and placed on storage upright at 40°C with the following results after the exclusion of some outliers.
-22 -kann ISD% Units 0 20 393_7 Sealing UniLs 1-10 Urnts I 120 ----0 at 4! 213T T U si Tii Ipt 42 sH i:i tIfli 6 r1i)[i Th2L These results show that only units sealed with amplitude 65% for 0.5 seconds had a tendency to leak. The units sealed with amplitude 65% for 1 second have a better seal. Therefore in order to further assess the effectiveness of seals produced under these conditions a further 10 units were filled with placebo and evaluated for weight loss.
NOROO1 PDO1I6O --j -RSI)4 [jJ* -----------------_-----------i 4O(1 I 2 3 4 5 6 7 9 1 This showed that the previous good seal was not repeatable consistently. It was observed that the sealing plugs were surrounded by white powder -dried buffer salts from leakage.
is After an evaluation adjustments were made to the ultrasonic welder.
Using the same settings that had previously been found to give the best results a further placebo lot identical to those lots previously used for device -23 -assessment was prepared (NOROO1 PDOI/69) and filled into 20 devices. It was observed that units 2 and 6 had plugs not completely joined to the device and so could be expected to leak. The units were weighed and placed at 4000. The weight loss found was; at Unit toss in n.ig 1 2 4 5 711[9 1011 12113 14 1116i7 18)2O I i T1 1TJf7' * L o -211 3 S 17 12 I I 21 4 I 4 H) o 1 1O8M 2 1 14 I 1t14 I M2O I r' :i;:tji i 21, The following placebo formulations were prepared for sterilisation testing of the units and for further leakage testing.
Citrate 50,0000 99.3457 25.0000 48002 Propylene 2.5.9000 5(L5570 0581558 Sodium 03293 ft6543 0.3293 0.6428 537 saccharin 50.3293 100.0 51.2293 100.0 * 2% citnc acid, 1% sodium hydroxide & 1% sodum ad used to 0U 8.2.
The lots were prepared as their active counterparts, see the formulation section above. PDO1/76a; 15 units were prepared with a mean fill of 403.5, RSD 0.57% ie highly consistent. PDO1/76b; 15 units were prepared with a mean fill of 413.9, RSD 1.54% ie consistent. The latter batch with propylene glycol did not seal very well. On some units there was a clear gap between the plug and the body of the device underneath the plug, on others white residue under the plug. The weight loss found after storage at 40°C was: -24 -Time NOROO1 PDO1/76a Unit loss in mg at 40°C 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 1 day 0.8 0.7 0.6 0.8 0.9 1.5 0.9 1.3 1.4 1.4 0.9 1.1 1,0 0.9 1.0 2 0.8 0.8 0.6 0.7 0.7 1.2 0.7 1.1 0.9 1.3 1.2 0.7 0.6 0.8 0.9 days 6 1.8 1.3 1.4 1.7 1.6 2.0 1.5 1.7 1.9 1.3 1.8 1.6 1.2 1.3 1.0 days 8 1.8 1.7 1.7 1.8 2.2 2.1 1.7 2.2 2.4 2.1 2.1 1.6 1.7 * 2.0 days * Unit used for other testing The other formulation with propylene glycol gave: Time NOROO1 PDO1/76b Unit loss in mg at ______ 40°C 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 1 day -40.2 -1.5 -2.4 -1.2 -7.7 16.3 1.7 -6.9 49.1 -1.1 --8.9 -24.0 _____ _____ 18.8 17.0 16.0 2days -40.5 -1.9 -3.0 -1.7 -7.3 15.7 1.6 -6.8 49.0 -1.1 --8.9 -24.4 ______ _____ 18.4 17.1 16.1 6 days -39.3 -1.1 -1.6 -2.4 -8.4 16.8 2.3 -5.8 50.2 -0.5 --7.7 - ______ _____ 18.1 16.5 15.1 2304 8 days -39.4 -0.8 -2.0 -2.5 -8.3 16.7 2.4 -6.0 49.8 -0.4 --8.2 -23.5 ______ _____ 18.1 16.1 15.4 * Unit used for other testing () 5 These results are thought to reflect water being gained from the atmosphere as a result of the hydroscopic nature of propylene glycol.
