Use of opioid formulations in needle-less drug delivery devices

[0001] The present invention relates to a needle-free drug delivery device suitable for delivering drugs through the skin surface to a human or animal body comprising a pharmaceutical composition with an opioid.

[0002] The present invention also relates to the use of opioid in a needle-free drug delivery device that is suitable for injecting a drug through the skin surface into a human or animal body.

[0003] Furthermore, the invention relates to a method of treating breakthrough pain by injecting an opioid into a human or animal body using a needle-free drug delivery device.

BACKGROUND OF THE INVENTION [0004] The treatment of severe chronic pain which may be spontaneous or result from diseases such as cancer, rheumatism and arthritis is a major task in the treatment of these conditions. The extent of pain experienced, for example, by cancer patients includes periosteal and bone pain as well as visceral and soft tissue pain.

[0005] All chronic, severe forms of pain make patients' daily lives unbearable and often lead to depressive conditions. Effective pain therapy leading to lasting improvement in the quality of life of patients is therefore as important for the success of comprehensive therapy as the treatment of the real causes of the disease.

[0006] It has become established practice to use strong painkillers, such as opioids, to treat chronic, severe pain in cancer patients as well as patients who experience pain for other reasons.

[0007] Typically, doses of strong painkillers, such as opioids, are adjusted in patients with chronic pain to find the appropriate dose range for a particular opioid, such as morphine or oxycodone. After identifying the dosage amount that is appropriate for constant control of the chronic pain experienced by these patients, the drug is taken according to a schedule with fixed intervals, which means that a certain dose will be taken e.g. every 8 hours, every 12 hours or only once a day. Such patients who would suffer from chronic pain in the absence of pain treatment are usually referred to as patients with controlled basic pain.

[0008] In order to achieve constant control of the baseline pain, patients will usually be administered so-called controlled release or sustained release formulations of a given analgesic. Sustained-release preparations, especially opioids, are well known, e.g. in the form of the "MST-Continus" tablets "Palladon" and "Oxygesic" (all sold by Mundipharma GmbH, Germany). These prolonged-release dosage forms are characterized in that they release the active agent over an extended period of time, which allows a reduction in the frequency of administration of these formulations. This in turn has a number of significant benefits for the patient because, for example, the patient can sleep for an uninterrupted period of 6 to 8 hours. In addition, the reduced frequency of administration often leads to better patient compliance with medication.

[0009] Although many cancer patients are currently being successfully treated with opioids and their baseline pain can be seen to be controlled, they occasionally experience from transient increase in pain to pain higher than normal moderate intensity.

[0010] This exacerbation of moderate to severe pain that "breaks through" despite the regimen with fixed analgesic dosing intervals for the treatment of chronic pain is usually described as breakthrough pain (BTP). The term breakthrough pain has been adopted by specialists treating chronic pain within the scope of the vocabulary, and therefore refers generally to the transient exacerbation of pain that occurs against the background of other constant controlled pain in a patient receiving analgesic therapy (see e.g. Portenoy et al. (1990), Pain, 41: 273-281, Cara et al (2004), Pain, 108: 1727, Portenoy et al (1999), Pain, 81: 129-134 and Portenoy et al (2006) Journal of Pain, 7 (8 ): 583-591). The phenomenon of breakthrough pain is also referred to as "incidental pain" and "episodic pain."

[0011] In cancer patient population studies, 50 to 90% of chronic pain patients experience breakthrough pain attacks, which have also been reported in patients treated with opioids with chronic pain other than cancer pain (see Portenoy et al. (2006), Journal of Pain , 7 (8): 583-591).

[0012] Thus, even if at present the treatment of pain, regardless of its origin, with strong painkillers such as opioids, does not encounter the same negative attitudes in physicians as in the past, a patient in whom the dose is well adjusted, being in During the continuous opioid regimen, he may still suffer from nagging and painful attacks. Of course, there is a strong need to explain the phenomenon of breakthrough pain, and various attempts have been made in the art to make the lives of those patients who suffer from sudden attacks of pain more comfortable.

[0013] In the treatment of breakthrough pain, the patient will usually receive an additional amount of a strong painkiller, such as opioid, which he takes continuously to control the baseline pain.