(\J Five devices prepared as NOROO1IPDO1I42 were examined gravimetrically to determine the dose delivered from the device. These had been prepared two months earlier. The results were summarised as; Unit Expelled Weight g1 % Contents Expelled 1 347.7 93.8 2 344.9 91.6 3 334.7 88.6 4 338.2 90.0 348.0 92.5 _____________ ________________________ Mean 91.3 SD 2.0 These results were considered to be good as they fell well within the proposed limits.
units of a modified device design were filled with the following placebo formulation prior to testing (NOROO1IPDO1I1 03); -25 -I _I -\lg itnt flflnd Leinentho Ph Eur 074 2.7 675mg i1 scch rn Ph Fur (. 74 27 EthmoL anhvdrous Ph Eur 4 50.1 375 Pu it Ph F H 57 44 10 ( I O(IIffl M55 The pH was adjusted to 8.2 using 0.01 M sodium hydroxide solution (from an initial 6.24). The devices were filled with 0.4 ml of the above placebo formulation and the plug ultrasonically welded in place (0.8 seconds at 69% amplitude). The units were weighed and placed in the 4000 incubator (1-5 inverted; 6-10 upright) and reweighed after storage overnight. The weight loss found varied between 0.4 and 0.8mg with no obvious orientation effect.
Following the successful testing of the modified device with a placebo formulation (NOROO1/PDO1/103) 100 of the devices were filled with active product for stability studies. The formulation (NOROO1IPDO1I1O7) was: ng_p urul o \ oJiirneOil) Sufcntani citrate Ph Eur ft075 O2 Levomciflhoi Ph F.ur 2700 0:74 Sodium saccharin Ph Ew 27OO O74 J_LLcL.!____J urded water Ph Er 2 O.OJO 57.44 0 21 __ 3c.5*75 100:00 O4U The pH of the formulation initially was 5.00 which was adjusted to 8.45 with 0.1 M NaOH which became 7.90 when made up to volume with water.
All units except one (spilled around filling port and lost solution) were filled sealed and autoclaved successfully. On examination post autoclaving some units were found to have lost or gained weight significantly, including a unit which was empty. Samples of the device were emptied and examined, which -26 -the caps were warping slightly causing the integral rubber plug to fail to seal and allowing solvent to escape.
Ten units were tested with placebo (NOROO1IPDO1I116) and autoclaving at 121°C for 15 minutes. These samples were found to have gained a little moisture <1 %) around the inner compartment and no loss of solvent was found. Thus this modification was successful.
A 100 unit batch was prepared with modified devices; (NOROO1/PDO1/118) using the same formulation as NOROO1/PDO1/107. The initial pH was 5.00 which was adjusted to 8.28 with 0.1 M sodium hydroxide solution. Autoclaving (Omega Medical Model JE21 105) was for 15 minutes at 121°C. Subsequent examination of the units produced shows 12 had lost a significant (>1 %) weight and a further 12 had gained a significant weight which was found to be water retained in the devices. The devices found to be OK were stored at 25 & 40°C for stability testing. See the Stability Results Section for details.
In view of the ongoing issues during the autoclaving process another units were filled with placebo (NOROO1/PDO1/126) and autoclaved in an industrial autoclave (Astell Scientific). Three units were found to have gained a significant weight. When the protective caps were removed water from the sterilisation process was found. An additional unit had lost a significant weight presumably by leakage.
Following from the initial sterilisation test devices were modified with small holes drilled into the device caps to allow steam to escape during the autoclaving process. The units were inverted for the process. Five units had these new caps fitted and were autoclaved at 120°C for 15 minutes.
-27 -The units after autoclaving were found to have droplets of water in the inner compartment but much reduced from previous tests. After standing for four days the droplets of water had dried, the units were reweighed and found not to have changed weight significantly during the autoclaving process.
These issues with sterilisation of the device mean it is preferable not to have to sterilise the product, but that may remain an option with alteration of device design. Instead it is desirable to use ethanol as a preservative in addition to its role as a solvent.
Stability Summary
Two formulations were considered in the early stages, both used ethanolic aqueous solutions. NOROO1IPDO1IOO7 also included racementhol whilst NOROO1IPDO1IO29 included racementhol, saccharin and citrate buffer.
Both of these batches were placed on stability test in incubators at 4, 25 and is 4000 (no humidity control).
NOROOI PDO l/MJ7 Theortica Actual Weights Hatch . -- -utentam1 cit uc Ph i 0.013 s 0.0 36 05-00fl I EthunoL anhydrous PhEur 2.08S 30905 05/665 A3 Racementhol Ph Fur 0.6974 0.7011 03322CC-4$5 Purified Water Ph Fur 31.3851 31.3876 upp1y 64.1683 64.1928 4°C pcaranceef Weight sukntinil solution Change Ui U2 31.2. Clear, colourless N/A I week 131.6 131.2 Clear. wkuuie. -2.6. .0.4 2 weeks [26.2 125.2 Clear, rolouries 0.i -0.4 3 weeks 130.4 129.9 CIar, colourless -0.3. .$ 1 0 0, (1ci OkU1 te' ) U -28 -25T Appearance of Weight 1 pH Degnidathm% sufentanil solution Change Ph Em' method, gradient, relative retention times t ci I 11 t it ( )Ufl N 1 1 I week 128.5 129.6 Clear, COiOUIIeSS -2.0, .. .4. 5.4 No significant clegradatntrt 0.9, -0.9 bend 2 weeks 125.6 1125.7 0.7, 01 fhund 3 weeks 134.7 31 1 Clear, colourless 0.0, -0.6. -5.5 No significant degradatton 0.5. 1.4 thund 4 vks' 131.1 j i1Thla, colon 0.6, 5.4 No if CU, -ft4' Idund 6 weeks 129.7 127.0 Clear, colourless.05 0.1,. , 5.5 0.05 0.05 0.1, *.( I ---.... .--40T r';w Degral --sufentanil solution Change _gjL._,.Jg@!> -----Ui U2 Ph Eur method, gradient, relative retention times Initial 131.2 Cleat, cootwless NA 5.3 9.4 0.6 9.7 I week 130.8 128.8 Clear, colourless 1.9, -0.9, 5.6 No significant degradation -. ..4-.7.4,-l.a.
2 wueks 126.1 12.8,7 (lesi, colourless, 0.9, 9,9, 5 5 Nc; significant degradation 0.7. -0.1 3 weeks 132.3 132.5 Clear, colnuukss -1,2, -9.5. 5 6 Nc significant degradation 0.2. -0.4 eck o I1.L (e uknrkss I06 7 -I -i-o.7.-C6 --.--------------------t 0 weeks lii.0 1 s2.7 (. ear, colourless -0.1, -0 S s 0.11 0.25 -0.2,4.1.4 -29 - 4(1114)01 / PDOO 1/929 ç W.S!!JgL ---------H Citrate Buffer; Citric acid, W1IV&1IOUS Ph 5 2.0 058712 1 Ear _________ SodiUm TiP atc 21L0 Ph 2 -19 M0 L1ur Sodium Hydion1c P11 Fm 2 5 IlL 1005 - 1.E!th*WhJ l.
l'heorcdca! % WIW Batch W.cIg!Ig) IM citric Acid; Civic tid Ph 1w --9 Watu Ph lut -ft SOnil -L thoi tOUpp1\ -J Sodium Hydroxide Ph Fur 20.0 JOGS Puiificd \\ atci h I n -to 1 Cthn ---I ahoiators upph Formulation; Sufentanil car ate Ph Far 0.0045 0.02 OSMO 111 Fth9noln1ydiouP1 Fui 9 006 -026 06'hk2 Racementhol Ph Ear 0.1659 0.74 03322CC-4$5 Saccharin Ph E.ur_____ 0.0558 0.25 537918316 (in ite_Buffci I 1 i55 73 LdhorJtop 1⁄4tppIv 22167 H00U -4°C Assay Appearance of Weight pH Degradation % sufontanil solution Change L4x. .......
L-.---t _.i Injtial 4 weeks f Clear, colourless No significant
-_____
S \\ LCr CLar vlourk\s No sigrutleaut deradationfouo4 12 weeks Uear colourless No significant L -.
16 weeks No significant I --------.------J, -30 -25°C Assay Appearance Weight pH Degradation % Sufentanil of solution Change ________ _____________ mg/day ____________________________________________ ________ _____________ ________ Ph Eur method, retention times (mins) _______ Lii U2 ___________ _______ -7.5 8.5 9.5 17.2 Initial _____________ ________ ____________________________________________ 4 weeks Clear, No significant degradation ________ colourless ________ _____________ _______ _______ _______ 8 weeks Clear 0.1 0.1 0.3 ________ colourless ________ _____________ _______ _______ _______ 12 0.3 weeks ____________ ________ ____________ ______ ______ ______ * 0.28 ________ _____________ ________ -In house method, retention_times_(minsj__ _______ ___________ _______ 4.4 6.8 19.8 23.4 16 -0.11 0.17 0.18 weeks ____________ ________ ____________ ______ ______ ______ ________ ____________ ________ -Modified Ph E r method, retention times s) _______ ___________ _______ 2.9 3.3 7.6 8.3 11 16 -0.18 0.57 0.12 0.1 weeks ____________ ________ ____________ ______ ______ ______ 40°C _______ ___________ ______ ________________________________ Assay Appearance of Weight pH Degradation % Sufentanil solution Change ________ ______ ________________ mg/day _____________________________________________ _______ Lii LJ2 ______________ ________ -Ph Eur method, retention times (mins) Initial _____________ _______ -7.5 I 8.5 I 9.5 I 17.2 I 4 Clear, colourless No significant degradation Cy) weeks ______________ ________ ___________ ______ ______ ______ ______ 8 Clearcolourless 0.9 0.6 0.5 1.3 Q weeks ______________ _______ -___________ ______ ______ _____ 12 0.9 1.0 0.9 1.3 1iJ_ weeks ______________ _______ -___________ ______ ______ _____ C\j * 0.85 0.96 0.86 1.31 _____ _______ _______________ ________ In house method, etention times (mins) ______ _____________ _______ 4.4 6.8 19.8 23.4 _____ 16 -______________ _______ -0.21 0.65 0.42 weeks ______________ ________ ___________ ______ ______ ______ ______ _______ ______________ ________ Modified Ph Eur_method, retention times (mins) ______ _____________ _______ -2.9 3.3 7.6 8.3 11 16 -0.27 0.18 2.2 0.25 0.4 weeks ______________ ________ ___________ ______ ______ ______ ______ The results appear to indicate an increase in the degradation of sufentanil as shown by the appearance and increase in the extra HPLC peaks with temperature and time. However no corresponding decrease in the sufentanil concentration was observed. Analysis of the sample prepared for preformulation and stored in a glass volumetric flask at 40°C for six months showed no comparable degradation. It would seem that the formulation is -31 -reacting with the polypropylene of the HPLC vials in which it was packed before being placed on stability storage or (much more likely) that the observed peaks are from material leached out of the plastic vials by the formulation. Since the delivery device used for this product uses plastic components selected for their stability to leaching this issue is much reduced in the final product.