[0014] Because attacks of breakthrough pain usually occur suddenly and require treatment within a short period of time, these additional dosages of analgesic will usually be provided as a fast-acting formulation. For opioids, therefore, an additional parenteral dose may be administered, which would give rise to an immediate onset of action, or alternatively immediate-release oral opioid preparations such as, for example, morphine and oxycodone may be administered.

[0015] Oral immediate release dosage forms may be in the form of a liquid or immediate release tablet.

[0016] Because of the recognition that breakthrough pain is a significant clinical problem, such "rescue medication" has been widely accepted for the treatment of pain.

[0017] However, due to the fact that short-acting opioid preparations are usually used to treat on-demand breakthrough attacks in patients who are in the course of an established scheduled opioid dosage regimen, care should be taken to ensure that the patient does not overdose. In addition, in the case of short-acting opioid preparations, such as liquids, which are ingested orally or parenterally administered, individuals are prone to notorious abuse, not attempting to take the drug to treat pain, but rather trying to isolate opioids and use them for illegal purposes recreational activities.

[0018] RIPAMONTI AND OTHERS (2005), in 'Palliative medical management', EUROPEAN JOURNAL OF CANCER, SUPLEMENT, PERGAMON, OXFORD, GB, volume 3 (3): 203-219 discloses: micro-infusions containing opioid (morphine), which are administered rectally as a bolus using a syringe without a needle; wherein these micro-infusions are successfully administered to patients with breakthrough pain.

[0019] Given the possibility that exposure to short-acting opioid preparations could increase the risk of abuse in a subpopulation predisposed to abuse or addiction, it is reasonable to implement rescue dose for each case after careful risk and benefit assessment. This usually leads to the situation that patients suffering from breakthrough pain receive the necessary short-acting drug only under the supervision of a doctor, which of course seriously negatively affects the freedom of such patients to move and to take the required drug at any place and time. A major disadvantage of parenteral administration of short-acting opioids is also that the administration of the drug through a needle device is poorly accepted. Furthermore, it has been found that patients receiving oral doses notice that the onset of the oral dose is sometimes too slow to be relieved, and thus better results are achieved with parenteral 'rescue' medication when treating breakthrough pain.

[0020] Thus, there is a great need in the art to provide a pharmaceutical composition that allows treatment of breakthrough pain and which can be taken by a patient on demand without medical supervision at any time. At the same time, these pharmaceutical compositions should be less prone to abuse than fast-acting opioid preparations that are commonly used to treat breakthrough pain attacks.

OBJECTIVE AND SUMMARY OF THE INVENTION [0021] The object of the present invention is to provide a medicament that can be used as an emergency medicine for the treatment of breakthrough pain. It is also an object of the present invention to provide a drug delivery device that allows delivery of a drug suitable for treating breakthrough pain that can be administered by patients themselves on demand and which is less prone to abuse, such as short-acting opioid preparations that are commonly used for the treatment of breakthrough pain attacks.

[0022] One embodiment of the present invention therefore relates to a needle-free drug delivery device suitable for injecting a pharmaceutical composition through the skin surface into a human or animal body, the needle-free drug delivery device comprising:

a) housing;

b) a means for generating a force capable of pushing the pharmaceutical composition out of the package into a human or animal body through the surface of the skin; c) a means for transferring this force to push the pharmaceutical composition out of the package into the human or animal body through the surface of the skin;

d) means for activating the device;

e) and a pharmaceutical composition comprising at least one opioid, the needle-free drug delivery device being a pen-type pen, the opioid preparation being in a replaceable container and the opioid preparation being placed in that container, separately from the second opioid antagonist preparation .

[0023] This opioid may be present in the pharmaceutical composition in the form of a solution, solid, dispersion or suspension.

[0024] Opioids from the group consisting of tramadol, dihydrocodeine, oxycodone, morphine, hydromorphone, oxymorphone, nalbuphine, etorphin, dihydroethorphine, fentanyl, sulfentanyl, remifentanyl and buprenorphine, or their pharmaceutically acceptable salts are preferred.

[0025] Particularly preferred opioids are hydromorphone and oxycodone, and their hydrochlorides are also particularly preferred.

[0026] The present invention also relates to the use of at least one opioid in a needle-free drug delivery device that is suitable for injecting a pharmaceutical composition through the skin surface into a human or animal body.