NOROO1IPDO1I1 18 was the first formulation to be successfully filled into the dispensing devices. This contained both levomenthol and sodium saccharin at a concentration of 0.74% (wlw) and 40% (wlw) ethanol 60% (wlw) as the solvent. After filling and sealing into the device the units were sterilised in an autoclave at 121°C for 15 minutes.
This formulation was prepared and put onto laboratory stability trials.
Stability analysis at 5 weeks showed peaks greater than 0.1 % in the samples taken from the device that were not observed in the corresponding bulk solution that had been stored in glass vials. The assay was however not significantly different from the initial. These peaks may therefore be due to leaching of material from the device components.
NOROO1/PDO1/1 18
I -
Sufeinanii citrate 0075 0.02 70) 74 Sodium Sccharin 2. 700 0.74 ISO. 100 4J Mo 0.
Water 2111000 57.44 0,21 TOTAL 365375 100.00 0.40 Adjusted to target pH 8.2 with sod iutn hydroxide Autodavd 1 2 1 C 5 miiutes.
-32 -Assay Bulk (not autoelaved) Assay Initial 32,4 2 weeks 4°C 125.1 25°C. 125.4 40"C' 124.7 25°C 22.9 9 Weeks 4°C 127,0 "C 12.6.0 1 Weeks -4°C 128.1 Assay Uthts -. Assay ..
Initial 130.6(n.2) I I Wicks °( 12/3 ji-2) 4;°C I 2LU (w=2) weeks 2.5<C 124.0 (n2) 40"C 1240 (m2) ...
40'C 130.6 (n'3) Delivered dose by weight ------Wugin (rng) -% ol till wught Initial 3610 (n= 1 1; RSD"3.0) 94.2 2Wks 2°C DStn 8 RSD-0'"l 943 40°C sô u (II S RSD 2j 94 1 S \eck s °c 3 (n-S itsu i o c S 40°L fl I in 8 RSI) ) 91 tj --Wicks 23 C 14' S (n3, RD-I 1) 92 1 IT TIlT 1171°77 IlT oTI RIlI -33 -Delivered dose by assay Sulentanil base J % of theory L...._ 42) -- 2 \Vuks 25 C 35 5 ir5 RSN4 5) 6 7 4Qç PL1) S Weeks 25 °C 420(nr6; RSD3.3) 90.5 I 40 C 403 (n6; RSD4.9) 902 Initial Assay = 130.6pg mr1 = 52.2 pg per 400pl dose Average delivered dose by weight 94.2% of fill weight Therefore delivered dose = 52.4 X 0.942 = 49.2pg Further formulations (NOROO1IPDO1I136 a -d) were prepared that contained just water or ethanol at approximately 10% (wlw). The pH of these formulations was not adjusted and only sodium saccharin at a concentration of 0.1 % (wlw) was added. The formulations were sterilised in an autoclave at 121°C for 15 minutes.
Initial analysis showed a drop in the sufentanil content of the formulations containing only water whereas the formulation containing 10% (wlw) ethanol was as expected. At 10 days analysis of the 40°C sample is showed no difference. However at 3 and 5 weeks a loss of sufentanil was observed at 40°C but not at 25°C.
The drop in sufentanil content is thought to be due to adsorption of the sufentanil to the polymer components of the device. The results suggest that this effect may be increased by the sterilisation or sealing process. The inclusion of a percentage of ethanol above 10% (wlw) is therefore desirable.
-34 -NOROO1 IPDO1 /1 36a ---\% eight (mgi \ olumc (ml) Sukntmd cimite (1 tPS 400 000 99 C,it u F]WII.,J tc iimiii:ic.
Assay Bulk Sufentanil citrate % diii from Sufèntauil (xg'mi) inilial base initiai 94c 631i eT 91 (1 C) r>i 1 3 Weeks 25°C 92,2 97.6 61.5 -40t Q15 96 6 0 Weeks 25 C 91,2 96.5 60.8 °C 90,8 96. 1 60.5 Assay Urdts Sufentanil citrate % thU from Su.fentan.il (g/mi) initial base' (OII) Initial 79.5 (w::7; 5$ C) RSD=7,4 1 0 days 40°C 77.6 (j:::$ 97.6 51.7 RSD:l 0.2) 3 Weeks 25°C 83.4 (n=3; 1(4.9 55.6 RSD0,7) °C 72.6 (n°3; 91.i 48.4 _____ P80=18.0) 1S\\eek 25°C 81 (n I 1U2 544 RSft{).9) 40°C 74,1 (ir3' 93.3 49.4 . Delivered dose (weigb Initial 374.2 (0=8: RSD=3.3) 93.6 i') day', 40°C 4 2 n 3 PSD 3 2) 94 6 \etks 25 $ 8(n RSL) 06) 94 40°C 380.6 (nH; RSDH.8) 95.1 25°C Th9 hn 3 R8D0 fl 9 1 lot. °fl2n 3 RSI) 71) 043 -35 -NOROO1 IPDO1 /1 36b -e4u ith4 voiuna (ml Sufenlanil citrate 0038 0. ifi Sodiun Saccharin 0.400 0. 1 0 Waler 400.000 99M9 0.40 I1OL 365575 -10000 040 Assay Bulk Sufentanil citrate % WIT from SufentanU initial base . initial 95.4 63.6 104 Ipoc. YTh... 2..2 3 \\cuL 25 L14 99(1 912 977 621 ---:sHc -40°C19 981 -Assay Units __-i;iii 1 CuWmJ) initial base 4.- I npal 0,(u c, RD-4p 3) --tOdays 4tYt 80.2 (u'3; RSD4.4) 99.3 53.4 2.1c PJ. Lo2i. -.
79 (::3 86.8 46.7 RSD:i0,2) -L5 SThtt RSD-io) 061 1 -- -.--.. .___J.cLiiL 7.?JoJQtki2qJ_ ±1188, :±i Delivered dose (weight) Vdt ") 3⁄4Pf fill WCIgW' 1 RD I 5 94 ç 404 jGQ 1(ri 3 RSD 3 1; P $ 8i2 (n3 RSD3.8) 95.3 49 °C 367(n2 RST) 1' Ol 918 W.eks ________ 25 "C $74.7 (n"3; RSD=0.8) 93,7 4{) C 368.8 (n:3: RSDH.1) 92.2 5..C.........E,,,,,.,....,..,,,. ,,.,..
-36 -NOROO1 IPDO1 /1 36c %Veight(ntg) %wiw Volume Sufentanil citrate 0.038 0.0 1 Scdium Saccharin 0.400 0,10 ___ LLtI1 3UcQ) Jo ft - 2000 49/6 -0 5 10! tL 365575 LJ°'!I Assay Bulk Sufentarni uti ate % tuft horn I Sukutanil (pg/nil) initial base Initial 94.7 63.1 day's 4OVC 92.2 97.4 61.5 3 Weeks 25C 92.7 97.9 61.8 -140DC 011 c14 s 1i._ T91 9 -1 -1fl>( U --612 Assay Units ---I Sufeutanilcitratftfltthft horn Sufentani -Qrginil) initial base -..__. . __.._..____ Initial 94.2 (n:8; 62.8 RSft4).6) Jaw -. 4(Y 90.5(n;:I I &
--
3 Weeks 25 "0 91 (m"3: 97.3 61.1
---
569 (p:3' 92.3 57.9 RSD=2.$) We''ks 25 47, 92.5 (n=3 O8,3 61.7 --_. __.
SQ i ccc
-
Delivered dose (weight) 1111.iiii± .i: iii±i i1III iL IpttHt 6' I n S R4) }0 0 S dav' 40 ( 362 n RD 2 8 90 3 \ks 2S T ml 0,n. RS.D 1 0 °C 358.1 (n=3 PSD"d.3) 895 \Veek' ----> °C Th8,n= .22L.......
4( : VS89n 2 RSD 5) 92) -_.-. ---.--.--.-.-_ ---_-_. -.-,_. - -37 -A formulation (NOROO1IPDO1I148b) was developed that would contain sufficient ethanol to act as a preservative and therefore negate the need to sterilise the formulation. The formulation contains 18% (wlw) ethanol.