[0027] Still another embodiment of the present invention relates to at least one opioid for use in the treatment of breakthrough pain, said opioid being administered through the skin surface to a human or animal body using a needle-free drug delivery device.

[0028] The present invention also relates to a needle-free drug delivery device that is suitable for injecting a drug through the skin surface into a human or animal body for use in treating breakthrough pain. In the latter case, the drug delivery device will obviously contain a pharmaceutical composition comprising at least one opioid.

[0029] In all of the abovementioned cases, at least one opioid may be in the form of a solid, liquid, dispersion or suspension.

[0030] It is also preferred to use opioids including tramadol, dihydrocodeine, oxycodone, morphine, hydromorphone, oxymorphone, nalbuphine, etorphine, dihydroethorphine, fentanyl, sulfentanyl, remifentanyl and buprenorphine, being preferred. Hydromorphone and oxycodone and their hydrochlorides are particularly preferred opioids.

[0031] Still another embodiment of the present invention relates to a method of treating breakthrough pain in a patient in need thereof, wherein at least one opioid is administered to the patient using a needle-free drug delivery device suitable for injecting the drug through the skin surface into the human or animal body. [0032] In addition, the opioid may be in the form of a solution, solid, dispersion, or suspension. Opioids such as tramadol, dihydrocodeine, oxycodone, morphine, hydromorphone, oxymorphone, nalbuphine, etorfin, dihydroethorphine, fentanyl, sulfentanyl, remifentanyl and buprenorphine, with particular regard to hydromorphone and oxycodone and their hydrochloride, will be preferred.

DETAILED DESCRIPTION OF THE INVENTION [0033] In the context of the present invention, the term "breakthrough pain" refers to a transient increase in pain to a more than moderate intensity pain that is superimposed on a moderate or less severe base pain.

[0034] "Baseline pain" means pain that a patient notes as experiencing moderate intensity pain for 12 or more hours in a patient during the opioid dosing regimen for the treatment of chronic pain.

[0035] The intensity of the baseline pain will usually be determined using common methods such as numerical-analogue scale (NAS) testing. Determination of breakthrough and baseline pain attacks has been described in detail in Portenoy above (see in particular Portenoy et al. (1999) (The Journal of Pain 7 (8): 583-591) and Portenoy et al. (1999) Pain 81: 129-134). Therefore, two criteria will be required to indicate controlled baseline pain. First, patients will have to answer the question: "Does your pain currently have a component that you could describe as" constant "or" almost constant "or that would be constant or almost constant if you did not receive treatment," the answer must be affirmative . Secondly, such patients are required to be treated according to an opioid dosing regimen that is consistent with relatively good pain control. Of course, the skilled artisan will know how to determine controlled baseline pain based on the information provided in these two references. Breakthrough pain will then be identified as a pain stroke that the patient experiences above the level of controlled baseline pain.

[0036] Pain intensity can thus be determined using, for example, a 5-point categorical scale with the points 'no', 'light', 'moderate', 'strong' and 'excruciating'. By definition, a patient will experience a bout of breakthrough pain if the bout has been rated by the patient as strong or excruciating.

[0037] As mentioned above, one embodiment of the present invention relates to a needle-free drug delivery device suitable for injecting a pharmaceutical composition through the skin surface into a human or animal body, the needle-free drug delivery device comprising:

a) housing;

b) a means for generating a force capable of pushing the pharmaceutical composition out of the package into a human or animal body through the surface of the skin; c) a means of transferring force to push the pharmaceutical composition out of the package into a human or animal body through the surface of the skin;

d) means for activating the device;

e) a pharmaceutical composition comprising at least one opioid;

wherein the needle-free drug delivery device is a pen-type pen, the opioid preparation being in a removable container, and wherein the opioid preparation is placed in that container separately from the second opioid antagonist-containing preparation.

[0038] Thus, the present invention in one embodiment relates to needle-less injection devices, as described in the prior art, except that a pharmaceutical composition comprising an opioid is incorporated into the injection device.

[0039] Of course, one skilled in the art is well aware of the various needle-free pen injectors described in the prior art. The skilled artisan is also aware that these various pen-type injection devices, such as those described in the prior art, e.g. for insulin or hormones such as human growth factor and follicle stimulating hormone, differ in their mechanical components and construction.

[0040] However, although these differences in design may impose certain requirements on the type of pharmaceutical composition that can be used in drug delivery devices, one of ordinary skill in the art will understand that these design differences in needless injection devices in the prior art are not relevant in relation to of the present invention, which consists in a surprising statement that such needle-free pen-type pens can ideally be used to treat breakthrough pain by administering strong painkillers such as opioids.

[0041] Thus, a needle-free injection device containing pre-introduced and pre-measured doses of analgesics that are ejected from the pen using compressed inert gas can be used. The pressure will be sufficient to break the liquid drug through the patient's skin surface.

[0042] Thus, for the purposes of the present invention, for example, a needle-less injection device as described in US Patent 5,851,198 can be used.

[0043] Pen-type injection devices described in WO 03/015843 A2 may also be used.

[0044] In a preferred embodiment, pen-type injection devices as described in WO 03/023773 A1 and WO 2004/014468 A1, both filed on behalf of Caretek Medical Ltd., can be used.

[0045] A person skilled in the art will of course know that there are various means for generating a force capable of pushing a drug out of the package into a human or animal body through the surface of the skin. These means for generating force may e.g. include a technique using pressurized gases or springs.

[0046] Similarly, means for transmitting this force are also well known to the person skilled in the art because they are means for actuating the device.

[0047] Although some of the aforementioned drug delivery devices rely on a technique that delivers a drug by creating a very thin stream of liquid at a high rate that causes an opening in the skin, the technique described in WO 03/023773 A1 and WO 2004/014668 A1 relates to an alternative technique in which a pellet bullet is pressed through the skin first, followed by a drug, which ensures effective transfer of the active agent across the skin surface. One of the advantages of the techniques described in WO 03/023773 A1 and WO 2004/014468 A1 is that a pharmaceutical composition can be used which contains the active agent in solid, liquid, semi-solid state, in the form of a paste or in liquid states different viscosities. Thus, the devices described in WO

03/023773 A1 and WO 2004/014468 A1 make it possible to provide analgesics, in particular opioids, for the treatment of breakthrough pain in the form of a liquid, which can be surrounded by a membrane, in the form of a liquid with a viscosity of at least 5000 centipoise, as a semi-solid pastes with a soft ductile consistency, in the form of a gel which is a liquid dispersed in a solid or solid state.

[0048] Advantages of using a needle-free drug delivery device containing at least one opioid for treating breakthrough pain include, but is not limited to, that the patient can use this device and will not feel as reluctant as with conventional needle technique. This will significantly increase ease of administration and at the same time reduce skin irritations that may arise using classic needle technique.

[0049] Furthermore, since the active agents, in this case being opioids, are administered through the skin surface, the active agent is absorbed systemically in a short time providing a rapid onset of action, which is required for effective treatment of breakthrough pain.

[0050] Furthermore, pen-type injection devices are much less prone to abuse. For example, a disposable pen pen may contain a dose of opioid already introduced into the ready-to-use pen, which could make it much more difficult to isolate a painkiller formulation from a pen pen than e.g. prior art liquid preparations that must be taken orally. If, on the other hand, the preparation is in a removable container to be inserted into the pen-type pen, the container can be designed in such a way that the unauthorized isolation of the analgesic preparation becomes very difficult. Of course, the skilled person is well aware that it is possible to construct such a needle-less pen-type injection device that it becomes difficult to isolate the opioid formulation from the needle-free drug delivery device. The opioid formulation is placed in the container separately from the other formulation containing the opioid antagonist in appropriate amounts. These two preparations are placed in the container of a pen-less needle pen in such a way that if someone tries to disassemble the container, both preparations will come into contact with each other, which will prevent any parenteral abuse of the preparations (so-called dual-chamber approach).

[0051] Depending on the construction elements, a needle-free pen injector for opioid delivery for treating breakthrough pain attacks can be configured to allow only single dose or multiple administration. Thus, needle-less pen-type injection devices can be used for single or multiple applications and can be, e.g., disposable or reusable injectors. Various components that may be necessary to make this single or reusable pen needle injection device are well known to those skilled in the art from other pen injection devices such as those used for insulin or hormone administration. growth.

[0052] Depending on the type of pen needle-less injection device, the dosage of opioid may be predetermined or adaptable. A pen injection device with a dose of opioid that can be adjusted will have the advantage that the responsible patient can administer the dose depending on the severity of the pain attack. On the other hand, the predetermined dosage amount will further limit the potential for abuse of analgesic compositions found in needle-less pen-type injection devices. Other advantages and forms of needle-less pen-type injection devices containing pharmaceutical compositions with at least one opioid will be apparent to those skilled in the art.