This and another formulation containing 16.2 % (wlw) ethanol (NOROO1/PDO1/148a) were preservative efficacy tested. The 18% (wlw) ethanol formulation was filled into 22 delivery devices and put on stability test.
NOROO1 IPDO1 /1 48b kutai ititt. () 018 0 01 Sodium Saccharin 0.400 0. 0 I thaiol ( 3 P 009 Wa.cr 313.00 -81,90 03 TOTAL 382.i(8 iOO.MO O4O Assay Bulk Sutcntanil dtnte Sufentanil base
__
initi& 95.1 63.4 2 Weeks 25 UC Assay U ni{ Sufentanil eitrate Su1entanfl base __ __ ___. II_ Initial 96.6 64.4 Vek 5 UC I 0 \ °ç 92.0 -Several delivery devices were filled with NOROO1/PDOI/148b using 400pl per unit and were sealed for use in the trial discussed below.
-38 -Pharmaceutical study A study was conducted to establish the single dose pharmacokinetics and absolute bioavailability of a sufentanil sublingual spray delivering 25pg in a 400pl aliquot.
The study was an open label, random ised, two ways cross-over study comparing 25pg sufentanil sublingual spray with 12.5pg IV sufentanil in 6 healthy Caucasian male subjects aged between 21 and 37 years of age. The formulation NOROO1 PDOII148b was used.
The primary objectives of the study were: to establish the single dose pharmacokinetics parameters; and to establish the absolute bioavailability of a single administration of sufentanil sublingual spray 25pg when compared to a single intravenous dose of 12.5pg sufentanil. Secondary objectives were the determination of safety, tolerability and taste.
Each subject was randomly allocated to one of two treatment sequences and participated in 2 treatment periods receiving a different treatment for each of their treatment periods, as illustrated below.
TM n4 I I )t \ * A 2rcg pr The IV sufentanil dose was chosen as the reference as this has been shown to be safe and well tolerated in healthy male subjects in previous studies and can be adequately measured in the plasma.
Blood samples were taken from the test subjects at regular intervals after testing and the concentration of sufentanil in the plasma was tested. The -39 -table below displays this for patients having a single intravenous dose of 12.5pg of sufentanil.
Table of IV results
Time Plasma Sufentanil Concentration (pg/mL) Mean SD SE CV (hour) ______ ______ Subject ID ______ ______ ______ 001 002 003 004 005 006 _____ _____ _____ ______ 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 N.App 0.03 3.4 292.0 45.8 59.8 285.5 37.4 120.7 131.5 53.7 109 0.8 171.3 119.7 95.0 117.8 162.8 119.6 131.0 29.5 12.1 23 0.17 133.2 83.1 69.0 114.5 98.5 86.0 97.4 23.3 9.5 24 0.25 85.7 48.3 77.3 82.0 68.3 95.9 76.2 16.5 6.7 22 0.33 56.2 48.2 62.5 67.8 49.9 73.1 59.6 9.9 4.0 17 0.5 48.2 35.4 60.0 49.6 45.2 70.4 51.4 12.2 5.0 24 0.75 32.4 27.1 49.4 3.9 34.1 44.6 36.9 8.4 3.4 23 1 28.9 19.4 38.4 33.6 32.1 38.4 31.8 7.1 2.9 22 1.5 18.9 15.0 26.3 22.9 27.6 29.9 23.4 5.7 2.3 24 2 16.1 13.9 20.7 16.2 17.2 24.3 18.1 3.8 1.5 21 2.5 15.4 10.5 16.0 17.3 16.4 17.6 15.6 2.6 1.1 17 4 8.3 6.4 9.1 7.1 7.6 11.1 8.3 1.7 0.7 20 6 4.4 2.7 5.1 3.2 2.8 3.1 3.6 1.0 0.4 27 12 0.0# 0.1* 1.9* 0.2* 4.7 1.5* 4.7 NA NA NA C') *LOQ of 2.5 pg/mI, N.App = not applicable, NA = not available The table below displays the data for patients having a single sub-lingual spray dose of 25pg of sufentanil.