[0053] With respect to a pharmaceutical composition comprising at least one opioid, of course, one of ordinary skill in the art is well aware that these preparations may take different forms and optionally contain various pharmaceutically acceptable excipients when necessary.

[0054] When developing a formulation of at least one opioid used for a pen-type needle-less injection device as described, one skilled in the art will consider mainly two aspects.

[0055] As the object of the present invention is to use the above-described needle-less pen-type injection devices for treating breakthrough pain attacks, the pharmaceutical compositions contained in the pen will have to ensure that the active agent is able to exert a rapid onset of action. Since pharmaceutical compositions containing at least one opioid will be administered by injection through the skin surface, the onset of action usually occurs earlier than when the same formulation is administered orally.

[0056] However, one of skill in the art will of course ensure that when the pharmaceutically active agent is administered, e.g. in liquid form by injection, the liquid will provide the properties of an immediate release formulation. Thus, a person skilled in the art intending to treat breakthrough pain will obviously avoid the use of excipients and ingredients that are known to significantly delay the release and absorption of the active agent in the human or animal body after injection of the active agent. A second aspect that will be considered by those skilled in the art when developing an active pharmaceutical composition will be whether the composition complies with the mechanical requirements of the needle-free pen-type pen to be used. [0057] As already outlined above, a person skilled in the art may consider a pharmaceutical composition that contains the active agent in the form of a solid, liquid, dispersion or suspension.

[0058] It is currently preferred to use a liquid opioid formulation. In its simplest form, such a liquid preparation may contain e.g. morphine or oxycodone in physiological saline at physiological pH values. However, one of ordinary skill in the art may also consider using a solid state injection. In this context, it will be clear that the smaller the particle size of the active agents, the faster the active agent will be absorbed systemically by the patient.

[0059] With respect to the opioids to be used, a person skilled in the art will consider the use of the free base as well as its pharmaceutically acceptable salts or derivatives which are also known to be therapeutically active and pharmaceutically acceptable. If opioid is mentioned in the context of the present invention, this always applies to the free base as well as the pharmaceutically acceptable salts or the aforementioned derivatives.

[0060] If, for example, oxycodone is mentioned, it also includes, in addition to the free base, their hydrochloride, sulfate, bisulfate, tartrate, nitrate, citrate, hydrogen tartrate, phosphate, malate, maleate, hydrobromide, hydroiodide, fumarate, succinate and the like .

[0061] For hydromorphone and oxycodone, the hydrochloride will be preferred.

[0062] As mentioned above, opioids are beneficial in treating breakthrough pain, and these opioids may include morphine, oxycodone, hydromorphone, propoxyphene, nicomorphine, dihydrocodeine, diamorphine, papaverium, codeine, ethylmorphine, phenylpiperidine and its derivatives, methpropene, dextrophene, , pentazocin, tilidine, tramadol, hydrocodone. Further examples of useful opioid analgesics according to the invention are buprenorphine, meperidine, oxymorphone, alphaprodyna, anileridine, dextromoramide, metopone, levorphanol, fenazocin, etheheptazine, propiram, profadol, fenampromid, thiambuten, fentinone diodeethodine -4-t'enyl-4-trans-kai'boethoxy -. \ '- CYCLohexene, 3-dimethylamino-O- (48 methoxyphenylcarbamoyl) propiophenone oxime, (-) b-2'-hydroxy-2,9-dimethyl- 5-phenyl-6,7-benzomorphan. (-) - 2'-hydroxy-2- (3-methyl-2-butenyl) -9-methyl-5-phenyl-6,7-benzomorphan, pyriditramide, (-) a-5,9-diethyl-2 ' -hydroxy-2-methyl-6,7-benzomorphane, 1- (2-dimethylaminoethyl) -4,5,6,7-tetrahydro-3-methyl-4-oxo-6-phenylindole-2-carboxylate, 1- benzoylmethyl-2,3-dimethyl-3- (m-hydroxyphenyl) piperidine, N-allyl-7- (1-R-hydroxy-1-methylbutyl) -6,14-endo-ethanotetrahydronororipavine, (-) 2'-hydroxy-2 -methyl-6,7-benzomorphan, noracylmetadol, phenoperidine, α-dl-metadol, α-1-metadol, β-dl-acetylmethadol, α-1-acetylmethadol and β-1-acetylmethadol.