-40 -Table of Spray results Time Plasma Sufentanil Concentration (pg/mL) Mean SD SE CV (hour) _____ ______ Subject ID ______ ______ ______ 001 002 003 004 005 006 ______ _____ _____ _____ 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 NA 0.03 0.0# 0.0# 0.0# 0.0# 0.0# 0.0# NA NA NA NA 0.8 6.0 0.0# 0.0# 1.9* 0.0# 0.0# 6.0 NA NA NA 0.17 37.2 14.3 3.5 4.3 16.6 0.5* 15.2 13.6 6.1 90 0.25 62.8 22.4 10.5 6.6 47.7 3.5 25.6 24.3 9.9 95 0.33 78.0 29.1 61.7 29.9 80.0 9.5 48.0 29.2 11.9 61 0.5 83.4 33.5 33.5 48.7 96.1 21.5 52.8 30.2 12.3 57 0.75 64.5 58.8 42.2 48.7 82.1 27.7 54.0 18.9 7.7 35 1 60.2 48.8 33.4 50.7 61.0 39.6 48.9 11.0 4.5 22 1.5 35.6 44.4 29.3 33.4 44.8 35.3 37.1 6.2 2.5 17 2 30.5 38.1 31.2 44.5 27.1 38.9 35.0 6.5 2.7 19 2.5 35.4 32.0 28.3 27.8 28.1 34.9 29.4 3.4 1.4 12 4 15.3 21.2 17.0 18.1 14.2 20.2 17.6 2.7 1.1 15 6 4.1 8.4 10.2 6.0 4.8 5.7 6.5 2.3 1.0 36 12 1.4* 1.8* 2.3* 0.1* 0.0# 0.0# NA NA NA NA *LOQ of 2.SpgIml, N.App = not applicable, NA = not available C') The mean plasma concentrations for the IV and spray delivery tests are plotted against time in Figure 1 below. -41 -
Figure 1 SufentanU Mean Concentrafion (pg/mL} vs Tftne (hour) 30ft01 -250.0 200.0 -g 150/2 100.0 SOD * 0.0 -:t__* ---tr-:-:-:- 2 4 6 8 10 12 Trne (hour) A summary of the resulting comparative data is shown in the table below.
iT p?.a\ ,. ti...Sn, tMflVt C-x 3-»=fl tic 4W' TnT bT Tnz th) 0G6 066 N/A OO22 N/A N-/A VU) t43 NA Ci 1jTit1. G11 3M N/A O7$4 N/A The absolute bioavailability of sufentanil sublingual spray was c.61 % which is similar to the bioavailability reported for the intranasal sufentanil of 76% (Helmers 1989) and on a normalised basis Cmax was c.19%.
The difference between the Tmax for the two routes of administration was statistically significant. For the sublingual formulation the mean -42 -concentrations between 20 and 60 minutes remained within a very narrow range of 48-58 pg/mI.
It is anticipated that a rapid onset of analgesia can be sustained for about an hour as the pharrnacokinetics profile would suggest, given that the rapid distribution phase that is normally seen in IV administration was not observed for the sublingual formulation. Additional studies will need to be carried out to confirm that.
No serious adverse events (AE5) were reported and none of severe severity. All reported AEs were of short duration and resolved spontaneously without the need of medical intervention. Altogether 18 adverse events were registered of which 10 were attributable to sufentanil IV and 8 to the sublingual spray formulation. The most common adverse effect was drowsiness and was reported 7 times by 6 volunteers.
Sufentanil spray adverse events were classified to be of mild severity.
Sufentanil IV adverse events were classified to be of moderate severity, thus suggesting that the sublingual spray is a better mode of delivery.
In summary this exploratory study demonstrated a good safety profile with no serious adverse events reported and was well tolerated with good acceptance of the taste, therefore meeting primary and secondary endpoints.
Given the pharmacokinetic profile of this formulation, it is assumed that the onset of analgesia occurs within 10-15 minutes from administration and lasts for about an hour or even longer and that the formulation is able to provide a predictable and stable response.
Claims (18)
- -43 -Claims 1. A pharmaceutical formulation to be delivered sublingually by spray comprising: -sufentanil or a pharmaceutically acceptable salt thereof; -an alcohol; and -water and/or an aqueous buffer.
- 2. A pharmaceutical formulation as claimed in claim 1, which further comprises a sweetener.
- 3. A pharmaceutical formulation as claimed in claim 2, in which the sweetener is saccharin.
- 4. A pharmaceutical formulation as claimed in any of the preceding claims in which the alcohol is ethanol.
- 5. A pharmaceutical formulation as claimed in any of the preceding claims, which further comprises menthol.
- 6. A pharmaceutical formulation as claimed in claim 5, in which the menthol is in the form of levomenthol or racementhol.
- 7. A pharmaceutical formulation as claimed in any of the preceding claims, wherein the sufentanil is in the form of sufentanil citrate.
- 8. A pharmaceutical formulation as claimed in any of the preceding claims, wherein a buffer is present.
- 9. A pharmaceutical formulation as claimed in claim 8, in which the buffer is a citrate buffer.
- 10. A pharmaceutical formulation as claimed in claim 8 or claim 9, in which the pH of the formulation is in the range of 7.5-9.0 and preferably 8.2.-44 -
- 11. A pharmaceutical formulation as claimed in any of the preceding claims, which comprises: -0.005 -0.05%wlw sufentanil or a pharmaceutically acceptable salt thereof; -0 -0.30 %w/w sodium saccharin; -0 -1.0 %w/w menthol; -10-50 %w/w ethanol; and -the balance water or a buffer.