[0063] Particularly preferred is a group of opioids including tramadol, dihydrocodeine, oxycodone, morphine, hydromorphone, oxymorphone, nalbuphine, etorphine, dihydroethorphine, fentanyl, sulfentanyl, remifentanyl and buprenorphine or their pharmaceutically acceptable salts. [0064] A particularly preferred embodiment of the present invention relates to the use of opioids, oxycodone or hydromorphone, and preferably their hydrochlorides, for the treatment of breakthrough pain attacks by introducing the oxycodone and hydromorphone formulation into the needle-free drug delivery device described above and injecting it through the skin into the human or animal body .

[0065] The dose to be administered to effectively treat breakthrough pain attacks will need to be determined for each opioid separately. However, it is preferred to use between about 10% to 30% of the dosed amount that a patient with controlled baseline pain adapted to the opioid regimen will receive during the day by oral route. In addition, it is preferred to use between about 10 to 20% and about 15% of the dosed amount which the patient with controlled baseline pain receives by oral administration throughout the day. The person skilled in the art is also aware that especially if the patient is treated with high doses of opioids, 10% -15% of the daily oral dose will be sufficient.

[0066] The term "about" indicates a deviation from a specific value of 10%, preferably 5%.

[0067] The skilled person is well aware that this calculated dose relates to the dosage amount for the treatment of breakthrough pain by oral administration of the analgesic preparation. Since the analgesic formulation according to the invention will be injected subcutaneously, the person skilled in the art will usually divide the dose for treating breakthrough pain by oral administration by a factor that is determined for each opioid. This ratio is usually based on known oral and intravenous dosage amounts and reflects the fact that the first pass effect may not occur after parenteral administration for many opioids or other analgesics. Such additional factors are usually not needed if the opioid reference amount relates to daily parenteral administration to control baseline pain.

In the case of morphine, this coefficient will be e.g. about 3, in the case of hydromorphone this coefficient will be e.g. about 5, in the case of oxycodone this coefficient will be about 2, in the case of tramadol this coefficient will be e.g. about 1, in the case of codeine, this factor will be, e.g., about 5. [0069] It is understood that the above oral: intravenous dose ratios are guidelines for determining the required dose. Inter-patient variability requires that the appropriate dose is carefully adjusted for each patient.

[0070] For morphine, the daily oral dose typically ranges from about 30 mg to about 1000 mg orally daily. The dosage amount of morphine administered orally to treat breakthrough pain attacks will therefore be in the range of about 9-3 mg to about 100 to 300 mg. The preferred dose range for oral morphine for treating breakthrough pain will be about 3-9 mg to about 40 mg to 120 mg. The subcutaneous dose for treating breakthrough pain attacks will suitably be in the range of about 1-3 mg to about 33 to 50 mg, and especially in the range of about 1 to 3 mg to about 13 - 40 mg.

[0071] For hydromorphone, it is known that a typical daily dose in a stable state ranges from about 2 mg to about 400 mg. The oral dose range for treating breakthrough pain attacks will therefore be from about 0.2 - 0.6 mg to about 40 - 120 mg, and preferably from about 0.4 - 1.2 mg to about 6.4 - 19.2 mg . The subcutaneous dose for treating breakthrough pain attacks will suitably be in the range of about 0.04 - 0.12 mg to about 8 to 20 mg, and preferably in the range of from about 0.08 - 0.24 mg to about

1.3 - 5.9 mg.

[0072] For tramadol, a typical daily dosing amount ranges from about 50 mg to about 600 mg, and preferably from about 50 mg to about 400 mg when administered in a stable state. In a typical treatment scenario for breakthrough pain, tramadol will be administered orally or subcutaneously at a dose of from about 5 - 15 mg to about 60 - 180 mg, and preferably from about 5 - 15 mg to about 40 - 120 mg.

[0073] Fentanyl is usually administered in an amount of 600 Pg to 2.4 mg per day intravenously or transdermally. Thus, the subcutaneous dose for treating breakthrough pain attacks will range from about 60 g - 180 μg to about 0.24 mg to 0.72 mg.

[0074] Codeine is usually administered subcutaneously in an amount up to 240 mg. Thus, the subcutaneous dose for treating breakthrough pain attacks will be up to about 24-72 mg.

[0075] Dihydrocodeine is usually administered intravenously in an amount up to 320 mg. Thus, the subcutaneous dose for treating breakthrough pain attacks will be up to about 32-96 mg.

[0076] In the case of oxycodone, a typical daily dosing amount ranges from about 5 mg to about 800 mg per day. To treat breakthrough pain attacks, oxycodone will therefore be used orally at a dose between about 0.5-1.5 mg to about 80 to 240 mg, and preferably between about 1-3 mg to about 16-48 mg. The subcutaneous dose for treating breakthrough pain attacks will suitably be in the range of about 0.25 - 0.75 mg to about 40 to 120 mg, and preferably about 0.5 - 1.5 mg to about 8 - 24 mg.

[0077] All of the above-mentioned preferably relate to the corresponding hydrochlorides.

[0078] It will be understood by those skilled in the art that the amount of opioid administered for effective treatment of a breakthrough pain attack will therefore depend on the amount that is used daily to control baseline pain. Thus, if it is to be treated for breakthrough pain attacks a patient who receives e.g. hydromorphone orally at a dose of 32 mg per day, the typical amount considered for the treatment of breakthrough pain attacks will be between 3.2 and 9.6 mg orally or between 1 and 3 mg subcutaneously or intravenously. If another patient who also receives hydromorphone therapy receives a dose of 8 mg per day, the amount needed to effectively treat breakthrough pain attacks may be, e.g., in the range of 0.8 to 2.4 mg orally or between 0.2 and 0, 5 mg intravenously.

[0079] With respect to the exact amount of opioid that will be required to successfully treat a breakthrough pain attack, one of skill in the art will consider various factors. As outlined above, one of the factors will be the total daily amount you take to control your baseline pain. This total amount will usually be the dosage amount that is taken orally for a period of 24 hours, and 10 to 30% of this dose will be a good first estimate for the treatment of breakthrough pain by the oral route. However, in this range of 10 to 30%, the specific amount may depend on the frequency and severity of the breakthrough pain attacks, and when administered subcutaneously using a needle-free subcutaneous injection drug delivery device this amount will often be less.

[0080] The skilled person is well acquainted with measuring both the frequency and severity of breakthrough pain attacks in clinical trials. The design of such clinical trials is described in detail in e.g. Portenoy et al. (The Journal of Pain (2006) 7 (8): 583-591). From this publication, it can be seen that for non-cancer patients with chronic controlled pain, most patients with breakthrough pain attacks will typically occur at a frequency of about 2.4 attacks per day. In addition, Table 2 of this publication provides an appropriate overview of the various pain symptoms that may be classified as breakthrough pain attacks. The skilled artisan will also know the type of clinical trial and design of such clinical trial to determine controlled baseline pain and breakthrough pain attacks. Typically, a specialist in the field will design a study for a group of about 15 to 100 people. However, 20 patients may be sufficient. These patients are recruited for this study based on certain inclusion and exclusion criteria that are in line with the recommendations of regulatory bodies such as FDA and EMEA. A suitable review of typical inclusion criteria such as age, gender, height, body weight, physical condition, type and frequency of treatment, etc. can be found in the above references.

[0081] It has previously been found that one of the advantages of using opioid formulations in a needle-free drug delivery device is that abuse of opioid formulations is less likely, given that it is more difficult to isolate opioid formulations from such a device.

[0082] In order to further reduce the potential for abuse of such formulations, an additional container containing opioid antagonists such as naltrexone, naloxefene, nalmefene, nalorphine, nalbuphine, naloxonazine, methylnaltrexone, ketylcyclazococin, norbinaltorfimine, naltrindole, 6- b-naloxol and 6b-naltrexol or their pharmaceutically acceptable salts, according to the above-mentioned two-chamber approach. Thus, the opioid and antagonist formulations are separated and only come into contact if anyone illegally attempts to disassemble the pen-type pen and / or damage the container to isolate the opioid formulation. This approach prevents the isolation of opioids without an antagonist and thus parenteral abuse. [0083] Particularly preferred antagonists include naltrexone, nalmefene and naloxone. Naloxone and its hydrochloride are particularly preferred as the antagonist.

[0084] The skilled person is well aware that the opioid formulation to be administered using the pen-type pen should not normally contain significant amounts of opioid antagonists, as this would result in withdrawal symptoms instead of effective treatment of breakthrough pain.

[0085] However, in one embodiment, the introduction into the pen system and / or container of pharmaceutical compositions containing opioids, in particular opioids such as tramadol, dihydrocodeine, oxycodone, morphine, hydromorphone, oxymorphone, nalbuphine, etorphin, dihydroetorphine, fentanyl, sulfentanyl, remifentanyl and buprenorphine, together with opioid antagonists such as naltrexone, naloxone, nalmefene, nalorphine, nalbuphine, being a μ receptor antagonist and an κ receptor agonist, naloxonazine, methylnaltrexone, ketylcyclazocin, norbinaltorfimine, naltrindole, 6-bnaloxol and 6-b-naltrexol, or pharmaceutically acceptable salts thereof, in one preparation. [0086] This can be considered if the formulation contains very small dosed amounts of antagonist, namely 10⁵ up to 10⁹ less antagonist than opioid agonist. Such very low antagonist doses would not cause withdrawal symptoms or affect the effectiveness of pain treatment, but may limit the development of tolerance and / or hyperalgesia (Burns et al. (2005) Recent developments in pain research: 115-136). In this context, peripherally acting antagonists, alvimopane and methylnaltrexone, may be particularly beneficial because they should also be able to counteract constipation and vomiting. Furthermore, if opiate opioid antagonists such as methylnaltrexone or alvimopane are selected or alternatively peptide based opioid receptor antagonists, almost no reduction in analgesic efficacy will be seen.

[0087] As described above, one of the objects of the present invention is the use of the above-mentioned opioid preparations of tramadol, dihydrocodeine, oxycodone, morphine, hydromorphone, oxymorphone, nalbuphine, etorphine, dihydroethorphine, fentanyl sulfentanyl, remifentanyl and buprenorphine, in the abovementioned amounts a drug delivery device that is suitable for injecting the pharmaceutical composition through the surface of the skin into a human or animal body. Such a needle-less injection device can then be used to treat breakthrough pain attacks.

[0088] Thus, one embodiment of the present invention also relates to at least one opioid in the abovementioned amounts for use in the treatment of breakthrough pain, wherein the at least one opioid in the abovementioned amounts is administered through the skin surface to the human or animal body using a needle-free device for delivering a drug that is suitable for injecting a drug through the skin surface into a human or animal body.

[0089] The use of opioids such as tramadol, dihydrocodeine, oxycodone, morphine, hydromorphone, oxymorphone, nalbuphine, etorphine, dihydroethorphine, fentanyl, sulfentanyl, remifentanyl and buprenorphine, in the above-mentioned types of injection, is used in the above-indicated pen types.

[0090] First of all, bouts of breakthrough pain are not treated with oral preparations, which, as described above, may not provide a fast enough onset of action. At the same time, the disadvantage of parenteral use resulting from the use of needle technique is avoided. Thus, because of the ease of use of such needle-less pen-type injection devices, the patient can take the drug with them and inject it at any time and place, whenever and where necessary. In addition, if the pen injection device allows repeated use or dose adjustment, drug administration can be appropriately tuned to the frequency and severity of pain attacks. On the other hand, if the frequency and severity of pain attacks is often known (see Portenoy et al. Publications above), the patient may use a disposable pen single-use injection device containing opioid preparations and administer them at a predetermined dose.

[0091] The skilled artisan will recognize that depending on whether or not such a formulation is administered repeatedly, for example, it may be necessary and recommended that it contain a preservative such as, for example, benzalkonium chloride or other known preservatives that are commonly used in reusable pen injectors, such as benzyl chloride.

[0092] In addition to the above-mentioned embodiments, the present invention also relates to a method of treating breakthrough pain in a patient in need thereof, wherein the patient is administered opioid formulations using a needle-free drug delivery device that is suitable for injecting a drug through the skin surface into the human body or animal.

[0093] For all of the above described embodiments of the invention, it should be emphasized that the use of hydromorphone and oxycodone as opioid analgesics is preferred. It is also understood that the use of liquid opioid preparations will now be advantageous in a needle-free drug delivery device.