- 12. A pharmaceutical formulation as claimed in any of the preceding claims which comprises: -0.01 %w/w sufentanil citrate; -0.1 %w/wsodium saccharin; -17.99 %w/w ethanol; and -81.90 %w/wwater.
- 13. A pharmaceutical formulation as claimed in claim 1 and substantially as herein described.
- 14. A disposable single dose dispensing canister loaded with a pharmaceutical formulation as claimed in any of the preceding claims and adapted to deliver that dose by a single sublingually spray.
- 15. A method of drug delivery comprising -providing a dose dispensing spray canister loaded with a pharmaceutical formulation as claimed in any of the preceding claims; and -manual operation of the spray canister to delivering the pharmaceutical formulation as a spray to the sublingual region.-45 -
- 16. A method of drug delivery as claimed in claim 11, wherein the canister holds only a single dose and this is all dispensed in a single action.
- 17. A method of drug delivery as claimed in claim 11 or claim 16, wherein canister is a single use item that is disposed of after drug delivery.
- 18. The use of sufentanil in the preparation of a medicament for sublingual spray delivery for the treatment of pain.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0922537A GB2476494A (en) | 2009-12-24 | 2009-12-24 | Formulation for the sublingual delivery of sufentanil |
| PCT/GB2010/052210 WO2011077169A2 (en) | 2009-12-24 | 2010-12-23 | Pharmaceutical preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0922537A GB2476494A (en) | 2009-12-24 | 2009-12-24 | Formulation for the sublingual delivery of sufentanil |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB0922537D0 GB0922537D0 (en) | 2010-02-10 |
| GB2476494A true GB2476494A (en) | 2011-06-29 |
Family
ID=41716886
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB0922537A Withdrawn GB2476494A (en) | 2009-12-24 | 2009-12-24 | Formulation for the sublingual delivery of sufentanil |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB2476494A (en) |
| WO (1) | WO2011077169A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2487007A (en) * | 2012-03-19 | 2012-07-04 | Londonpharma Ltd | Cyclic olefin copolymer containers and delivery devices for the sublingual administration of opioids |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160296498A1 (en) * | 2015-04-09 | 2016-10-13 | Insys Development Company, Inc. | Ketorolac Sublingual Spray Formulations |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030190290A1 (en) * | 2000-06-22 | 2003-10-09 | Calvin Ross | Pharmaceutical compositions |
| WO2007007059A1 (en) * | 2005-07-08 | 2007-01-18 | Sosei R & D Ltd. | Fentanyl formulation containing an essential oil |
| WO2008100434A1 (en) * | 2007-02-09 | 2008-08-21 | Durect Corporation | Transoral dosage forms comprising sufentanil and naloxone |
| EP2054162A1 (en) * | 2006-08-26 | 2009-05-06 | Norwich Pharma Technologies Limited | Dosage dispensing canister |
| US20090124554A1 (en) * | 1997-10-01 | 2009-05-14 | Dugger Iii Harry A | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004080382A2 (en) * | 2003-03-11 | 2004-09-23 | Arakis Ltd. | Novel compositions containing fentanyl |
-
2009
- 2009-12-24 GB GB0922537A patent/GB2476494A/en not_active Withdrawn
-
2010
- 2010-12-23 WO PCT/GB2010/052210 patent/WO2011077169A2/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090124554A1 (en) * | 1997-10-01 | 2009-05-14 | Dugger Iii Harry A | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
| US20030190290A1 (en) * | 2000-06-22 | 2003-10-09 | Calvin Ross | Pharmaceutical compositions |
| WO2007007059A1 (en) * | 2005-07-08 | 2007-01-18 | Sosei R & D Ltd. | Fentanyl formulation containing an essential oil |
| EP2054162A1 (en) * | 2006-08-26 | 2009-05-06 | Norwich Pharma Technologies Limited | Dosage dispensing canister |
| WO2008100434A1 (en) * | 2007-02-09 | 2008-08-21 | Durect Corporation | Transoral dosage forms comprising sufentanil and naloxone |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2487007A (en) * | 2012-03-19 | 2012-07-04 | Londonpharma Ltd | Cyclic olefin copolymer containers and delivery devices for the sublingual administration of opioids |
| GB2487007B (en) * | 2012-03-19 | 2013-06-05 | Londonpharma Ltd | COC containers and delivery devices for the sublingual administration of opioids |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011077169A3 (en) | 2012-03-15 |
| WO2011077169A2 (en) | 2011-06-30 |
| GB0922537D0 (en) | 2010-02-10 |
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| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |