RU2575906C2 - Automatic injector - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine and may be used to provide a subcutaneous injection of a substance into a user. An automatic injector comprises a body having an open first end and a second end, and a syringe movable in the body. The syringe comprises a sleeve portion for the substance, a hollow needle and a plug for sealing the sleeve portion and supplying pressure selectively onto the substance to force the substance to flow into the hollow needle. A piston for advancing the syringe comprises a rod connected at the first end to the plug, a compressible expanded centre and a flange between the second end of the rod and the compressible expanded centre. A bias mechanism for displacing the piston to the first open end of the body surrounds the second end between the flange and second end of the body.

EFFECT: injector enables the patient to introduce medicinal products independently.

12 cl, 27 dwg, 10 tbl

Description

Technical field

The present invention relates to an injection device for injecting a substance, such as a drug, to a patient.

State of the art

One of the most common routes of drug administration is through injection, such as intravenous, subcutaneous or intramuscular injection. A syringe containing the drug is used for injection, which is usually given by trained medical personnel. In certain cases, the patient is prepared to use a syringe to enable self-injection. In addition, certain drugs are formulated into pre-filled syringes for use by the patient to avoid the need for the patient to fill the syringe. However, some patients may be reluctant to conduct an independent injection, especially if the patient is afraid of injections with needles.

Automatic injection devices provide an alternative to a syringe for drug delivery. Automatic injection devices have been used, for example, to deliver drugs under emergency conditions, such as to administer epinephrine to counteract the effects of severe allergic reactions, such as those caused by food allergies. Automatic injection devices have also been described for use in administering antiarrhythmic drugs and selective thrombolytic agents during a heart attack (see, for example, US Pat. Nos. 3,910,260, 4,045,777, 4,689,042, 4,755,169 and 4,795,433). Various types of automatic injection devices are also described, for example, in US patent No. 3941130, 4261358, 5085642, 5092843, 5102393, 5267963, 6149626, 6270479 and 6371939.

In general, prior automatic injection devices during operation cause the syringe needle to move forward and extend from the protective housing in front of the syringe drive to expel a dose of fluid through the needle. Moving the syringe in the direction of the patient’s skin so that the needle exits the syringe before increasing the pressure of the fluid filling the syringe helps prevent dripping of fluid from the needle before the actual injection occurs.

Such previous automatic injection devices have several drawbacks. For example, previous devices include a naked needle, which the patient must insert into his body, which in most patients causes concern and anxiety, in particular, in those patients who have a “needle phobia”. Previous devices are also difficult for patients to use, maintain their unpolluted state and / or provide an accurate dosage of the drug. In addition, patients with chronic autoimmune diseases, such as rheumatoid arthritis, as well as elderly and physically weak patients, may not be able to independently conduct biological treatment using existing injection devices. Therefore, there is a need for such devices for the delivery of self-administered drugs that patients can safely use, and which facilitate compliance by patients with the prescribed biological therapy regimens.

TNFα inhibitors are effective agents for the treatment of autoimmune disorders, such as rheumatoid arthritis, psoriatic arthritis, and Crohn's disease. Such inhibitors, which include biological agents, such as antibodies, fusion proteins, are usually delivered by injection. For example, a TNFα adalimumab inhibitor (HUMIRA®, Abbott Laboratories, Lake County, Illinois) has been marketed as a pre-filled syringe for self-administration by patients, and therefore appears to be an important candidate for use using advanced automatic injection devices and methods.

SUMMARY OF THE INVENTION

The present invention provides improved devices, its components and methods for administering injectable medications to a patient. In one embodiment, the invention provides an automatic injection device for ejecting a dose of a liquid drug from a syringe needle movably located inside the device body. Before use, the syringe according to the invention is in a retracted position inside the housing. During the first operating stage, initiated by pressing the start button, the drive pushes the syringe towards the proximal end of the housing to extend the syringe needle from the proximal end. At this first working stage, the drive causes the needle to be inserted into the subcutaneous region of the user when the proximal end of the device abuts the injection site. In a second working step, the actuator, which may be the same or different component as the actuator, which causes the needle to be inserted, expels the fluid located in the syringe into the subcutaneous region.

The automatic injection device of the invention can be used to inject a dose of a tumor necrosis factor-α inhibitor (TNFα) to treat any number of diseases, including rheumatoid arthritis, psoriasis, Crohn’s disease, psoriatic arthritis and juvenile rheumatoid arthritis. In one embodiment, the patient has a disorder in which TNFα has a deleterious effect selected from the group consisting of rheumatoid arthritis, psoriasis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis and juvenile rheumatoid arthritis.

The automatic injection device may include a window to enable the user to visualize the contents and / or level of the contents of the syringe. In addition, the automatic injection device may include an indicator to indicate completion of the injection. A “prototype” or auto-injection training demonstration device may also be provided to prepare a user for use of an automatic injection device for injecting a substance without actually injecting the substance to the user.

The invention provides an automatic injection device for providing a subcutaneous injection of a substance to a user or patient, comprising a body having an open first end and a second end, a syringe movably located in the body, the syringe including a sleeve portion for containing the substance, a hollow needle in fluid communication with the sleeve part for expelling the substance from the syringe, and a plug for sealing the sleeve part and selectively applying pressure to the substance to force it to move through the hollow needle, the syringe of the drive of the syringe for the first movement of the syringe towards the first end of the body so that the needle protrudes from the first end and for the subsequent supply of pressure to the plug, the syringe drive component includes a blower for selectively applying pressure to the plug, a compressible expanded central part and a flange between a second end of the syringe drive component and a compressible expanded central portion and a first biasing mechanism for biasing the syringe drive component toward the first open end of the housing, the first a biasing mechanism is located between the flange of the syringe drive component and the second end of the housing.

In one embodiment, the automatic injection device further includes a start button located on the housing for actuating a syringe drive component. In another embodiment, the automatic injection device includes a start button connected to the housing to actuate a syringe drive component.

In another embodiment, the automatic injection device further includes a latch actuated by a start button to latch the syringe drive component in the retracted position before the start button is actuated.

The invention also includes an automatic injection device for providing a subcutaneous injection to a user, comprising a body having an open first end and a second end, a syringe movably located in the body, the syringe including a sleeve portion for containing a substance, a hollow needle in fluid communication with the sleeve portion for pushing the substance out of the syringe, and a stopper for sealing the sleeve part and selectively applying pressure to the substance to force it to move through the hollow needle, a drive for selective transfer moving the syringe towards the first end of the body so that the needle protrudes from the open first end of the body and the drive to push the substance out of the syringe after moving the syringe towards the open first end of the body. The first removable cap may cover the first end of the housing.

The drive may include a first biasing mechanism, a second biasing mechanism, a plunger-type syringe drive and / or other drive means.

In one embodiment, the automatic injection device further includes a dose of a substance, for example, a TNFα inhibitor, loaded into the sleeve of the syringe.

The invention includes an automatic injection device for providing subcutaneous injection of a substance to a user, comprising a body having an open first end, a second end and a window located in a side wall to visualize the internal cavity of the body, a syringe movably located in the body, the syringe including a sleeve portion for holding substances, a hollow needle in fluid communication with the sleeve part for expelling the substance from the syringe, and a plug for sealing the sleeve part and selective pressure supply on the substance to force it to move through the hollow needle, a drive for selectively moving the syringe towards the first end of the body so that the needle protrudes from the open first end of the body and a drive for pushing the substance out of the syringe after moving the syringe towards the open first end of the body .

In one embodiment, the window has a substantially keyhole shape. In yet another embodiment, the window includes a fill line at some position in the window to indicate the full dose of the substance.

The invention further provides an automatic injection device for providing subcutaneous injection to a user, comprising a body having an open first end and a second end, a syringe movably located in the body, the syringe including a sleeve portion for containing a substance, a hollow needle communicating in fluid with a sleeve part, for expelling the substance from the syringe, and a stopper for sealing the sleeve part and selectively applying pressure to the substance to force it to move through the hollow needle, the component an ode of a syringe for selectively applying pressure to the plug, the syringe actuator component comprising a supercharger configured to be inserted into the sleeve of the syringe, a compressible expanded central portion, and an indicator located between the compressible expanded central portion and the second end of the syringe drive component to indicate when ejection has been performed the contents of the syringe.

The invention includes an automatic injection device for providing a subcutaneous injection of a substance to a user, comprising a housing having an open first end, a second end and having a window formed in its side wall, a syringe movably located inside the housing to place and selectively expel the substance from the open first end; and

an indicator that aligns with the window in the side wall when the syringe is essentially empty of the substance.

Another aspect of the invention includes an automatic injection device, comprising a housing having a substantially tubular configuration, with an open first end and a second end; a syringe movably located inside the body, the syringe containing a dose of a substance, for example, a TNF inhibitor, where the syringe is moved inside the body for injection of the TNF inhibitor to the user.

In one embodiment, the automatic injection device further includes an indicator to indicate when a substance, such as a TNF inhibitor, has been pushed out of the syringe.

In one embodiment, the automatic injection device further includes a window formed in the housing to allow visualization of the internal cavity of the housing.

In one embodiment, the automatic injection device further includes an indicator that aligns with a window in the side wall when a substance, such as a TNF inhibitor, has been pushed out of the syringe.

Another aspect of the invention is an automatic injection device for providing subcutaneous injection of a substance to a user, comprising a housing having an open first end and a second end, a plunger comprising a rod configured to connect at the first end to a syringe plug compressible by the expanded center portion and the flange between the second rod end and compressible expanded center portion; and a biasing mechanism for biasing the plunger toward the first open end of the housing, a biasing mechanism located around the second end of the shaft between the flange and the second end of the housing.

In one embodiment, the automatic injection device further includes a start button located on the housing for actuating the plunger.

In one embodiment, the automatic injection device further includes a latch actuated by a start button to latch the plunger in the retracted position before being actuated by the start button.

In one embodiment, the automatic injection device further includes a window on the housing for visualizing the interior cavity of the housing.

In yet another embodiment, the automatic injection device further includes an indicator to indicate emptying of the syringe.

In another embodiment, the automatic injection device includes a syringe containing a dose of a substance, such as a TNF inhibitor, to be injected to a user.

In yet another embodiment, the automatic injection device includes a removable cap to cover one of the first end and the second end of the housing.

In another embodiment, the invention provides an automatic injection device, further comprising a sheath of a needle that advances along a needle protruding through a first end after expelling the substance from the syringe.

The invention describes an automatic injection device comprising a dose of a TNFα inhibitor, for example adalimumab. In one embodiment, the automatic injection device further includes a dose of a TNF inhibitor loaded into the sleeve portion of the syringe.

The invention includes a housing for an automatic injection device, comprising a hollow, essentially tubular casing, including an open first end, and a second end, the hollow essentially tubular casing configured to receive the syringe by sliding inside the casing; a first stopper on the inner surface of the housing to limit the movement of the syringe in the first direction, and a second stopper on the inner surface of the housing to limit the movement of the syringe in the second direction.

In one embodiment, the housing further includes a protrusion formed between the open first end and the first stopper to seat the biasing mechanism for mixing the syringe away from the first end of the housing. In one embodiment, the housing also includes a window formed in the side wall of the housing to allow visualization of the internal cavity of the housing. In one embodiment, the housing further includes a start button located on the second end of the tubular casing for selectively actuating the syringe to move from the first retracted position to the second protruding position in which the syringe needle projects from the first end, and while the syringe is in a second, protruding position, applying pressure to expel the substance from the syringe.

The invention also includes a syringe for use in an automatic injection device, comprising a sleeve portion for containing a substance; a hollow needle in fluid communication with the sleeve portion; a plug for sealing the sleeve portion, the plug being displaceable inside the sleeve portion to increase pressure inside the sleeve portion to force the substance to move through the hollow needle; a first stopper formed on the intermediate portion of the sleeve portion for stopping the stopper in the housing of the automatic injection device to restrict the movement of the syringe in the first direction; and a second stopper formed at the distal end of the sleeve portion to restrict the movement of the syringe relative to the body of the automatic injection device in the second direction. In another embodiment, stoppers may be formed at other locations throughout the sleeve.

In one embodiment, the syringe further includes a plunger first to selectively move the syringe toward the open first end of the casing of the automatic injection device, so that the needle protrudes from the first end, and subsequently pressurizes the cork in order to eject syringe through a hollow needle.

In one embodiment, the plunger includes a rod connected at the first end to a plug and a compressible expanded central portion. In another embodiment, the plunger further includes an indicator to indicate when the syringe has expelled substantially all of the material through the cannula. In one embodiment, the syringe also includes a dose of a TNF inhibitor loaded into the sleeve portion of the syringe.

The invention further provides a syringe drive component for an injection device comprising a rod portion having a first end, a second end and a compressible expanded central portion, and a blower formed at the first end of the rod portion to apply pressure to the syringe tube.

In one embodiment, the syringe drive component further includes a fastening portion formed at a second end of the shaft portion for attaching the coil spring to the syringe drive component. In one embodiment, the syringe drive component further includes an indicator for indicating completion of an injection formed in the solid core portion between the compressible expanded central portion and the second end of the stem portion. In one embodiment, the syringe actuator component further includes a holding flange for holding the coil spring in a compressed position prior to actuation. In one embodiment, the syringe actuator component further includes a spring base for a coil spring extending between the fastening end and the holding flange. In one embodiment, the spring base includes flexible struts near the spring coils. In another embodiment, the fastening end includes supports with ears extending from the base and configured to engage in a snap engagement with a start button.

The invention further provides a manufactured article comprising packaging material and an automatic injection device comprising a TNFα inhibitor. In one embodiment, the TNFα inhibitor comprises adalimumab. In one embodiment, the dose of adalimumab is 40 mg. The manufactured product may also include an alcohol swab to prepare the skin area for injection and / or a dose tray for placing the automatic injection device.

The invention also provides a manufactured article comprising an automatic injection device having a pre-filled syringe containing a dose of a TNFα inhibitor; and an alcohol swab for preparing a skin site for injection, packaged with instructions for use for treating arthritis by injecting a dose into a user's skin using an automatic injection device.

The invention also includes a method of injecting a substance, comprising the steps of providing an automatic injection device comprising a case having an open first end, a second end, a syringe movably located inside the case, containing a substance, a cap covering the first end, and a cap covering the start button at the second end ; removal of the first cap; removing the second cap to provide access to the start button; the location of the open first end of the device in contact with the skin of the user; pressing the start button in order to cause the syringe needle to extend from the open first end and into the skin of the user and subsequently push the substance through the needle into the subcutaneous region of the user; and removing the device after expelling the substance.

In one embodiment, the automatic injection device is held at an angle of about 90 degrees relative to the surface of the user's skin. In one embodiment, the indicator provides the user with an indication when the syringe is substantially empty of the substance. In one embodiment, the substance loaded into the syringe is a dose of a TNF inhibitor.

In yet another embodiment of the invention, the method includes (a) placing an automatic injection device in an injection site on a surface of a user's skin; (b) activating an activation mechanism to initiate an injection of a substance to a user; (c) maintaining the activation mechanism for a prescribed period of time to continue injecting the substance; and (d) removing the automatic injection device from the injection site after passing the prescribed period of time.

In yet another embodiment of the invention, the method includes (a) locating an automatic injection device at the injection site; (b) activating an activation mechanism to initiate an injection of a substance to a user; (c) maintaining the activation mechanism to continue the injection of the substance until a visible indicator of completion of the injection is detected; and (d) removing the automatic injection device from the injection site after detecting a visible indicator of completion of the injection.

The invention also describes a method for preparing a recipient for use of an automatic injection device.

One aspect of the invention includes a device for preparing a recipient for use of an automatic injection device, comprising a housing having a window, a start button at a first end of the housing; and an indicator movably located inside the housing, the indicator being aligned with the housing window after the user presses the start button.

In one embodiment, the device further includes an inclusion component for selectively moving the indicator from a hidden position to a position aligned with the window. In one embodiment, the inclusion component includes a rod having a fastening portion at a first end that is latched by a start button, a flanged portion for holding the biasing mechanism toward the first end of the housing, and where an indicator is formed between the second end of the rod and the flanged portion.

The invention also provides a kit for preparing a recipient for use of an automatic injection device, wherein the automatic injection device includes a needle and a drug, the kit including: (a) a demonstration automatic injection device in which there is no needle and drug; and (b) instructions for using the automatic injection device.

In one embodiment, the instructions inform the recipient of a method for using a demonstration automatic injection device, the method comprising: (a) locating the automatic injection device at the injection site; (b) activating a drive mechanism to initiate drug injection; (c) maintaining the activation of the drive mechanism for a prescribed period of time to continue the injection of the drug; and (d) removing the automatic injection device from the injection site after the prescribed time period has elapsed.

In one embodiment, the prescribed time period is 10 seconds. In another embodiment, the prescribed period of time is at least 10 seconds.

In another embodiment, the instructions also inform that the initial activation of the drive mechanism is accompanied by an audible sound. In another embodiment, the instructions also inform that completion of the drug injection is accompanied by a visible completion indicator.

In one embodiment, the instructions also inform that the injection site can be sterilized before placing the automatic injection device in the injection site.

In one embodiment, the instructions further inform that the automatic injection device must be examined to determine the appropriate dosage and formulation of the drug before placing the automatic injection device in the injection site.

In one embodiment, the instructions also convey to the recipient at least one message selected from the group consisting of messages that: (a) using an automatic injection device is less painful than using a pre-filled syringe; (b) the use of an automatic injection device by patients is preferred over a pre-filled syringe; (c) it is easier for the patient to use an automatic injection device than a pre-filled syringe; (d) it is more convenient for the patient to use an automatic injection device than a pre-filled syringe; (e) an automatic injection device reduces anxiety in patients who are afraid of needles compared to a pre-filled syringe because the needle is not visible in the device; and (f) an automatic injection device is designed for ease of use from the initial use of the device.

In one embodiment, the recipient is a doctor who prescribes a drug. In another embodiment, the recipient is a patient who is taking the drug. In yet another embodiment, the recipient is a caregiver, such as a family member.

The invention also includes a demonstration automatic injection device, including

a housing having an open first end, a second end, and having a window formed in its side wall, a syringe movably located inside the housing; an actuating mechanism associated with the syringe for squeezing the syringe; and an indicator that aligns with the window in the side wall when the syringe is fully squeezed.

The invention describes an audiovisual device for advertising to a recipient an automatic injection device containing a drug, the device transmits to the recipient at least one message selected from the group consisting of messages that: (a) the use of the automatic injection device is less painful, than using a pre-filled syringe; (b) the use of an automatic injection device by patients is preferred over a pre-filled syringe ;; (c) it is easier for the patient to use an automatic injection device than a pre-filled syringe; (d) it is more convenient for the patient to use an automatic injection device than a pre-filled syringe; (e) an automatic injection device reduces anxiety in patients who are afraid of needles compared to a pre-filled syringe because the needle is not visible in the device; and (f) an automatic injection device is designed for ease of use from the initial use of the device.

The invention also includes an audiovisual device or printed material for preparing a recipient for use of an automatic injection device, wherein the automatic injection device includes an actuation mechanism and a medicament, the audiovisual device instructing: (a) to position the automatic injection device at the injection site; (b) turn on the actuation mechanism to initiate drug injection; (c) support the activation mechanism for a prescribed period of time to continue the injection of the drug; and (d) remove the automatic injection device from the injection site after the expiration of the prescribed period of time.

The invention also includes an audiovisual device or printed material for preparing a recipient for use of an automatic injection device, wherein the automatic injection device includes an actuation mechanism and a medicament, the audiovisual device instructing: (a) to position the automatic injection device at the injection site; (b) turn on the actuation mechanism to initiate drug injection; (c) maintain the activation mechanism for a prescribed period of time to continue the injection of the drug until a visible indicator of completion of the injection is detected; and (d) remove the automatic injection device from the injection site when a visible indicator of completion of the injection is detected.

The invention also provides a method for preparing a recipient for use of an automatic injection device, wherein the automatic injection device includes an actuation mechanism and a drug. In one embodiment, the method includes instructing the recipient to: (a) position the automatic injection device at the injection site; (b) turn on the actuation mechanism to initiate drug injection; (c) support the activation mechanism for continued drug injection until a visible indicator of completion of the injection is detected; and (d) remove the automatic injection device from the injection site when a visible indicator of completion of the injection is detected.

In one embodiment, the automatic injection device includes an indicator window, and the visible indicator of completion of the injection includes a color indicator, such as yellow, appearing in the indicator window.

In one embodiment, the instructions also report that initial activation of the activation mechanism is accompanied by an audible sound.

In one embodiment, the instructions also report that activation of the activation mechanism is maintained for a prescribed period of time, such as 10 seconds, to continue the injection of the drug. In one embodiment, the instructions further advise that the injection site should be sterilized before the automatic injection device is located at the injection site.

In one embodiment, the instructions also report that the automatic injection device must be examined to determine the appropriate dosage and formulation of the drug before placing the automatic injection device in the injection site.

In another aspect, the invention relates to a method for preparing a user to use an automatic injection device, wherein the automatic injection device includes a needle and a drug, the method comprising providing the user with: (a) a demonstration automatic injection device that does not have a needle and a drug; and (b) instructions for use of the automatic injection device.

In yet another aspect, the invention relates to a kit for preparing a recipient for use of an automatic injection device comprising a needle and a drug, the kit comprising: (a) a demonstration or “training” automatic injection device in which there is no needle and drug; and (b) instructions for use of the automatic injection device.

In another aspect, the invention relates to a method for preparing a recipient for use of an automatic injection device, wherein the automatic injection device includes an actuation mechanism and a medicament. The preparation method includes instructing the recipient to: (a) position the automatic injection device in the injection site; (b) turn on the actuation mechanism to initiate drug injection; (c) support the activation mechanism for a prescribed period of time to continue the injection of the drug; and (d) remove the automatic injection device from the injection site after the expiration of the prescribed period of time.

Preferred prescribed activation times for the activation mechanism include 10 seconds, or activation of the activation mechanism for at least 10 seconds. In certain embodiments, the instructions also report that initial activation of the activation mechanism is accompanied by an audible sound. In certain embodiments, the instructions also report that completion of the drug injection is accompanied by a visible indicator of completion of the injection. In certain embodiments, the instructions further inform that the injection site should be sterilized before placing the automatic injection device in the injection site. In certain embodiments, the instructions further inform that the automatic injection device must be examined to determine the appropriate dosage and formulation of the drug before placing the automatic injection device at the injection site.

In another aspect, the invention relates to a method for preparing a recipient for use of an automatic injection device, wherein the automatic injection device includes an actuation mechanism and a medicament. The preparation method includes instructing the recipient to: (a) position the automatic injection device in the injection site; (b) turn on the actuation mechanism to initiate drug injection; (c) support the activation mechanism for continued drug injection until a visible indicator of completion of the injection is detected; and (d) remove the automatic injection device from the injection site when a visible indicator of completion of the injection is detected.

In a preferred embodiment, the automatic injection device includes an indicator window, and the visible indicator of completion of the injection includes a color indicator that appears in the indicator window. The color indicator may be, for example, a yellow indicator.

In one embodiment, instructions are provided in a printed document or in an audiovisual device. In another embodiment, the audiovisual device is a home video system (VHS) cassette or a digital video disc (DVD). In one embodiment, instructions are communicated orally to the recipient.

In one embodiment, the recipient is a doctor who prescribes a drug. In one embodiment, the recipient is a patient who is taking the drug.

The invention also includes a manufactured product, including packaging material; TNFα inhibitor such as adalimumab; and a label or package insert inside the packaging material indicating that studies of a TNFα inhibitor using the automatic injection device of the invention to treat a disorder in which a TNFα inhibitor has a deleterious effect, such as rheumatoid arthritis, are the most common side effects ( AE) were bronchitis, hypersensitivity, arthritic pain, cough and rhinitis.

The invention also provides a manufactured product, including: packaging material; an automatic injection device, for example a pen-shaped auto-injector filled with a TNFα inhibitor; and a package label or liner contained within the packaging material indicating that the bioequivalence of the TNFα inhibitor is the same regardless of whether the injection site is a hip or abdomen.

A manufactured article of the invention may include a label. In one embodiment, the label of the invention indicates how a TNFα inhibitor, for example, an anti-TNF inhibitor antibody, or an antigen binding portion thereof, is packaged as a manufactured article. In one embodiment, the label of the invention indicates a TNFα inhibitor, for example, an anti-TNF inhibitor antibody, or an antigen binding portion thereof, is dispensed in a cardboard box containing 6 alcohol swabs to prepare the skin for injection and 6 dose trays (for example, labeled “Initial” packaging for the treatment of Crohn’s disease ”). In another embodiment, the label indicates that each dose tray consists of a disposable pen, each pen containing a pre-filled 1 ml glass syringe with a fixed ½ inch 27-gauge needle that provides 40 mg (0.8 ml) TNFα inhibitor.

The present invention relates to automatic injection devices for administering drugs and, in particular, relates to compositions and methods for promoting the use of such agents and to compositions and methods for preparing users (eg, patients and medical personnel) for using such devices. The invention is based, at least in part, on the results of a clinical study comparing an automatic injection device for administering adalimumab (HUMIRA®) with a pre-filled syringe for administering adalimumab (HUMIRA®). The study revealed numerous advantageous features of an automatic injection device and identified certain aspects of the use of the device that should be highlighted when preparing an individual for use of the device.

Accordingly, in one aspect, the invention relates to a method for attracting a recipient to use an automatic injection device comprising a drug. The method includes transmitting to the recipient at least one message selected from the group consisting of messages that:

(a) using an automatic injection device is less painful than using a pre-filled syringe; (b) the use of an automatic injection device by patients is preferred over a pre-filled syringe; (c) it is easier for the patient to use an automatic injection device than a pre-filled syringe; (d) it is more convenient for the patient to use an automatic injection device than a pre-filled syringe; (e) an automatic injection device reduces anxiety in patients who are afraid of needles compared to a pre-filled syringe because the needle is not visible in the device; and (f) an automatic injection device is designed for ease of use from the initial use of the device.

In a preferred embodiment, the recipient is informed that using an automatic injection device is less painful than using a pre-filled syringe, for example, that 80% of patients in a clinical trial rated the automatic injection device as less painful than a pre-filled syringe. In another preferred embodiment, the recipient is informed that using an automatic injection device is less painful than using a pre-filled syringe, for example, 90% of patients in a clinical trial rated the automatic injection device as less painful than a pre-filled syringe.

In a specific embodiment, a message is sent to the recipient that the automatic injection device comprises a five-chamfered needle, compared to a three-chamfered needle for a prefilled syringe.

In another aspect, the invention relates to an audiovisual device for attracting a recipient to use an automatic injection device comprising a medicament, the device transmitting to the user at least one of the above message. In the methods and compositions of the invention, engaging messages or preparation instructions may be conveyed to the recipient, for example, orally and / or in writing. Alternatively or in addition, the audiovisual device is a home video system (VHS) cassette or a digital video disc (DVD).

In the methods of the invention, the recipient of the attracting message or preparatory instructions may be, for example, a doctor who prescribes the drug, a patient who takes the drug, or a person who cares for the patient.

In the methods and compositions of the invention, the automatic injection device preferably provides subcutaneous injection of the drug. Preferred embodiments of an automatic injection device are described herein.

The automatic injection device used in the methods and compositions of the invention may include a substance or drug, which is, for example, an antibody, cytokine, vaccine, fusion protein, or growth factor. In a preferred embodiment, the drug is a TNFα inhibitor (for example, an anti-TNF antibody or antigen binding portion thereof, a TNF fusion protein or a recombinant TNF binding protein), such as infliximab (Remicade ^™ , Centocor, Horsham, PA), CDP 571 , CDP 870, anti-TNF dAb, golimumab, adalimumab, etanercept (Enbrel ^™ , Amgen, California), p55TNFRIgG (Lenercept) or r-TBP-1. A particularly preferred drug for use in an automatic injection device is adalimumab (HUMIRA®). Another particularly preferred drug for use in an automatic injection device is an isolated human antibody that dissociates from human TNFα at K _d 1 × 10 ^-8 M or less and a rate constant K _off 1 × 10 ^-3 s ^-1 or less, both determined by plasmon surface resonance, and neutralizes the cytotoxicity of human TNFα in a standard in vitro L929 assay at an IC _{50 of} 1 × 10 ^-7 M or less. In one embodiment, the automatic injection device, including its uses and compositions, comprises a dose of a TNFα inhibitor.

In one embodiment, the anti-TNFα antibody or antigen binding portion thereof is selected from the group consisting of a chimeric antibody, a humanized antibody, a human antibody, and a multivalent antibody.

In one embodiment, the anti-TNFα antibody is an isolated human antibody or an antigen binding portion thereof with the following characteristics: a) dissociates from human TNFα at a rate constant K _{off of} 1 × 10 ⁻³ s ⁻¹ or less, as determined by surface resonance plasmon; b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or is modified from SEQ ID NO: 3 by substituting one alanine at position 1, 4, 5, 7 or 8, or from one to five conservative amino acid substitutions at positions 1 , 3, 4, 6, 7, 8 and / or 9; and c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or is modified from SEQ ID NO: 4 by substituting one alanine at position 2, 3, 4, 5, 6, 8, 9, 10, or 11, or from one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and / or 12.

In one embodiment, the anti-TNFα antibody is an isolated human antibody or antigen binding portion thereof, the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1, and the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2.

In one embodiment, the anti-TNFα antibody or antigen binding portion thereof is selected from the group consisting of infliximab, golimumab and adalimumab.

In one embodiment, the TNFα inhibitor is selected from the group consisting of infliximab, CDP 571, CDP 870, anti-TNF dAb, golimumab, adalimumab, etanercept, p55TNFRIgG and r-TBP-1.

In one embodiment, the substance that is loaded into the automatic injection device is a formulation comprising adalimumab, sodium chloride, monobasic sodium dihydrogen phosphate, dibasic sodium dihydrogen phosphate, sodium citrate, citric acid monohydrate, mannitol, polysorbate 80 and water.

In one embodiment, an automatic injection device is used to deliver to the user an anti-TNFα antibody or antigen binding portion thereof, the administration being 2 times / day or multiple variable doses.

Brief Description of the Drawings

The previous and other objects, features and advantages of the present invention, as well as the invention itself, will be more fully understood from the following description of preferred embodiments when read along with the accompanying drawings, in which:

Figure 1 is a perspective view of an automatic injection device in accordance with an illustrative embodiment of the invention.

2 is an exploded view of an automatic injection device in accordance with an illustrative embodiment of the invention.

Figure 3 is a schematic sectional view of an automatic injection device of one embodiment of the invention before use.

FIG. 4 is a schematic sectional view of the automatic injection device of FIG. 3 during a subsequent operation step.

Figure 5 is a schematic sectional view of the automatic injection device of Figure 3 during the final stage of operation.

6 illustrates an embodiment of an automatic injection device in accordance with one embodiment of the invention.

FIG. 7 is an exploded view of a trigger mechanism of an automatic injection device of FIG. 6 in accordance with an illustrative embodiment of the invention.

8A-8C are various views illustrating a distal component of the housing, a coil spring and a syringe trigger component of the trigger mechanism of FIG. 7 when assembled without a trigger button.

Fig.9 is a perspective view of a distal component of the housing of the trigger mechanism of Fig.7.

FIG. 10 is a perspective view of a syringe driving component of the trigger mechanism of FIG. 7.

11 is an exploded view of a syringe body kit of the automatic injection device of FIG. 6 in accordance with an illustrative embodiment of the invention.

FIG. 12 illustrates an embodiment of the syringe holder of the syringe body kit of FIG. 11.

Fig. 13 illustrates an embodiment of a casing with ledges of the syringe body kit of Fig. 11.

Fig. 14 illustrates an embodiment of a proximal cap of the syringe body kit of Fig. 11.

Figa and 15b are respectively a side view in perspective and side view in section of the assembled set of the casing of the spring of 11 in accordance with one embodiment of the invention.

16A and 16B are sectional views at 90 degrees apart from each other, illustrating an automatic injection device assembly where the syringe body kit and the trigger mechanism are connected together.

17 is a detailed view of the interface between the syringe body kit and the trigger mechanism of the automatic injection device of one embodiment of the invention, illustrating an indicator of the syringe actuating component in accordance with one embodiment of the invention.

Figures 18-22 are a sectional view of an automatic injection device in accordance with another embodiment of the invention.

23 is a detailed view of a display window of an automatic injection device in accordance with one embodiment of the invention.

24 illustrates the use of an automatic injection device of an illustrative embodiment to inject a drug, such as a TNF inhibitor, into the subcutaneous region of a user.

25 illustrates a diagram of an auto-injection pen for self-administration of adalimumab.

On Fig shows the results of the final analysis of patient preferences after the third visit.

On Fig illustrates the results showing the probability of switching to the handle, and the probability of recommending the use of the handle to others.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides automatic injection devices, their components and methods for injecting a patient with a substance, such as a liquid drug, to assist or cure a medical condition. In one embodiment, the automatic injection device is a pen, i.e. an autoinjector pen or a pen for autoinjection (interchangeably used in this document). The present invention also provides a demonstration or “training” automatic injection device that can be used to teach a patient how to use an automatic injection device.

The present invention also relates to automatic injection devices for administering substances (also referred to herein as drugs) and, in particular, relates to compositions and methods for attracting the use of such devices and to compositions and methods for preparing people to use such devices. The invention is based at least in part on the results of a clinical study comparing an automatic injection device for administering adalimumab (HUMIRA®) with a pre-filled syringe for administering adalimumab (HUMIRA®). The study, described in detail in this document in examples 1 and 2, revealed numerous advantageous features of the automatic injection device according to the invention and identified certain aspects of the methods of using the device that should be highlighted when preparing recipients for using the device.

I. Definitions

In order to make it easier to understand the invention, certain terms are defined below.

As used herein, the term “automatic injection device” (or “autoinjector”) is intended to mean a device that allows an individual (also referred to in this document as a user or patient) to independently administer a dosage of a substance such as a liquid drug, the device being different from the standard the syringe by turning on the mechanism for automatically delivering the drug to the individual by injection when the mechanism is turned on.

As used herein, the term “pre-filled syringe” is intended to mean a syringe that is filled with the drug immediately before the drug is administered to the individual, and a syringe that is filled with the drug and stored in this pre-filled form for a period of time before the drug is administered to the individual .

As used herein, the term “recipient” is intended to mean any person or individual who receives messages involving the use of the device of the invention, or instructions for preparing to use the methods and compositions of the invention described herein. Preferred recipients include physicians who prescribe the drug for administration by the automatic injection device, and patients who use the drug intended for administration by the automatic injection device, and their carers.

As used herein, the term “transfer to a recipient” is intended to mean any means by which a message involving the use of the device of the invention, or instructions for preparing to use the methods and compositions of the invention described herein, is transmitted or expressed to the recipient. Non-limiting examples of means of transmitting a message or instructions to the recipient include oral communication, written communication and communication through an audiovisual device.

As used herein, the term “initial use of an automatic injection device” is intended to indicate a first episode of use of an automatic injection device for administering a substance, such as a medicine, to an individual.

As used herein, the term “paper document” is intended to mean any document that contains a printed written message. Non-limiting examples of printed documents include brochures, leaflets, product inserts, posters, magnetic whiteboards, desktop information boards, and packaging labels.

As used herein, the term “audiovisual device” is intended to mean any device that is capable of communicating information in an audible or visible form. Non-limiting examples of audiovisual devices include home video system (VHS) cassettes, digital video discs (DVDs), CD-ROMS (compact discs containing data available for a computer), digital video cassettes, 8 mm or 35 mm transparencies, and computers that display files The Internet.

As used herein, the term “automatic demonstration injection device” or “preparation device” or “preparation” is intended to mean an automatic injection device that is used to demonstrate a procedure for using an automatic injection device, including inspection and sensation of using the device, but which does not suitable for administering a substance, for example a medicine, because it lacks one or more of the necessary components agents for administering a substance, for example a medicine, and / or a needle. In a preferred embodiment, the demonstration automatic injection device lacks a needle and a substance, for example a medicine, compared to the automatic injection device.

II. Automatic injection device

Below the invention will be described with respect to certain illustrative embodiments. Although the present invention has been described with respect to the use of a device for providing a subcutaneous injection of a dose of a TNF inhibitor, one skilled in the art will understand that the invention is not limited to the illustrative embodiment and that the injection device can be used to inject any suitable substance to the user. In addition, the components and method of use of the automatic injection device are not limited to the illustrative embodiments described below.

As used herein, the term “distal” refers to a part or end of an automatic injection device or component in an automatic injection device farthest from the injection site when the device is pressed against an individual’s skin for injection, or to simulate an injection. The term “proximal” refers to the part or end of an automatic injection device or component in an automatic injection device closest to the injection site on the user's body during the injection.

1 and 2 superficially illustrate an automatic injection device 10 suitable for subcutaneous injection of a dose of a substance, such as a liquid preparation, in accordance with an illustrative embodiment of the invention. The automatic injection device 10 includes a housing 12 for containing a container, such as a syringe, containing a dose of a substance to be injected into a patient, as described in detail below. The housing 12 preferably has a tubular configuration, although one skilled in the art will recognize that the housing 12 may be of any suitable size, shape, and configuration to accommodate a syringe or other container of the substance to be injected. Although the invention will be described with respect to a syringe mounted in a housing 12, one skilled in the art will recognize that any suitable container for storing and supplying the substance may be used in the automatic injection device 10.

In figure 2, the syringe is preferably slidably mounted in the housing 12, as described in detail below. In the non-activated position, the syringe is surrounded by a shell and retracted back inside the housing 12. When the device is actuated, the syringe needle projects from the first (proximal) end 20 of the housing 12 to allow the substance to be expelled from the syringe into the patient’s body. As shown, the first end 20 of the housing 12, i.e. the proximal end includes an opening 28 through which the syringe needle projects during actuation of the device 10.

1 and 2, the second (distal) end 30 of the housing 12, i.e. the distal end includes a start button 32 for actuating the syringe with movement from the enclosed position inside the housing 12 to the protruding position, and for subsequent ejection of the substance from the needle into the patient’s body. The housing 12 contains one or more actuators that perform the functions of moving the syringe and expelling the substance from the syringe.

The illustrative automatic injection device 10 shown in FIGS. 1 and 2 may also include a first removable cap 24 (or needle cap) to cover the first end 20 of the housing 12 to prevent exposure of the needle in the syringe before use. In an illustrative embodiment, the first cap 24 may include a spacer 26 for closing and / or coating the internal components of the device 10 until the user is ready to start the device 10. Alternatively, the first cap 24 may include a threaded screw portion, and the inner surface of the housing 12 at the opening 28 may include screw threads. In accordance with the provisions of the invention, you can use any connecting mechanism.

A second removable cap 34 (or starter cap) may cover the second end 30 of the housing 12 to prevent accidentally pressing the start button 32.

The second cap 34 may have a distinctive color for differentiating the first end 20 and the second end 30 of the device, although one skilled in the art will recognize that cap 34 and housing 12 may have any suitable color, size, and configuration.

In the illustrative embodiment of FIGS. 1 and 2, the housing 12 and caps 24 and 34 may further include graphic images, symbols and / or numbers to facilitate the use of the automatic injection device 10. For example, in the illustrative embodiment, the housing 12 includes an arrow 125 on the outer surface, pointing toward the first end 20 of the device, to indicate how the device 10 should be held relative to the patient’s skin surface (i.e., pressing the first end to the injection site), as shown in FIG. In addition, the first cap 24 is marked with the number “1” to indicate that the user should first remove the first cap 24 of the device, and the second cap is marked with the number “2” to indicate that the second cap 34 should be removed after removing the first cap 24 in preparation time for the subsequent injection using the illustrative automatic injection device 10. One skilled in the art will recognize that the automatic injection device 10 may have any suitable graphic images, with symbols and / or numbers to facilitate instruction of the user, or the automatic injection device may not be provided with such graphic images, symbols and / or numbers.

As shown in FIG. 2, the first end 20 of the housing 12 may have a larger diameter than the second end 30. The protrusion 29 may be formed at the junction between the two diameters to abut the cap 34 to facilitate the fit of the second cap 34 on the second end 30 of the housing.

As illustrated in figures 1 and 2, the housing 12 also preferably includes a display window 130 to enable the user to see the contents of the syringe contained within the housing 12, as described in detail below. The window 130 may include a hole in the side wall of the housing 12 or may include transparent material in the housing 12 to allow visualization of the internal cavity of the device 10.

The housing 12 may be made of any suitable surgical material, including, without limitation, plastic and other known materials.

FIGS. 3-5 are schematic views of the internal components of an automatic injection device 10 in accordance with one embodiment of the invention. As shown, a syringe 50 or other suitable substance container is located within the interior cavity of the housing 12. The illustrative syringe 50 includes a hollow sleeve portion 53 for containing a dose of a liquid substance to be injected. The illustrative sleeve portion 53 has a substantially cylindrical shape, although one skilled in the art will recognize that the sleeve portion 53 may have any suitable shape or configuration. The sealant, illustrated as a plug 54, seals the dose inside the sleeve portion 53. The syringe 50 may also include a hollow needle 55 connected to the sleeve portion 53 and connected to it through the fluid, through which the dose can be expelled by applying pressure to the plug 54. The hollow needle 55 protrudes from the first, proximal end 53a of the sleeve portion 53. The second end 53b of the sleeve portion 53 includes a flange 56 or other suitable mechanism for stopping the stopper, schematically represented by the element under the number 123, in the housing 12 to limit movement I syringe 50 within the housing 12 as described below. One skilled in the art will understand that the invention is not limited to the illustrative embodiment of the syringe 50, and that any suitable container for containing the dose of the substance to be injected can be used in accordance with the provisions of the invention. In the illustrative embodiment shown in FIGS. 3-5, the needle 55 is a fixed needle of a twenty-seventh gauge of a half-inch length. The tip of the illustrative cannula 55 may include five chamfers to facilitate insertion. However, the needle 55 may be of any suitable size, shape and configuration suitable for puncturing the user's skin to deliver the substance to the subcutaneous region, and is not limited to the illustrative embodiment. Suitable types of needles are well known in the art.

The automatic injection device 10 shown in FIGS. 3-5 further includes a syringe actuator 70, illustrated in the form of a plunger, for selectively moving and actuating the syringe 50 to inject the dose contained in the syringe 50 into the user's body. Illustrative plunger 70 includes a shaft portion 71 having a first end 71a which is an integral part, connected or connected through fluid to a plug 54 to selectively apply pressure to the plug 54 to expel a dose from the needle 55. The plunger 70 may include a flanged second end 72.

In one embodiment, the syringe actuator includes multiple components and / or more actuators are present in the automatic injection device of the invention.

The plunger 70 in FIGS. 3-5 is biased forward toward the first end 20 of the device 10 with a first biasing mechanism, illustrated as a coil spring 88 located near or above the flange of the second end of the plunger 70. In the embodiment illustrated in FIGS. 3- 5, the proximal end 88a of the coil spring 88 abuts the second end 72 of the plunger 70 having a flange for selectively applying pressure and proximal movement of the plunger 70. Alternatively, the plunger 70 extends through the center of the spring 88. Before using the device and 10, the coil spring 88 (or other suitable mechanism) is compressed between the plunger 70 and the housing 12, storing energy. The trigger 91, which is activated by any suitable trigger, such as the trigger 32 shown in FIGS. 1 and 2, holds the plunger 70 and the first biasing mechanism 88 in the retracted, fixed position shown in FIG. 3, the trigger 32 is pressed . In an exemplary embodiment, the trigger 91 locks the second end 72 of the plunger 70 having a flange. When the user presses a button 32 or activates another trigger means, the trigger 91 releases the second end 72 of the plunger 70 having a flange, allowing the coil spring 88 to apply pressure to the flange the second end 72, push the plunger 70 towards the first end of the device 10.

A second biasing mechanism, illustrated as a coil spring 89 in FIGS. 3-5, holds the syringe 50 in a retracted position inside the housing 12 before use, as shown in FIGS. 1 and 3. In the retracted position, the needle 55 is preferably completely surrounded by a sheath inside the housing 12. The cylindrical spring 89 of the illustrative syringe is located near the proximal portion of the sleeve portion 53 and can be fitted onto the protrusion 121 formed within the inner surface of the housing. The upper end of the coil spring 89 abuts the second end 56 of the syringe 50 having the flange. The elastic force of the second biasing mechanism 89 pushes the second end 56 of the syringe 50 having the flange off the first end 20 of the housing 12, thereby holding the syringe 50 in its retracted position until actuation. Other components of device 10 may also position syringe 50 relative to housing 12.

The first biasing mechanism 88 and the second biasing mechanism 89 may be of any suitable configuration and tensile stress, suitable for use in biasing certain components of the device. For example, the first biasing mechanism 88 has any suitable size, shape, energy, and properties suitable for moving the plunger 70 and syringe 50 forward upon release. The second biasing mechanism 89 has any suitable size, shape, energy, and properties suitable for retracting the syringe 50 before being actuated. Other suitable means may also be used to facilitate movement and expulsion from the syringe.

In the illustrative embodiment shown in FIGS. 3-5, the plunger 70 further includes a compressible expanded central portion 76. In an illustrative embodiment, the shaft 71 is split in the central portion to form a pair of protruding elbows 78 that define a compressible expanded central portion 76. The protruding elbows 78 may be preformed as part of a molded plunger 70, or may be separately attached to the plunger 70. The protruding elbows 78 are compressible so that they can move atsya radially inwardly so that this part of the rod circumference acquired similar to the rest of the circumference of the rod. The compressible expanded central portion 76 facilitates the movement of the syringe 50, followed by dose expulsion in two essentially separate stages, as described below.

As shown in FIG. 4, when the drive means 320 drives the starter 91 to release the plunger 70, the spring force of the coil spring 88 pushes the plunger 70 forward (proximally). During the first working stage, the moving plunger 70 pushes the syringe 50 forward so that the tip of the needle 55 protrudes from the first end 20 of the housing 12. The first biasing force provided by the first coil spring 88 is sufficient to overcome the biasing force of the second coil spring 89 to allow movement syringe 50 against the backward shear force of the second coil spring 89. In the first working stage, the expanded region 76 of the plunger 70, formed by the protruding elbows 78, abuts against the second end 56 of the sleeve part 53, preventing the plunger 70 from moving inside the sleeve portion 53 of the syringe. Thus, all of the shear force from the first coil spring 88 is applied to move the syringe 50 forward towards the first end 20 of the device 10.

The drive means 320 illustrated in FIGS. 3-5 may have any suitable size, shape, configuration, and location suitable for releasing the plunger 70 or otherwise actuating the device 10. For example, in the same figure 2, the drive means 320 may be a start button 32 formed at the distal end 30 of the housing 12, or may include another suitable device, such as a latch, a torque-actuated switch, and other devices known in the art. Although the illustrative drive means 320 is located toward the distal end 30 of the device 10, one skilled in the art will recognize that the drive means 320 may be located in any suitable location on the device 10.

The forward movement of the syringe 50 toward the proximal end 20 of the device 10 continues against the biasing force of the coil spring 89 until the second end 56 of the sleeve portion 53 having the flange abuts against the stopper 123, such as the protrusion of the flange on the housing 12, as shown in FIG. four. One skilled in the art will understand that alternative locking or limiting mechanisms can be used, and that the invention is not limited to an illustrative locking mechanism.

As shown in FIG. 4, in the first functional stage, the tip of the needle 55 is driven through the hole 28 at the first end 20 of the device 10 so that the needle 55 can pierce the patient’s skin. During this stage, the sleeve portion 53 of the syringe preferably remains hermetically sealed without expelling the substance through the needle 55. The counteraction by the locking mechanisms 56, 123 holds the needle 55 in its selected position, protruding from the proximal open end 28 of the device 10 in subsequent steps. Until the mechanisms 56, 123 stop the movement of the syringe 50, the compressible expanded central portion 76 of the plunger 70 prevents the plunger 70 from moving relative to the sleeve portion 53.

The stops 56, 123 can be located in any suitable area relative to the open first end 20 in order to enable the syringe 50 to allow the needle to penetrate the skin to any desired depth suitable for injection.

In the second working stage, which begins after the flange portion 56 is latched by the locking mechanism 123 or another locking mechanism of the housing 12, which stops further movement of the sleeve portion 53, the continued biasing force of the coil spring 88 continues to push the plunger 70 relative to the housing 12, as shown in FIG. 5. The biasing force causes a radial compression inside the elbows 78 of the plunger 70 and its sliding inside the sleeve part 53. Although the interaction between the components 123 and 56 keeps the sleeve part 53 in the selected position (with the protruding needle) and with the elbows 78 in a collapsed state, the coil spring 88 pushes the plunger 70 inside the sleeve portion. After the plunger 70 overcomes the necessary force to allow compression and the elbows 78 to enter the sleeve portion 53, the plunger 70 exerts pressure on the plug 54, causing the contents of the syringe 50 to be pushed out through the protruding needle 55. Since the needle was displaced in the first working stage 55 into the skin, the contents of the sleeve portion 53 are injected directly into the subcutaneous region of the patient.

6, in one embodiment of the invention, the automatic injection device 10 may include 2 blocking components: a syringe assembly assembly 121 comprising proximal components of the device 10 (e.g., syringe sleeve 53, coil spring 89, needle 55, and other proximal components) and a set of a trigger mechanism 122 containing distal components of the device (for example, means for actuating a syringe). The assembly of the syringe assembly 121 and the kit of the trigger mechanism 122 may be connected by any suitable means. In an illustrative embodiment, the proximal end 122a of the trigger assembly kit 122 may be sized and configured to fit into the distal end 121b of the syringe assembly assembly 121. In addition, one or more tabs 127 (shown in detail in FIGS. 7, 8A-8C and 9) at the proximal end 122a of the set of the trigger mechanism 122, can snap into the corresponding holes 126 on the distal end 121b of the set of the trigger mechanism 122 to ensure alignment and connection of the two devices in the assembly 121, 122, and the components contained therein in.

FIG. 7 is an exploded view of a kit of a trigger mechanism 122 in accordance with an illustrative embodiment of the invention. As shown, the set of the trigger mechanism 122 includes an illustrative trigger button 32, an illustrative actuator cap 34, an illustrative distal housing component 12b (trigger housing), and a coil spring 88 or other biasing mechanism. An exemplary trigger mechanism kit 122 further includes a syringe actuator, illustrated as a syringe actuator component 700 that extends from the proximal end 122a of the distal body component 12b to move the syringe 50 in a first stage and actuate the syringe 50 to expel its contents in the second phase.

FIGS. 8A-8C illustrate a distal housing component 12b, a coil spring 88, and a syringe actuator 700 component when assembled without a start button 32. FIG. 9 is a perspective view of a distal housing component 12b, and FIG. 10 is a perspective view of a drive component 700 syringes in accordance with an illustrative embodiment of the invention.

As shown in FIGS. 1-2 and 7-9, the distal housing component 12b includes a substantially tubular housing, which may include circuits 128 to facilitate gripping of the device 10 by the user. The protrusion 29 may be formed in the distal region 30 to facilitate the fit of the actuator cap 34, as described above. To the front of the protrusion 29, the distal body component 12b has a size and shape configured to fit into the distal end of the syringe body 121. The ears 127 are formed to facilitate joining and / or fixing together of the two body components, 12a and 12b. As shown in FIG. 9, the tabs 127 can be formed in a recess 127a on the surface of the proximal end of the distal casing component 12b and can also or alternatively include ribs 127b to guide the lugs in the closing position relative to the proximal casing component 12a. One of ordinary skill in the art will understand that any suitable means can be used to join the two components together and that the invention is not limited to illustrative connecting means.

As shown in FIGS. 2 and 8C, the distal casing component 12b may include a fastening cap 12c connected to the distal end of the smaller diameter of the distal casing component 12b to secure the triggering mechanisms for driving the device 10 to the distal casing component 12b. The interface between the fastening cap 12c and the distal housing component 12b may form a groove 1234 to facilitate snapping on the start button 32 at the distal end of the distal housing component 12b, or it may be connected by other suitable connecting means, as described above.

3 and 10, the syringe drive component 700 is preferably an integrated component made of a suitable material, such as acetal-based plastic, although other suitable materials can also be used. The syringe drive component 700 includes an overpressure end 754 for applying pressure to the plug 54 of the corresponding syringe 50, a plunger stem 70 with a compressible expanded central portion, illustrated as plunger elbows 78, and other components, such as components for securing the coil spring 88 to the syringe drive component 700, as described below. The compressible expanded central portion 76 facilitates the movement of the corresponding syringe 50 to the forward position and the ejection of the contents of the syringe 50 in two separate stages, as described above. Alternatively, the syringe actuator may include multiple actuators to move and / or facilitate the expulsion of contents from the syringe 50.

The syringe drive component 700 of FIGS. 2 and 10 may further include an indicator 190 in the solid shaft portion 70 further from the elbows 78. During operation of the device 10 and upon completion of the injection, the indicator 190 is configured to align with a window 130 on the housing 12 for indication complete the injection. Indicator 190 preferably has a distinctive color or design to represent completion of an injection.

As shown in FIGS. 2, 7, 8C and 10, the exemplary syringe drive component 700 further includes a holding flange 720 for holding the actuating coil spring 88 in a compressed position until actuated. The holding flange 720 is dimensioned and made of a material that preferably allows the syringe drive component 700 to slide and easily move within the housing 12 when the device 10 is actuated. Extending distally from the holding flange 720, the syringe drive component 700 forms a base 788 for the actuating coil spring 88. The base 788 ends with a starter attachment portion 789. Illustrative base 788 may include flexible legs 788a, 778b around which a spring 88 is wound. The fastener portion 789 of the starter may include an earstand 7891 extending from the base 788 and configured to selectively engage with the fastening cap 12c and / or the distal body component 12b. A start button 32 connected to the distal end of the distal housing component 12b is configured to hold the starter attachment portion 789 until actuated. When actuated, the start button 32 releases the starter holding portion 789, allowing the coil spring 88 to push the syringe drive component 700 toward the proximal end 20 of the device 10 in the above-described manner.

In the retracted, fixed position shown in FIGS. 2, 8C and 10 (corresponding to the schematic illustration in FIG. 3), the starter fixing portion 789 interacts with the housing 12, which holds the ear-mounted strut 7891 in the latched position, against the action of the cylindrical biasing force springs 88 for holding the syringe drive component 700 in a retracted position. In this position, the flange 720 moves the spring 88 all the way into the rear, distal wall 712 of the distal housing component 12b. A hole 713 in the fixing cap 12c provides access to the start button 32 to the fixing part 789. In the retracted position, the blower 754 of the syringe drive component 700 protrudes from the opening 228 at the proximal end 122a of the distal body component 12b. When the distal casing component 12b is connected to the corresponding syringe trigger 121, the blower 754 protrudes into the sleeve portion of the syringe enclosed therein. The blower 754 may communicate with the plug 54 of the syringe 50 enclosed in the device 10 by combining with it, being it, by connecting with it or in another way, and may have any suitable size, shape and configuration suitable for applying pressure to the plug 54. In one embodiment, the blower 754 has a cross-section corresponding to the shape of the sleeve portion 53 of the corresponding syringe 50 so as to substantially seal the sleeve portion 53, and the blower 754 is configured to slide by sliding inside the sleeve portion 53 for I apply pressure to the plug 54 and actuate the syringe 50.

In the preferred embodiment of Figs. fifty.

11 is a spatially exploded view of a syringe body kit 121 of an illustrative embodiment of the invention that is configured to connect and interact with a trigger mechanism kit 122 of FIGS. 7-10. An exemplary syringe body kit 121 includes a proximal component of the body 12a, a proximal cap 24, a second biasing mechanism 89, a syringe holder 500 and a casing with a step 12d forming the proximal portion 20 of the body 12 during assembly and includes a proximal opening 28, as also shown in FIG. 2 . Components 12a, 12d, 89, 500 and 24 work together to place a syringe 50 containing the substance to be injected and to facilitate the operation of the device 10 in two different stages of operation, as described above.

Illustrative embodiments of a syringe holder 500, a casing with a shoulder 12d, and a proximal cap are shown in detail in FIGS. 12, 13, and 14, respectively. FIGS. 15a and 15b are respectively a side view in perspective and a side view in section of an assembled set of a casing of a spring 121 in in accordance with one embodiment of the invention. One skilled in the art will appreciate that the invention is not limited to these illustrative embodiments.

1, 2, 11, 12 and 15b, the syringe holder 500 of the illustrative embodiment covers the distal half of the syringe 50 used in the device 10. The syringe 50 is placed in the holder 500, and they are both contained in the housing 12. During operation, the syringe 50 and the holder 500 move forward (eg, proximal) within the housing 12. The housing 12 stops and restricts the movement of the holder 500, and the holder 500 in turn stops and restricts the movement of the syringe 50. The exemplary syringe holder 500 has a substantially tubular structure including cutouts in eye view 501, preferably aligned with the window 130 on the housing 12a to allow the user to inspect the contents of the syringe 50 before operation. The syringe holder 500 may include a flange-shaped distal end 562 configured to form an interface with a flanged distal end 56 (shown in FIGS. 3 and 15b) of the syringe 50. The flange-shaped distal end 562 may serve as a damper for the syringe 50. The holder 500 the syringe may also include an intermediate flange 563, which in the illustrative embodiment forms a stopper for the syringe 50, which interacts with the internal stopper 256 (shown in Fig.15b) on the proximal component 12A of the body for the ogre forward movement of the syringe 50. The exemplary syringe holder 500 may further include a proximal securing portion 503 that restricts the movement of the syringe 50 in a distal, backward direction. In an exemplary embodiment, the proximal securing portion 503 includes a radial groove configured to engage with the internal stop 256. The syringe holder connector 504 is rubbed forward past the proximal securing portion 503 to facilitate the connection of the syringe holder 500 to the distal end of the spring 89 and the casing with a shoulder 12d as shown in FIG. 15b. In one embodiment, the syringe holder 500 is stationary fixed within the housing 12, and the syringe 50 selectively and controllably slides inside and relative to the syringe holder 500. Alternatively, the syringe holder 500 is slidably disposed within the housing 12 and selectively carries the syringe 50 inside the housing 12. The syringe holder 500 may be of any suitable configuration and size suitable for transporting or guiding the syringe 50 within the housing 12.

13 and 15b, the illustrative casing with the step 12d forms the proximal end 20 of the housing 12. The illustrative casing with the step 12d has a substantially tubular body including a proximal sleeve 112 defining a proximal opening 28 of the device 10 through which the syringe needle 55 projects during operation of the device 10. The step 113 from the main part 116 of the tubular body forms a proximal sleeve 112 of smaller diameter than the main part 116 of the tubular body of the casing with a step 12d. As shown in FIG. 15b, the step 113 forms a stop for forward movement of the spring 89 to limit the spring 89 and prevent the spring 89 from moving forward toward the proximal end 20 of the device 10. In the illustrative embodiment shown in FIG. 15b, the distal edge 115 of the casing with the step 12d abuts against the proximal side of the stopper 256 of the proximal component 12A of the housing. 13, the distal shoulders 114 protrude from the casing with the step 12d to lock in the casing with the step 12d to prevent accidental needle pricking.

14, 15a and 15b, the interior of the illustrative cap 24 may include a plurality of radial grooves 241, 243 for receiving protruding parts of the casing with a shoulder 12d and the proximal component 12a of the casing. For example, as best illustrated in FIG. 15b, the first radially outer groove 241 receives the proximal end of the side wall 242 of the proximal casing component 12a. A second, radially inner groove 243 receives the proximal end of the sleeve 112. The cap sleeve 26 projects into the inner lumen 1012 of the housing 12 and surrounds the proximal end of the syringe 50 loaded into it when the cap 24 is connected to the housing 12. In one embodiment, the inner coating 246 of the needle (as shown in FIG. 15b), the cap 24 surrounds the syringe needle 55 as a sheath. When the cap 24 is removed, the syringe needle 55 is exposed inside the lumen 1012 of the housing 12. The cap 24 may also include an opening at its proximal end 248.

As described above and shown in FIG. 15a, the openings 126 in the proximal housing component 12a receive the ears 127 of the set of the trigger mechanism 122 to facilitate assembly of the device 10. The above-described window 130 to allow the user to inspect the contents of the syringe contained in the set 121, as well as to see an indicator 190, which fills the window 130, after completion of the injection, can be formed in the proximal component 12A of the body.

16A and 16B are cross-sectional views at 90 degrees apart, illustrating the automatic injection device 10 assembly, where the syringe assembly assembly 121 and the trigger assembly 122 are connected together so that the supercharger 754 of the actuation component 700 the syringe protrudes into the sleeve portion 53 of the syringe 50 enclosed in the housing of the syringe assembly 121 and in communication with the plug 54 of the syringe 50.

As shown in FIG. 16b, the attachment portion 789 of the actuator of the syringe actuator component 700 is secured toward the distal end of the housing 12 by the start button 32. When the user presses the start button 32, the drive arms 32a connected to the start button 32 squeeze the ear stand 7891 of the fixing part 789 of the starter, releasing the drive mechanism of the syringe 700, and releasing the spring 88. Before operation, the compressible expanded central part 76, illustrated in the form of elbows 78, the syringe actuator component 700 is higher Lanza 56 of the syringe 50 to provide a compressible expanded central portion 76 when pushing the liberated coil spring 88 pressure supply capabilities on the barrel portion 53 of the syringe thereby moving the syringe 50 forward within the housing 12 upon actuation. As described above, when the stopper, such as the stopper 256 on the proximal body component 12a, as shown in FIGS. 15b and 16a, engages the syringe and stops the additional forward movement of the protruding syringe 50, the biasing force that continues to act on the spring 88 will continue to move the component 700 actuating the syringe forward, causing compression of the compressible expanded central portion 76 and moving it into the sleeve portion 53 of the syringe 50. Forward movement of the syringe actuating component 700 within the sleeve portion 53 causes odachu pressure supercharger 754 on the stopper 54, causing ejection of the contents of the syringe into the injection site.

As also shown in FIGS. 16a and 16b, the actuator cap 34 may include a stabilizing protrusion 340 that extends through the start button 32 and between the ears of the strut 7891 of the syringe actuator component 700 to stabilize the components of the device before being actuated.

FIG. 17 is a detailed view of the interface between the syringe body kit 121 and the trigger kit 122 (as shown in FIGS. 6 and 8a) of the automatic injection device 10 of one embodiment of the invention, illustrating an indicator 190 of the syringe actuator component 700 in accordance with one embodiment of the invention. The indicator 190 may have a distinctive color and / or design to indicate to the user that the injection is complete. Also in FIG. 2, the indicator 190 is configured to align with the window 130 of the housing 12 after the syringe actuating component 700 with the compressible expanded central portion 76 in a compressed state and shifted forward inside the sleeve portion 53 completes the injection and either completely or essentially completely expels the contents of the syringe 50 from the needle 55 and into the patient’s body. Thus, before the operation of the device 10, the sleeve 53 of the syringe is aligned with the window 130, and its contents are visible in it. After injection, by moving the proximal end 20 of the device 10 forward with the sleeve portion 53 of the syringe, so that the needle 55 protrudes from the proximal end 20 into the injection site, and the syringe actuating component 700 moves forward inside the sleeve portion 53 of the syringe, the indicator 190 is aligned with the window 130 to indicate completion of the injection. Therefore, even if the first stage of operation (moving the syringe 50 to the exposed position with the protruding needle 55) is completed, the indicator 190 will not be compatible with the window 130 or otherwise indicate the completion of the injection until the syringe actuation component 700 expels the contents of the syringe 50 of sleeve 53.

18-22 are a sectional view of an assembled automatic injection device 10 'in accordance with an illustrative embodiment of the invention. An exemplary embodiment of an automatic injection device 10 'includes two interlocking proximal and distal body components 12a, 12b. The proximal and distal casing components 12a, 12b are joined to form the complete structure of the casing 12. As shown, the proximal casing component 12a forming the proximal end of the casing 12 receives the proximal end of the distal casing component 12b. Jointly acting protrusion 312 and a groove 313 or a plurality of jointly acting protrusions 312 and grooves 313 facilitate the joining of the proximal and distal components 12a, 12b in an illustrative embodiment. Alternatively, other suitable docking mechanisms may be used. A step 29 formed on the outer surface of the distal housing component 12 b may form a stopper for the second removable cap 34.

As shown, the trigger 32 'may be a cap covering the distal end of the distal housing component 12b. An exemplary trigger 32 'slides relative to a distal housing component 12b to actuate a syringe actuator, such as a plunger 70 or a syringe actuator component 700. A step / support 138 formed on the outer surface of the distal housing component 12b near the distal end 30 of the distal housing component 12b allows the trigger button 32 'to be moved relative to the housing 12 and is limited as shown in FIGS. 20 and 22. This illustrative trigger button 32 'holds releasably the flexible securing arms 172 of the plunger 70'. When pressed, the start button 32 ′ releases the flexible securing arms 172 to enable the first biasing mechanism, illustrated as a spring 88 ′, to push the plunger 70 ′ toward the proximal end of the device 10 ′.

In the embodiment shown in FIGS. 18-22, the plunger 70 'further includes a flange 72' located between the compressible expanded middle portion 78 and the distal end of the plunger shaft 71 '. A first biasing mechanism 88 'is seated between the inner distal end of the housing 12 and the flange 72' to bias the plunger 70 toward the proximal end of the housing 12 '. As described above, when the start button 34 ′ releases the securing arms 172, a coil spring 88 ′ or other biasing mechanism pushes the plunger 70 ′ toward the proximal end 20 of the device 10.

The exemplary embodiment 10 ′ further includes an indicator 190 formed on the intermediate portion of the plunger shaft 71 ′ between the flange 72 ′ and the compressible expanded portion 76, illustrated as flexible elbows 78 ′.

The syringe 50 'shown in Fig.18-22. may include protrusions or another suitable component to facilitate controlled movement of the syringe within the housing 12 '. For example, in FIG. 18, the syringe 50 ′ includes a sleeve 157 defining a proximal protrusion 158 for abutting against the proximal side of a first protrusion 168 formed on the inner surface of the housing 12 ′ for limited movement of the syringe 50 ′ in the distal direction within the housing 12 ′. The sleeve 157 may also form a flange 159, which can abut against the distal side of the first protrusion 168 to restrict the movement of the syringe 50 'in the proximal direction during injection.

In the embodiment shown in FIGS. 18-22, a second biasing mechanism, illustrated as a coil spring 89 ', is located near the proximal portion of the syringe 50'. A step 169 formed on the proximal inner surface of the casing 12 'receives the proximal end of the coil spring 89'. 19, the proximal protrusion 158 of the syringe sleeve 157, or other suitably positioned mechanism, receives the distal end of the coil spring 89 '. As described above, the second biasing mechanism 89 ′ biases the syringe 50 ′ to a retracted position within the housing 12 ′ prior to actuating the device 10.

As shown in FIGS. 18-22, the automatic injection device 10 ′ includes an indicator 190 to indicate to the user of the device 10 when the dose from the syringe 50 has been completely or substantially completely expelled. In an illustrative embodiment, an indicator 190 is formed on a portion of a plunger rod 71 ′ between a compressible expanded center portion 76 and a flange 72 ′. As the plunger rod 71 moves during operation, the indicator 190 advances toward the window 130 and aligns with it when the dose is emptied from the syringe. The indicator 190, which preferably has a color or type different from the injected substance, completely fills the window 130 to indicate that the dosage has been injected. You can use any suitable indicator.

After the dose is injected from the device 10 through the needle 55, the needle sheath 112, which can be formed by the proximal end 20 of the casing 12d, can automatically advance over the bare needle 55 protruding from the proximal end 20 of the body to prevent accidental injections.

23, an illustrative housing 12 includes a window 130 formed through a side wall of the housing 12 to allow a user to view the contents of the syringe.

Illustrative window 130 preferably has the shape of a keyhole. For example, the window 130 includes a first end 132, which is substantially linear, and may include a curved inner edge 132a. The second end 134 of the window 130 may be substantially hemispherical and wider than the first end 132 of the window 130. The window 130 may include a fill line 135 to enable verification of the exact dosage inside the syringe.

In accordance with one embodiment of the invention, an illustrative automatic injection device can be used to deliver a dose of a TNF inhibitor used to treat arthritis and other diseases. In one embodiment, the solution contained in the 50 or 50 ′ syringe contains 40 mg of the drug product (TNFα blocker or inhibitor), 1 ml of adalimumab: 40 mg of adalimumab, 4.93 mg of sodium chloride, 0.69 mg of monobasic sodium dehydrogen phosphate, 1.22 mg of dibasic sodium dehydrogen phosphate, 0.24 mg of sodium citrate, 1.04 mg of citric acid monohydrate, 9.6 mg of mannitol, 0.8 mg of polysorbate 50 and water for injection, if necessary with the addition of sodium hydroxide according to the US Pharmacopoeia for adjusting the pH to about 5.2.

24 illustrates the use of a device for delivering a dosage of a substance, such as a TNF inhibitor, to the subcutaneous region of a user, in accordance with an illustrative embodiment of the invention. In a first step, the user is provided with a preloaded automatic injection device, such as the device 10 or device 10 ′ described above. Then, the user selects and prepares the injection site 400 to receive the substance into the subcutaneous region. For example, the user can clean the injection site using a suitable cleaning device, such as an alcohol preparation swab, which can be combined with the device 10 or 10 'of the present invention. After preparation, the user prepares the dose for injection. For example, a user may examine the solution through a window 130 to ensure that the solution has the desired color and consistency, and that the liquid level is on the fill line to ensure an appropriate dosage. After providing the appropriate dosage and contents in the pre-filled syringe 50, the user then removes the first cap 24 and the second cap 34 of the device 10 or 10 'to expose the hole 28 at the first end 20 and the start button 32 at the second end 30. Then the user places the automatic injection device 10 or 10 'with open first end 20 adjacent or proximal to the injection site. The user can apply pressure on the skin in this area to facilitate injection. The automatic injection device 10 or 10 ′ is preferably held at an angle of about 90 degrees to the surface of the user's body, pressing against the skin, as shown in FIG. 24. After placement, the user presses the start button 32 to start the injection. Pressing the start button may cause an audible indicator (noise), such as a “click”, to indicate the start of the injection. As described above, pressing the start button 32 causes the start button to release a fastener, such as the fastening end 789 of the syringe actuation component 700, allowing biasing spring 88 to push the syringe actuation component 700 and, thus, the syringe 50 toward the proximal end 20 devices 10 or 10 '. After the syringe 50 pierces the skin or otherwise enters the injection site, the forward movement of the syringe 50 stops, and then the syringe actuator or other mechanism pushes the syringe plug 54 to eject the contents of the syringe 50. The user holds the automatic injection device 10 or 10 ' in the position shown in FIG. 24 for a predetermined period of time. If the indicator 190 is provided in the automatic injection device 10, the user holds the automatic injection device 10 in the indicated position until the indicator 190 fills the window 130, indicating that a full or substantially complete dose of the substance has been injected. After that, the user removes the device 100 to remove the needle 55 from the skin. Needle 55 is preferably automatically sheathed to prevent accidental injections. The user can then discard the empty automatic injection device 10 or 10 '.

In accordance with another embodiment of the invention, an automatic training injection device may be provided to prepare users for using the automatic injection device 10 or 10 '. An exemplary training automatic injection device mimics the functionality of a training automatic injection device 10 or 10 'without injecting the substance into the patient's body. An automatic training injection device may have substantially the same components as the automatic injection devices 10 or 10 'described above, but it does not have a needle and / or medication. For example, a training automatic injection device may be filled with air, which when actuated is expelled from the sleeve portion 53 of the syringe. In working condition, the training automatic injection device advances the syringe forward and expels air or other neutral substance, preferably without penetration into the user's skin. The automatic training injection device preferably includes an indicator, such as indicator 190. The automatic training injection device can help prepare the user for getting used to imitating manipulation, sound, sensation, operation, use of indicator 190 and / or time of use of the automatic injection device without spending valuable resources .

The present invention provides significant advantages over methods of administration of drugs, in particular TNFα inhibitors of the prior art. For example, an automatic injection device increases the completeness and ease of insertion, less painfully, includes a hidden needle to eliminate the expectation and anxiety of patients suffering from “needle fear” to one degree or another, so that fear is eliminated as a factor in influencing patients. In addition, an automatic injection device effectively delivers a drug or other substance while being safe. The automatic injection device of the invention also provides security benefits. Unlike traditional syringes, using an automatic injection device does not expose the needle. The automatic injection device contains a white needle sleeve that surrounds the needle and protects patients from injury by a sticking needle before and after use. In addition, the protective cap on the automatic injection device prevents accidental erroneous starting, which can occur when using pre-filled syringes. An audible “click” indicates the start of the injection, and a distinctive indicator in the viewing window shows the patient that the full dose has been fully administered.

Examples of the use of the automatic injection device according to the invention are also described in detail in the provisional application for US patent under serial number 60/818231, which is specifically fully incorporated herein by reference to it. Other examples of an automatic injection device are described in detail in document PCT / EP2005 / 002487, which is specifically incorporated herein by reference in its entirety. U.S. Patent Applications 29/265691 and 29/265646 also describe automatic injection devices, each of which is also incorporated herein by reference.

III. TNFα Inhibitors for Use in the Compositions and Methods of the Invention

The present invention can be used to administer to a user (also referred to herein as a patient) a dose of a substance, such as a liquid drug, such as a TNFα inhibitor. In one embodiment, the dose delivered by the automatic injection device of the invention comprises anti-human TNFα antibodies or an antigen binding portion thereof. A particularly preferred drug is a TNFα inhibitor.

Термин «человеческий TNFα» предназначен для включения рекомбинантного человеческого TNFα (rhTNFα), который можно получить стандартными способами рекомбинантной экспрессии, или приобрести в торговой сети (R&D Systems, Catalog No. 210-TA, Minneapolis, MN). TNFα также именуется TNF.As used herein, the term “human TNFα” (abbreviated hTNFα, or simply hTNF, herein) is intended to mean a human cytokine that exists in the form of a secreted form of 17 kDa and a membrane-bound form of 26 kDa, of which the biologically active form is composed of trimmer non-covalently bound molecules of 17 kDa. The structure of hTNFα is also described, for example, in documents

The term “human TNFα” is intended to include recombinant human TNFα (rhTNFα), which can be obtained by standard methods of recombinant expression, or purchased from a distribution network (R&D Systems, Catalog No. 210-TA, Minneapolis, MN). TNFα is also referred to as TNF.

The term "TNFα inhibitor" refers to an agent that interferes with TNFα activity. The term also includes each of the human anti-TNFα antibodies (interchangeably used herein with anti-TNFα antibodies) and to portions of the antibodies described herein, as well as to antibodies described in US Pat. Nos. 6,090,382; 6,258,562; 6509015 and in applications for US patents under serial No. 09/801105 and 10/302356. In one embodiment, the TNFα inhibitor used in the invention is an anti-TNFα antibody or fragment thereof, including infliximab (Remicade®, Johnson and Johnson; described in US Pat. No. 5,656,272, incorporated herein by reference), CDP571 ( humanized monoclonal anti-TNF-alpha IgG4 antibody), CDP 870 (fragment of a humanized anti-TNF-alpha monoclonal antibody), and anti-TNF dAb (Peptech), CNTO 148 (golimumab; medarex and centocor, see WO 02/12502), and adalimumab (HUMIRA® Abbott Laboratories, human anti-TNF mAb described in US Pat. No. 6090382 as D2E7). Additional anti-TNF antibodies that can be used in the invention are described in US Pat. Nos. 6,593,458; 6,498,237; 6451983 and 6448380, each of which is incorporated herein by reference to it. In another embodiment, the TNFα inhibitor is a TNF fusion protein, for example etanercept (Enbrel®, Amgen; described in WO 91/03553 and WO 09/406476, incorporated herein by reference). In another embodiment, the TNFα inhibitor is a recombinant protein that binds TNF (r-TBP-I) (Serono).

As used herein, the term “antibody” is intended to refer to immunoglobulin molecules consisting of four polypeptide chains, two heavy (H) chains, and two light (L) chains mutually connected by disulfide bonds. Each heavy chain consists of a variable region of the heavy chain (abbreviated herein as HCVR or VH) and a constant region of the heavy chain. The constant region of the heavy chain consists of three domains, CH1, CH2 and CH3. Each light chain consists of a variable region of the light chain (abbreviated herein as LCVR or VL) and a constant region of the light chain. The constant region of the light chain consists of one domain, CL. The VH and VL regions can also be subdivided into hypervariability regions, referred to as complementarity determining regions (CDRs), with inserted regions that are more preserved, called framework regions (FR). Each VH and VL is composed of three CDRs and four FRs located from the amino end to the carboxy end in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Antibodies of the invention are further described in detail in US Pat. Nos. 6,090,382; 6258562 and 6509015, each of which is fully incorporated herein by reference to it.

Такие одноцепочечные антитела также охватываются термином «связывающая антиген часть» антитела. Охватываются также другие формы одноцепочечных антител, такие как диатела. Диатела представляют собой бивалентные, биспецифические антитела, в которых домены VH и VL экспрессированы на одной полипептидной цепи, но с использованием линкера, который является слишком коротким для обеспечения возможности спаривания между двумя доменами на той же цепи, принуждая, посредством этого, домены к спариванию с комплементарными доменами другой цепи, и созданию сайтов связывания антигена

Части антитела по изобретению более детально описаны в патентах США №№ 6090382, 6258562, 6509015, каждый из которых полностью включен в настоящий документ ввиду ссылки на них.As used herein, the term “antigen binding portion” of an antibody (or simply “antibody portion”) refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (eg, hTNFα). It has been shown that full length antibody fragments can fulfill the antigen binding function of an antibody. Examples of binding fragments encompassed by the term “antigen binding portion” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F (ab ′) ₂ fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge in the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of one arm of the antibody, (v) a dAb fragment (Ward et al. (1989) Nature 341: 544-546), which consists of the VH and VL domains; (vi) an isolated complementarity determining region (CDR); and (vii) an antibody against a double variable domain (DVD). In addition, although the two domains of the Fv fragment are encoded by separate genes, they can be coupled using recombinant methods, with a synthetic linker, which makes it possible to obtain them as a single protein chain in which the VL and VH regions are paired to form monovalent molecules (known as single chain Fv (scFv);

Such single chain antibodies are also encompassed by the term “antigen binding portion” of an antibody. Other forms of single chain antibodies, such as diabodies, are also encompassed. Diabodies are bivalent, bispecific antibodies in which the VH and VL domains are expressed on the same polypeptide chain, but using a linker that is too short to allow pairing between two domains on the same chain, thereby forcing the domains to mate with complementary domains of another chain, and the creation of antigen binding sites

Parts of an antibody of the invention are described in more detail in US Pat. Nos. 6,090,382, 6,258,562, 6,509,015, each of which is fully incorporated herein by reference.

In one embodiment, the TNF inhibitor used in the methods and compositions of the invention comprises a TNF fusion protein such as etanercept (Enbrel®, Amgen; described in WO 91/03553 and WO 09/406476 incorporated herein by reference) as well as recombinant TNF-binding protein (r-TBP-I) (Serono).

В другом варианте осуществления, ингибитор TNFα, используемый в изобретении, представляет собой антитело против TNFα или его фрагмент, включающий инфликсимаб (Remicade®, Johnson and Johnson; описанный в патенте США № 5656272, включенном в настоящий документ ввиду ссылки на него), CDP571 (гуманизированное моноклональное IgG4 антитело против TNF-альфа), CDP 870 (фрагмент гуманизированного моноклонального антитела против TNF-альфа), dAb против TNF (Peptech), и CNTO 148 (голимумаб; медарекс и центокор, см. WO 02/12502).In one embodiment, the TNF inhibitor used in the methods and compositions of the invention comprises isolated human antibodies or antigen binding parts thereof that bind to human TNFα with high affinity and low rejection frequency and have a high neutralizing ability. Preferably, the human antibodies of the invention are recombinant, neutralizing antibodies against human hTNFα. The most preferred recombinant, neutralizing antibody of the invention is referred to herein as D2E7, also referred to as HUMIRA® or adalimumab (the amino acid sequence of the VL region of D2E7 is shown in SEQ ID NO: 1 of US patent No. 6090382; the amino acid sequence of the VH region of D2E7 is shown in SEQ ID NO: 2 U.S. Patent No. 6,090,382). The properties of D2E7 (HUMIRA®) have been described in US Pat. Salfield et al. No. 6090382, 6258562 and 6509015, each of which is incorporated herein by reference to it. Other examples of TNFα inhibitors include chimeric and humanized murine antibodies against hTNFα that have been clinically tested for the treatment of rheumatoid arthritis (see, for example,

In another embodiment, the TNFα inhibitor used in the invention is an anti-TNFα antibody or fragment thereof comprising infliximab (Remicade®, Johnson and Johnson; described in US Pat. No. 5,656,272, incorporated herein by reference), CDP571 ( humanized monoclonal anti-TNF-alpha IgG4 antibody), CDP 870 (fragment of a humanized anti-TNF-alpha monoclonal antibody), anti-TNF dAb (Peptech), and CNTO 148 (golimumab; medarex and centocor, see WO 02/12502).

As used herein, the term “recombinant human antibody” is intended to include all human antibodies that are obtained, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described below), antibodies isolated from a library of recombinant, combinatorial human antibodies (described below), antibodies isolated from animals (e.g., mice) that are transgenic to for human immunoglobulin genes (see, for example, Taylor et al. (1992) Nucl. Acids Res. 20: 6287), or antibodies obtained, expressed, created, or isolated by any other means that include splicing human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies undergo in vitro mutagenesis (or in vivo when an animal transgenic for human Ig sequences is used), and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequenced, which, although obtained from the VH and VL sequences of the human germ line and associated with them, cannot naturally exist within the repertoire of the germ line of human antibodies in vivo.

Such chimeric, humanized, human, and dual-specific antibodies can be obtained by recombinant DNA techniques known in the art, for example, using methods described in PCT International Application No. PCT / US86 / 02269; European patent application No. 184187; European Patent Application No. 171496; European Patent Application No. 173494; PCT International Publication No. WO 86/01533; U.S. Patent No. 4,816,567; European Patent Application No. 125023;

As used herein, the term “isolated antibody” is intended to mean an antibody that is substantially lacking other antibodies having different antigenic specificities (for example, an isolated antibody that specifically binds hTNFα is essentially lacking antibodies that specifically bind antigens other than hTNFα) . An isolated antibody that specifically binds hTNFα may, however, have cross-reactivity with other antigens, such as TNFα molecules from other species. In addition, an isolated antibody may be substantially devoid of other cellular material and / or chemicals.

As used herein, the term “neutralizing antibody” (or “an antibody that neutralizes hTNFα activity”) is intended to mean an antibody whose binding to hTNFα leads to inhibition of the biological activity of hTNFα. This inhibition of the biological activity of hTNFα can be evaluated by measuring one or more indicators of the biological activity of hTNFα, such as cytotoxicity induced by hTNFα (either in vitro or in vivo), cellular activation induced by hTNFα, and binding to hTNFα receptors. These indicators of the biological activity of hTNFα can be evaluated by one or more standard in vitro or in vivo assays known in the art (see US Pat. No. 6,090,382). Preferably, the ability of an antibody to neutralize hTNFα activity is assessed by the inhibition of hTNFα cell cytotoxicity of L929. As an additional or alternative indicator of hTNFα activity, one can evaluate the ability of an antibody to inhibit hTNFα-induced expression of ELAM-1 on HUVEC, as a measure of cellular activation caused by hTNFα.

As used herein, the term “surface plasmon resonance” refers to an optical phenomenon that enables real-time analysis of biospecific interactions by detecting changes in protein concentrations within the biosensor matrix, for example using the BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway , NJ). Additional descriptions are presented in example 1 of US patent No. 6258562 and in documents

As used herein, the term “K _off ” is intended to mean a constant for decreasing the dissociation rate of an antibody from an antibody / antigen complex.

As used herein, the term “K _d ” refers to the dissociation constant of a particular antibody-antigen interaction.

As used herein, the term «IC _50" refers to the concentration of inhibitor required to inhibit representing biological outcome of interest, such as neutralization of cytotoxic activity.

As used herein, the term “dose” refers to the amount of a substance, such as a TNFα inhibitor, that is administered to a user, preferably using an automatic injection device of the invention. In one embodiment, the dose includes an effective amount, for example, including 20 mg, 40 mg, 80 mg and 160 mg of a TNFα adalimumab inhibitor.

As used herein, the term “dosage” refers to the administration of a substance (eg, anti-TNFα antibody) to achieve a therapeutic goal (eg, treatment of rheumatoid arthritis).

An “administration schedule” describes a treatment plan for a substance such as a TNFα inhibitor, for example, a treatment plan for an extended period of time and / or throughout the course of treatment, for example, administering a first dose of a TNFα inhibitor at 0 week followed by a second dose of a TNFα inhibitor according to the schedule introduction 2 times a week.

The terms “dosing schedule 2 times a week”, “dosing 2 times a week” and “dosing 2 times a week” as used herein refer to the dynamics of administration of a substance (eg, anti-TNFα antibody) to a patient to achieve a therapeutic goal, for example, in course of treatment. The administration schedule 2 times a week is not intended to include the administration schedule 1 time per week. Preferably, the substance is administered 1 time in 9-19 days, more preferably 1 time in 11-17 days, even more preferably 1 time in 13-15 days, and most preferably 1 time in 14 days. In one embodiment, a 2 times weekly schedule is started in a patient at 0 week of treatment. In another embodiment, the maintenance dose is administered by the schedule of administration 2 times a week. In one embodiment, both the shock and maintenance doses are administered in accordance with the administration schedule 2 times a week. In one embodiment, a 2 times weekly schedule includes a schedule whereby a dose of a TNFα inhibitor is administered to a patient once every 2 weeks starting at week 0. In one embodiment, administration 2 times per week includes an administration regimen in which doses of a TNFα inhibitor are administered to the patient once every 2 weeks sequentially for a given period of time, for example 4 weeks, 8 weeks, 16 weeks, 24 weeks, 26 weeks, 32 weeks, 36 weeks, 42 weeks, 48 weeks, 52 weeks, 56 weeks, etc. Methods of administration once every 2 weeks are also described in US patent application No. 20030235585, incorporated herein by reference.

The term "combination", as in the phrase "first agent in combination with a second agent", includes the joint administration of the first agent and the second agent, which, for example, can be dissolved or mutually mixed in the same pharmaceutically acceptable carrier, or the introduction of the first agent followed by the introduction of the second agent, or the introduction of the second agent, followed by the introduction of the first agent.

The term “concomitant,” as in the phrase “concomitant therapeutic treatment,” includes administering an agent in the presence of a second agent. A method of concomitant therapeutic treatment includes methods in which the first, second, third or additional substances are co-administered. The concomitant therapeutic treatment method also includes methods in which the first or additional agent is administered in the presence of a second or additional substance, wherein the second or additional substance may, for example, be administered earlier. The method of concomitant therapeutic treatment can be performed in stages by different patients. For example, one individual can introduce the first agent to the user, and the second individual can introduce the second substance to the user, and the administration steps can be performed at the same time or almost at the same time, or at times separated by time intervals until the first substance (and additional substances) is after administration in the presence of a second substance (and additional substances). The person performing the introduction and the user can be the same creature (for example, a person).

As used herein, the term “combination treatment” refers to the administration of two or more therapeutic substances, for example, anti-TNFα antibodies and other drugs. Another drug (s) can be administered simultaneously, before or after administration of an anti-TNFα antibody.

The term “treatment” as used in the context of the present invention is intended to include therapeutic treatment as well as prophylactic or suppressive measures for treating a disorder, such as a disorder in which TNFα has a damaging effect, for example rheumatoid arthritis.

In one embodiment, the invention provides an improvement in the methods of use and composition for treating a disorder in which TNFα has a damaging effect, for example rheumatoid arthritis, with a TNFα inhibitor, for example, an anti-human TNFα antibody, or an antigen binding portion thereof, by an automatic injection device.

The substance that is delivered via an automatic injection device may be a TNFα inhibitor. A TNFα inhibitor includes any agent (or substance) that interferes with TNFα activity. In a preferred embodiment, the TNFα inhibitor can neutralize TNFα activity, in particular the damaging TNFα activity, which is associated with disorders in which TNFα activity has a damaging effect, including without limitation rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, psoriasis and psoriatic arthritis.

In one embodiment, the TNFα inhibitor used in the invention is an anti-TNFα antibody (also referred to herein as a TNFα antibody), or an antigen binding fragment thereof, including chimeric, humanized and human antibodies. Examples of TNFα antibodies that can be used in the invention include, without limitation, infliximab (Remicade®, Johnson and Johnson; described in US Pat. No. 5,656,272, incorporated herein by reference), CDP571 (humanized monoclonal anti-TNF alpha IgG4 antibody) , CDP 870 (fragment of a humanized monoclonal antibody against TNF-alpha), dAb against TNF (Peptech), CNTO 148 (golimumab; medarex and centocor, see WO 02/12502), and adalimumab (HUMIRA® Abbott Laboratories, human mAb against TNF described in US Pat. No. 6,090,382 as D2E7). Additional anti-TNF antibodies that can be used in the invention are described in US Pat. Nos. 6,593,458; 6,498,237; 6451983 and 6448380, each of which is incorporated herein by reference to it.

Other examples of TNFα inhibitors that can be used in the methods and compositions of the invention include etanercept (Enbrel described in WO 91/03553 and WO 09/406476), soluble type I TNF receptor, pegylated type I TNF soluble receptor (PEG TNF-α R1), p55TNFRIgG (Lenercept), and recombinant TNF-binding protein (r-TBP-I) (Serono). Examples of TNFα inhibitors include, but are not limited to, infliximab (Remicade ^™ ), CDP 571, CDP 870, anti-TNF dAb, golimumab, adalimumab, etanercept (Enbrel ^TM ), p55TNFRIgG (lenercept) and r-TBP-1. A particularly preferred TNFα inhibitor is adalimumab (HUMIRA®).

In one embodiment, the term “TNFα inhibitor” excludes infliximab. In one embodiment, a "TNFα inhibitor" excludes adalimumab. In another embodiment, a “TNFα inhibitor" excludes adalimumab and infliximab.

In one embodiment, the term “TNFα inhibitor” excludes etanercept and, optionally, adalimumab, infliximab and adalimumab and infliximab.

In one embodiment, the term “TNFα inhibitor” excludes infliximab. In another embodiment, the term “TNFα inhibitor” excludes adalimumab and infliximab.

In one embodiment, the invention describes uses and a composition for treating or determining the effectiveness of a TNFα inhibitor for treating rheumatoid arthritis, wherein the TNFα antibody is an isolated human antibody, or an antigen binding portion thereof that binds to human TNFα with high affinity and low rejection rate , and also has a high neutralizing ability. Preferably, the human antibodies used in the invention are recombinant, neutralizing antibodies against human hTNFα. The most preferred recombinant, neutralizing antibody of the invention is referred to herein as D2E7, also referred to as HUMIRA® or adalimumab (the amino acid sequence of the VL D2E7 region is shown in SEQ ID NO: 1; the amino acid sequence of the VH D2E7 region is shown in SEQ ID NO: 2). The properties of D2E7 (adalimumab / HUMIRA®) have been described in US patents Salfeld et al. No. 6090382, 6258562 and 6509015, each of which is incorporated herein by reference to it. The methods of the invention can also be performed using chimeric and humanized murine antibodies against hTNFα that have been clinically tested for the treatment of rheumatoid arthritis (see, for example,

In one embodiment, the method of the invention comprises determining the effectiveness of antibodies against adalimumab and parts of antibodies, antibodies associated with adalimumab, and parts of antibodies, or other human antibodies and parts of antibodies with equivalent properties for adalimumab, such as binding with high affinity for hTNFα with low dissociation kinetics and high neutralizing ability, for the treatment of rheumatoid arthritis. In one embodiment, the invention provides treatment with an isolated human antibody or antigen binding portion thereof that dissociates from human TNFα at K _d 1 × 10 ⁻⁸ M or less and a rate constant K _off 1 × 10 ⁻³ s ⁻¹ or less, both determined by plasmon surface resonance, and neutralizes the cytotoxicity of human TNFα in a standard in vitro L929 assay at an IC _{50 of} 1 × 10 ^-7 M or less. Preferably, the isolated human antibody or antigen binding portion thereof is dissociated from human hTNFα at K _off 5 × 10 ⁻⁴ s ⁻¹ or less, or even more preferably, the isolated human antibody or antigen binding portion thereof is dissociated from human hTNFα at K _off 1 × 10 ^-4 s ^-1 or less. Preferably, an isolated human antibody or antigen binding portion thereof neutralizes the cytotoxicity of human TNFα in an in vitro standard L929 assay at an IC _{50 of} 1 × 10 ^-8 M or less, more preferably at an IC _{50 of} 1 × 10 ^-9 M or less, and even more more preferably, with an IC _{50 of} 1 × 10 ⁻¹⁰ M or less. In a preferred embodiment, the antibody is an isolated human recombinant antibody or an antigen binding portion thereof.

It is well known in the art that the CDR3 domains of an antibody heavy and light chain play an important role in the specificity / affinity of binding of an antibody to an antigen. Accordingly, in another aspect, the invention relates to the treatment of Crohn’s disease by administering human antibodies that have slow dissociation kinetics for association with hTNFα and which have heavy and light chain CDR3 domains that are structurally identical or linked to D2E7 domains. Position 9 of the D2E7 VL CDR3 may be occupied by Ala or Thr essentially without affecting K _off . Accordingly, the consensus motif for D2E7 VL CDR3 includes the amino acid sequence: QRYNRAPY- (T / A) (SEQ ID NO: 3). In addition, position 12 of the D2E7 VH CDR3 may be occupied by Tyr or Asn with substantially no effect on K _off . Accordingly, the consensus motif for D2E7 VH CDR3 includes the amino acid sequence: VSYLSTASSLD- (Y / N) (SEQ ID NO: 4). In addition, as demonstrated in Example 2 of US Pat. No. 6,090,382, the CDR3 domain of the D2E7 heavy and light chains tends to be replaced with one alanine residue (at position 1, 4, 5, 7, or 8 within VL CDR3 or at position 2, 3, 4 , 5, 6, 8, 9, 10, or 11 within VH CDR3) substantially without affecting K _off . In addition, one of ordinary skill in the art will understand, given the tendency of the D2E7 VL and VH CDR3 domains to be replaced by alanine, it may be possible to replace other amino acids within the CDR3 domains, however, while maintaining a low constant for the rejection frequency of the antibody, in particular, conservative substitutions amino acids. Preferably, no more than one to five conservative amino acid substitutions are made within the D2E7 VL and / or VH CDR3 domains. More preferably, no more than one to three conservative amino acid substitutions are made within the D2E7 VL and / or VH CDR3 domains. In addition, conservative amino acid substitutions should not be made at amino acid positions that play a crucial role in binding to hTNFα. It appears that positions 2 and 5 of D2E7 VL CDR3 and positions 1 and 7 of D2E7 VH CDR3 play a decisive role in interacting with hTNFα, and thus, conservative amino acid substitutions are preferably not made at these positions (although alanine substitution at position 5 of D2E7 VL CDR3 acceptable, as described above) (see US patent No. 6090382).

Accordingly, in another embodiment, the antibody or antigen binding portion thereof preferably has the following characteristics:

a) is dissociated from human TNFα at a rate constant K _off 1 × 10 ^-3 s ^-1 or less. According to the definition of plasmon surface resonance;

b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 with one substitution of alanine at position 1, 4, 5, 7 or 8 from one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and / or 9;

c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 with one substitution of alanine at position 2, 3, 4, 5, 6, 8, 9, 10, or 11 from one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and / or 12.

Preferably, the antibody or antigen binding portion thereof is dissociated from human TNFα at K _off 5 × 10 ⁻⁴ s ⁻¹ or less. Even more preferably, the antibody or its antigen binding portion dissociates from human TNFα at K _off 1 × 10 ⁻⁴ s ⁻¹ or less.

In yet another embodiment, the antibody or antigen binding portion thereof preferably comprises a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 with one substitution of alanine at position 1, 4, 5, 7 or 8, and with a variable region of the heavy chain (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 with one substitution of alanine at position 2, 3, 4, 5, 6, 8, 9, 10, or 11. Preferably, the LCVR also has a CDR domain 2 comprising the amino acid sequence of SEQ ID NO: 5 (i.e., D2E7 VL CDR2) and HCVR, furthermore, has a CDR2 domain including the amino acid sequence of SEQ ID NO: 6 (i.e., D2E7 VH CDR2). Even more preferably, the LCVR also has a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 7 (i.e., D2E7 VL CDR1) and HCVR has a CDR1 domain including the amino acid sequence of SEQ ID NO: 8 (i.e., D2E7 VH CDR1). The framework regions for VL are preferably from the family of the human germline V _to 1, more preferably from the V gene _{to the} human germline A20, and most preferably from the framework sequences D2E7 VL shown in FIGS. 1A and 1B of US Pat. No. 6,090,382. Frame regions for VH is preferably from the human germline family V _H 3, more preferably from the VH gene of the human germline DP-31, and most preferably from the D2E7 VH framework sequences shown in FIGS. 2A and 2B of US Pat. No. 6,090,382.

Accordingly, in another embodiment, the antibody or antigen binding portion thereof preferably comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 (i.e., D2E7 VL) and a heavy chain variable region (HCVR) including the amino acid sequence of SEQ ID NO: 2 (i.e., D2E7 VH). In certain embodiments, the antibody comprises a heavy chain constant region, such as an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region. Preferably, the heavy chain constant region is an IgG1 heavy chain constant region or an IgG4 heavy chain constant region. In addition, the antibody may include a constant region of the light chain, or a constant region of the light chain Kappa, or a constant region of the light chain lambda. Preferably, the antibody comprises a kappa light chain constant region. Alternatively, the antibody portion may be, for example, a Fab fragment or a single chain Fv fragment.

, или с вариабельной областью тяжелой цепи (HCVR), имеющей домен CDR3, включающий аминокислотную последовательность, выбранную из группы, состоящей из

In other embodiments, the invention uses an isolated human antibody or antigen binding portion thereof comprising D2E7-linked CDR3 VL and VH domains. For example, antibodies or antigen-binding parts thereof with a light chain variable region (LCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of

or with a heavy chain variable region (HCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of

The TNFα antibody used in the methods and compositions of the invention can be modified for improved treatment of rheumatoid arthritis. In some embodiments, the TNFα antibody or antigen binding fragment thereof is chemically modified to provide the desired effect. For example, pegylation of antibodies and antibody fragments of the invention can be carried out by any pegylation reaction known in the art, as described, for example, in the following references: Focus on Growth Factors 3: 4-10 (1992); EP 0154316 and EP 0401384 (each of which is fully incorporated herein by reference to it). Preferably, pegylation is carried out by an acylation reaction or an alkylation reaction with a reactive polyethylene glycol molecule (or a similar reactive water-soluble polymer). A preferred water soluble polymer for pegylation of antibodies and antibody fragments of the invention is polyethylene glycol (PEG). As used herein, the term “polyethylene glycol” is intended to encompass any form of PEG that has been used to derivatize other proteins, such as mono (C1-C10) alkoxy or aryloxy polyethylene glycol.

Methods for preparing pegylated antibodies and antibody fragments of the invention generally include the steps of (a) reacting an antibody or antibody fragment with a polyethylene glycol, for example a reactive ester or aldehyde derivative of PEG, under conditions by which the antibody or antibody fragment becomes attached to one or more PEG groups, and (b) obtaining reaction products. For the average person skilled in the art, the choice of optimal conditions for the interaction or acylation reactions based on known parameters and the desired result is obvious.

Pegylated antibodies and antibody fragments can generally be used to treat rheumatoid arthritis by the administration of TNFα antibodies or antibody fragments described herein. In general, pegylated antibodies and antibody fragments increased the elimination half-life, as compared to non-pegylated antibodies and antibody fragments. Pegylated antibodies and antibody fragments can be used separately, together or in combination with other pharmaceutical compositions.

In yet another embodiment, the TNFα antibodies or fragments thereof can be modified, where the constant region of the antibody is modified to reduce at least one mediated constant region of the biological effector function relative to the unmodified antibody. To modify the antibody of the invention so that it exhibits reduced binding to the Fc receptor, the constant region segment of an immunoglobulin antibody can mutate in certain regions necessary for Fc receptor (FcR) interactions (see, for example,

A decrease in the ability of an antibody to bind to FcR can also reduce other effector functions that are determined by FcR interactions, such as opsonization and phagocytosis and antigen-dependent cellular cytotoxicity.

The antibody or part of an antibody used in the compositions and methods of the invention may be derivatized or linked to another functional molecule (e.g., another peptide or protein). Accordingly, the antibodies and antibody portions of the invention are intended to incorporate derivatized or otherwise modified forms of anti-human TNFα antibodies described herein, including immunoadhesion molecules. For example, an antibody and a portion of an antibody of the invention may be operably linked (by chemical coupling, gene hybridization, non-covalent association, or otherwise) to one or more other molecular elements, such as another antibody (e.g., a bispecific antibody or diabody), a detectable agent, a cytotoxic agent, pharmaceutical agent and / or protein or peptide that can mediate the association of an antibody or part of an antibody with another molecule (such as the core region of streptavidin or polyhistidino Single label).

One type of derivatized antibody is obtained by cross-linking two or more antibodies (of the same type or of different types, for example, to create bespecifically antibodies). Suitable crosslinking agents include those that are heterofunctional, having two distinctly reactive groups, separated by an appropriate spacer (e.g., m-maleimidebenzoyl-N-hydroxysuccinimide ester) or homobifunctional (e.g., disuccinimidyl succinate). Such linkers are available from Pierce Chemical Company, Rockford, IL.

Useful detectable agents by which an antibody or part of an antibody can be derivatized include fluorescent compounds. Illustrative fluorescent detectable agents include fluorescein, fluorescein isocyanate, rhodamine, 5-dimethylamine-1-naphthalenesulfonyl chloride, phycoerythrin, and the like. The antibody can also be derivatized with detectable enzymes such as alkaline phosphatase, horseradish peroxidase, glucose oxidase and the like. When an antibody is derivatized with a detectable enzyme, it is detected by the addition of additional reagents, which the enzyme uses to produce a detectable reaction product. For example, when a detectable horseradish peroxidase agent is present, the addition of hydrogen peroxide and diaminobenzidine results in a colored reaction product that is detectable. The antibody can also be derivatized with biotin and detected by indirect measurement of avidin or streptavidin binding.

An antibody or part of an antibody used in the methods and compositions of the invention can be prepared by recombinant expression of immunoglobulin light and heavy chain genes in a host cell. For recombinant expression of an antibody, the host cell is transfected with one or more recombinant expression vectors carrying DNA fragments encoding the antibody immunoglobulin light and heavy chains, so that the light and heavy chains are expressed in the host cell and are preferably secreted into the medium in which it is cultured a host cell, and antibodies can be recovered from this medium. Standard recombinant DNA methodologies are used to generate antibody heavy and light chain genes, incorporate these genes into recombinant expression vectors, and introduce vectors into host cells, such as those described in documents

содержание каждой из которых специально включено в настоящий документ ввиду ссылки на нее). Для получения фрагмента ДНК, кодирующего вариабельную область тяжелой цепи D2E7 или связанного с D2E7 антитела, член семейства V_H3 генов VH человеческой зародышевой линии амплифицируется стандартной PCR. Наиболее предпочтительно, амплифицируется последовательность VH DP-31 зародышевой линии. Для получения фрагмента ДНК, кодирующего вариабельную область легкой цепи D2E7 или связанного с D2E7 антитела, член семейства V_к1 генов VL человеческой зародышевой линии амплифицируется стандартной PCR. Наиболее предпочтительно, амплифицируется последовательность A20 VL зародышевой линии. Затравки PCR, подходящие для использования в амплификации последовательностей VH и A20 зародышевой линии DP-31, можно обозначить на основании нуклеотидных последовательностей, раскрытых в приведенных выше ссылках, с использованием стандартных способов.To express adalimumab (D2E7) or an adalimumab-bound (D2E7) antibody, DNA fragments encoding the variable regions of the light and heavy chains are first prepared. These DNA can be obtained by amplification and modification of the variable sequences of the light and heavy chains of the germ line using polymerase chain reaction (PCR). Germ line DNA sequences for the heavy and light chain variable region genes are known in the art (see, for example, the Vbase human germline sequence database; see also

the content of each of which is specifically included in this document due to the link to it). To obtain a DNA fragment encoding the variable region of the heavy chain of D2E7 or associated with D2E7 antibodies, a member of the family V _H 3 VH genes of the human germ line is amplified by standard PCR. Most preferably, the germline VH DP-31 sequence is amplified. To obtain a DNA fragment encoding the variable region of the light chain of D2E7 or associated with D2E7 antibodies, a member of the V _to 1 family of VL genes of the human germ line is amplified by standard PCR. Most preferably, the germline sequence A20 VL is amplified. PCR seeds suitable for use in amplification of the DP-31 germline VH and A20 sequences can be designated based on the nucleotide sequences disclosed in the above references using standard methods.

After obtaining germline VH and VL fragments, these sequences can be mutated to encode D2E7 or the D2E7-related amino acid sequences disclosed herein. Amino acid sequences encoded by the germline VH and VL DNA sequences are first compared with D2E7 or D2E7-linked amino acid sequences to identify amino acid residues in D2E7 or D2E7-linked sequences that are different from the germline. The corresponding nucleotides of the DNA sequences are then mutated so that the mutated germline sequence encodes a D2E7 or D2E7-related amino acid sequence using a genetic code to determine which nucleotide changes should be made. Germ line sequence mutagenesis is carried out by standard methods, such as PCR-mediated mutagenesis (in which mutated nucleotides are included in the PCR primers so that the PCR product contains mutations), or site-directed mutagenesis.

In addition, it should be noted that if the germline sequences obtained by PCR amplification encode amino acid differences in the framework regions from the actual germline configuration (i.e., differences in the amplified sequence compared to the actual germline sequence, for example, as a result of somatic mutation), it may be desirable to change these amino acid differences by returning them to the actual germline sequences (ie, “reverse mutation” framework residues in the germline configuration).

After obtaining DNA fragments encoding D2E7 or VH and VL segments associated with D2E7 (amplification and mutagenesis of the germline VH and VL genes as described above), these DNA fragments can be further manipulated using standard recombinant DNA techniques, for example, for converting variable region genes into full-length chain genes of antibodies, into Fab fragment genes or into scFv gene. In these manipulations, a DNA fragment encoding VL or VH is operably linked to another DNA fragment encoding another protein, such as a constant region of an antibody or a flexible linker. The term “operably linked”, as used herein, is intended to mean that two DNA fragments are connected so that the amino acid sequences encoded by these two DNA fragments remain within the frame.

, и фрагменты ДНК, охватывающие эти области, можно получить стандартной амплификацией PCR. Константная область тяжелой цепи может представлять собой константную область IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM или IgD, но наиболее предпочтительно, представляет собой константную область IgG1 или IgG4. Для гена тяжелой цепи фрагмента Fab, ДНК, кодирующая VH, может быть оперативно связана с другой молекулой ДНК, кодирующей только константную область СН1 тяжелой цепи.Isolated DNA encoding the VH region can be converted into a full-length heavy chain gene by operatively linking the DNA encoding VH with another DNA molecule encoding the constant regions of the heavy chain (CH1, CH2 and CH3). The sequences of human heavy chain constant region genes are known in the art (see, for example,

, and DNA fragments spanning these regions can be obtained by standard PCR amplification. The constant region of the heavy chain may be a constant region of IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD, but most preferably, is a constant region of IgG1 or IgG4. For the heavy chain gene of the Fab fragment, DNA encoding VH can be operably linked to another DNA molecule encoding only the constant region of the CH1 heavy chain.

,Isolated DNA encoding the VL region can be converted into a full-length light chain gene (as well as the Fab light chain gene) by operatively linking the VL-encoding DNA to another DNA molecule encoding the light chain constant region, CL. The sequences of human genes of the constant region of the light chain are known in this field (see, for example,

,

and DNA fragments spanning these regions can be obtained by standard PCR amplification. The light chain constant region may be a kappa or lambda constant region, but most preferably, it is a kappa constant region.

To create the scFv gene, DNA fragments encoding VH and VL are operatively linked to another fragment encoding a flexible linker, for example, encoding the amino acid sequence (Gly ₄ -Ser) ₃ , so that the VH and VL sequences can be expressed as an adjacent single-stranded protein with regions VL and VH connected by a flexible linker (see, for example,

To express the antibodies or parts of the antibodies used in the invention, DNA encoding the partial and full length light and heavy chains obtained as described above are inserted into expression vectors, so that the genes are operatively linked to transcriptional and translational control sequences. In this context, the term “operably linked” is intended to mean that the antibody gene is ligated into the vector so that the transcriptional and translational control sequences within the vector have their intended function of regulating the transcription and translation of the antibody gene. The expression vector and expression control sequence are selected for compatibility with the expression of the host cell used. An antibody light chain gene and an antibody heavy chain gene can be inserted into a separate vector or, most typically, both genes are inserted into the same expression vector. Antibody genes are inserted into the expression vector by standard methods (for example, by ligation of complementary restriction sites on the antibody gene fragment and vector, or ligation of the blunt end if there are no restriction sites). Before the insertion of the light and heavy chain sequences of D2E7 or linked to D2E7, the expression vector may already carry the constant region sequences of the antibody. For example, one approach to converting VH and VL sequences of D2E7 or D2E7-linked into full-length antibody genes is to insert them into expression vectors already encoding respectively the constant region of the heavy chain and the constant region of the light chain, so that the VH segment is operatively linked with the segment (s) of CH within the vector and the VL segment was operatively associated with the CL segment within the vector. Additionally or alternatively, the recombinant expression vector may encode a signal peptide that promotes secretion of the antibody chain from the host cell. An antibody chain gene can be cloned into a vector so that the signal peptide is bound within the frame to the amino end of the antibody chain gene. The signal peptide may be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin protein).

In addition to antibody chain genes, the recombinant expression vectors of the invention carry regulatory sequences that regulate the expression of antibody chain genes in a host cell. The term “regulatory sequence” is intended to include promoters, enhancers, and other expression control elements (eg, polyadenylation signals) that regulate the transcription or translation of antibody chain genes. Such regulatory sequences are described, for example, in the document (see, for example, in Goeddel; Gene Expression Technology: Method in Enzymology 185, Academic Press, San Diego, CA (1990). Those skilled in the art will appreciate that the construction of the expression vector , including the choice of regulatory sequences, may depend on factors such as the choice of the host cell to be transformed, the desired level of protein expression, etc. Preferred regulatory sequences for the expression of mammalian host cells include viral elements that direct high levels of protein expression in mammalian cells, such as promoters and / or enhancers derived from cytomegalovirus (CMV) (such as promoter / enhancer CMV), monkey virus 40 (such as promoter / enhancer SV 40), adenovirus (e.g. late promoter of adenovirus (AdMLP)) and polyoma. Further description of viral regulatory elements is found, for example, in US Pat. No. 5,168,062 Stinski, US Pat. No. 4,510,245 to Bell et al. and U.S. Patent No. 4,968,615 to Schaffner et al.

In addition to antibody chain genes and regulatory sequences, the recombinant expression vectors in the invention may carry additional sequences, such as sequences that regulate vector replication in host cells (e.g., replication sources) and selectable marker genes. Selectable marker genes facilitate the selection of host cells into which the vector has been introduced (see, for example, US Pat. Nos. 4,399,216, 4,634,665 and 5,179,017, all issued by Axel et al.). For example, usually marker genes that are selected will confer resistance to drugs, such as G418, hygromycin or methotrexate, to the host cell into which the vector has been introduced. Preferred selectable marker genes include the dehydrofolate reductase gene (DHFR) (for use in dhfr host cells by methotrexate selection / amplification) and the neo gene (for G418 selection).

For expression of light and heavy chains, the expression vector (s) encoding the light and heavy chains are transfected into the host cell by standard techniques. Various forms of the term “transfection” are intended to encompass a wide variety of techniques commonly used to introduce exogenous DNA into a prokaryotic or eukaryotic host cell, for example, electroporation, precipitation of calcium phosphate, transfection with DEAE-dextran and the like. Although it is theoretically possible to express the antibodies of the invention in either prokaryotic or eukaryotic host cells, expression of antibodies in eukaryotic cells, and most preferably mammalian host cells, is most preferred because such eukaryotic cells, and in particular mammalian cells, are more more likely than prokaryotic cells will assemble and secrete a properly folded and immunologically active antibody. It has been reported that prokaryotic expression of antibody genes is ineffective for the production of active antibodies in high yield (Boss, M.A. and Wood, C.R. (1985) Immunology Today 6: 12-13).

Preferred mammalian host cells for recombinant expression of antibodies of the invention include Chinese hamster ovary cells (CHO cells) (including dhfr-CHO cells described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77: 4216- 4220 used with a DHFR selectable marker, for example, as described in RJKaufman and PASharp (1982) Mol. Biol. 159: 601-621), NS0 myeloma cells, COS cells and SP2 cells. When recombinant expression vectors encoding antibody genes are introduced into mammalian host cells, the antibodies are produced by culturing the host cells for a period of time sufficient to allow expression of the antibody in the host cells, or, preferably, secreting the antibody into the culture medium in which they are grown host cells. Antibodies can be removed from the culture medium using standard protein purification methods.

Host cells can also be used to produce portions of intact antibodies, such as Fab fragments or scFv molecules. It is understood that changes to the above procedure are within the scope of the present invention. For example, it may be desirable to transfect a host cell with DNA encoding either the light chain or heavy chain (but not both of them) of the antibodies of the present invention. Recombinant DNA technology can also be used to remove some or all of the DNA encoding each of either or both light and heavy chains, which is not necessary for binding to hTNFα. Molecules expressed from such truncated DNA molecules are also encompassed by the antibodies of the invention. In addition, functional antibodies can be produced in which one heavy and one light chain are an antibody of the invention and the other heavy and light chain are specific for an antigen other than hTNFα by crosslinking the antibody of the invention with a second antibody by standard chemical crosslinking methods .

In a preferred system for recombinant expression of an antibody or antigen binding portion thereof of the invention, a recombinant expression vector encoding both an antibody heavy chain and an antibody light chain is introduced into dhfr-CHO cells by transfection mediated by calcium phosphate. Within the recombinant expression vector, each of the antibody heavy and light chain genes is operatively linked to regulatory elements of the CMV enhancer / AdMLP promoter to stimulate high levels of gene transcription. The recombinant expression vector also carries the DHFR gene, which allows the selection of CHO cells that have been transfected with the vector using methotrexate selection / amplification. Selected transformant host cells are cultured to allow expression of the antibody heavy and light chains, and the intact antibody is recovered from the culture medium. Standard molecular biology techniques are used to produce a recombinant expression vector, transfect host cells, select transformants, cultivate host cells and extract antibodies from the culture medium.

In connection with the above, nucleic acid, vector and host cell compositions that can be used for recombinant expression of antibodies and portions of antibodies used in the invention include nucleic acids and vectors including these nucleic acids, including the human TNFα adalimumab antibody (D2E7) . The nucleotide sequence encoding the variable region of the light chain of D2E7 is shown in SEQ ID NO: 36. The CDR1 domain of LCVR spans nucleotides 70-102, the CDR2 domain spans nucleotides 148-168, and the CDR3 domain spans nucleotides 265-291. The nucleotide sequence encoding the variable region of the D2E7 heavy chain is shown in SEQ ID NO: 37. The HCVR domain CDR1 covers nucleotides 91-105, the CDR2 domain covers nucleotides 148-198, and the CDR3 domain covers nucleotides 295-330. One skilled in the art will recognize that the nucleotide sequence encoding antibodies associated with D2E7, or parts thereof (e.g., a CDR domain, such as a CDR3 domain), can be obtained from the nucleotide sequence encoding D2E7 LCVR and HCVR using the genetic code and standard molecular biology techniques.

The recombinant human antibodies of the invention, in addition to the D2E7 or antigen binding portion thereof, or the antibodies described herein associated with D2E7, can be isolated by screening a library of recombinant combinatorial antibodies, preferably a scFv phage library obtained using VL and VH cDNA derived from mRNA derived from human lymphocytes. Methodologies for obtaining and screening such libraries are known in the art. In addition to commercially available phage expression development kits (e.g.

examples of methods and reagents, especially suitable for use in the creation and screening of libraries of manifestations of antibodies, can be found, for example, in documents

In a preferred embodiment, to isolate human antibodies with a high affinity for hTNFα and a low rejection frequency constant, a murine anti-hTNFα antibody having a high affinity for hTNFα and a low rejection frequency constant (for example, MAK 195, hybridoma for which has a deposit number of ECACC 87 050801 ) is first used to select human heavy and light chain sequences having the same hTNFα binding activity using the epitope imprinting methods described in Hoogenboom et al., PCT Publication No. WO 93/06213. The antibody libraries used in this method are preferably scFv libraries obtained and screened as described in documents

Screening of scFv antibody libraries is preferably carried out using recombinant human TNFα as an antigen.

After selecting the source segments of human VL and VH, “mixing and matching” experiments are performed, in which various pairs of initially selected VL and VH segments are screened for hTNFα binding to select preferred combinations of VL / VH pairs. In addition, to further improve the affinity and / or decrease the frequency of rejection for hTNFα binding, the VL and VH segments of the preferred VL / VH pair (s) can be randomly mutated, preferably within the CDR3 region of VH and / or VL, during similar to the in vivo somatic mutation process responsible for maturation of antibody affinity during the natural immune response. This in vitro affinity maturation can be achieved by amplification of the VH and VL regions using PCR primers complementary to VH CDR3 or VL CDR3, respectively, with the primers being “spliced” by exposure to a random mixture of four nucleotide bases at specific positions such that the resulting PCR products encode segments VH and VL into which random mutations were introduced from the VH and / or VL region of CDR3. You can re-screen these randomly mutated VH and VL segments to detect binding to hTNFα, and sequences that exhibit high affinity and low rejection rates for hTNFα can be selected.

After screening and isolating the hTNFα antibody of the invention from the recombinant immunoglobulin development library, the nucleic acid encoding the selected antibody can be removed from the development package (e.g., from the phage genome) and subcloned into other expression vectors by standard recombinant DNA techniques. If desired, further manipulations can be performed with the nucleic acid to create other forms of the antibody of the invention (e.g., linked to a nucleic acid encoding additional immunoglobulin domains, such as additional constant regions). For expression of a recombinant human antibody isolated by screening a combinatorial library, the DNA encoding the antibody is cloned into the recombinant expression vector and introduced into mammalian host cells, as described in more detail above.

Methods for isolating human neutralizing antibodies with high affinity and low rejection rates for hTNFα are described in US Pat. Nos. 6,090,382, 6,258,562 and 6,509,505, each of which is incorporated herein by reference.

IV. Substances for use in the automatic injection device

The methods and compositions of the invention can be used with automatic injection devices that administer essentially any substance or drug suitable for administration by injection. Typically, the substance or drug should be in a fluid, for example liquid, form, although drugs in other forms, such as gels or semi-solid substances, suspensions, solutions of particulate substances, etc., may also be suitable for use if automatic the injection device is designed to allow administration of such forms of the drug.

Preferred drugs are biological agents such as antibodies, cytokines, vaccines, fusion proteins, and growth factors. Methods for producing antibodies are described above.

Non-limiting examples of other biological agents that can be used as a medicine in an automatic injection device include, but are not limited to, antibodies or antagonists of human cytokines or growth factors, for example, TNF, LT, IL-I, IL-2, IL-3, IL-4 , IL-5, IL-6, IL-7, IL-8, IL-15, IL-16, 1L-18, 1L-21, IL-23, interferons, EMAP-II, GM-CSF, FGF and PDGF ; antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD38, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands, including CD154 (gp39 or CD40L); TNFα converting enzyme inhibitors (TACE); IL-1 inhibitors (inhibitors of the enzyme converting interleukin-1, IL-1RA, etc.); interleukin-11; IL-18 antagonists, including IL-18 antibodies or soluble IL-18 receptors, or IL-18 binding proteins; non-depleting anti-CD4 inhibitors; CD80 (B7.1) or CD86 (B7.2) co-stimulatory pathway antagonists, including antibodies, soluble receptors or antagonistic ligands; agents that inhibit signaling by pro-inflammatory cytokines, such as TNFα or IL-1 (for example, IRAK, NIK, IKK, p38 or MAP kinase inhibitors); IL-1β converting enzyme inhibitors (ICE); T cell signaling inhibitors, such as kinase inhibitors; metalloproteinase inhibitors; angiotensin converting enzyme inhibitors; soluble cytokine receptors and their derivatives (for example, soluble TNF receptors p55 and p75 and derivatives p75TNFRIgG (Enbrel ^TM and p75TNFRIgG (Lenercept)), sIL-1RI, sIL-1RII, sIL-6R); anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-11, IL-13, and TGF-beta); rituximab; IL-1 TRAP; MPA CTLA4-Ig; IL-18 BP; anti-IL-18; anti-IL15; IDEC-CE9.1 / SB 210396 (non-depleting, primatized anti-CD4 antibody; IDEC / SmithKline; see, for example, Arthritis & Rheumatism (1995) Vol. 38, S185); DAB 486-IL-2 and / or DAB 389-IL-2 (fusion proteins of IL-2; Seragen; see, for example, Arthritis & Rheumatism (1993) Vol. 36, 1223); anti-Tac (humanized anti-IL-2Ra; Protein Design Labs / Roche); IL-4 (anti-inflammatory cytokine; DNAX / Schering); IL-10 (SCH 52000; recombinant IL-10, anti-inflammatory cytokine; DNAX / Schering); agonists of IL-10 and / or IL-4 (e.g., agonistic antibodies); IL-IRA (IL-1 receptor antagonist; Synergen / Amgen); Anakinra (Kineret® / Amgen); TNF-bp / s-TNF (soluble TNF binding protein; see, e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S284; Amer. J. Physiol. - Heart and Circulatory Physiology (1995 ) Vol. 268, pp. 37-42); R973401 (type IV phosphodiesterase inhibitor; see, for example, Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S282); MK-966 (COX-2 inhibitor; see, for example, Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S81); iloprost (see, for example, Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S82); zap-70 and / or 1ck inhibitor (zap-70 and / or 1ck tyrosine kinase inhibitor); VEGF inhibitor and / or VEGF-R inhibitor (vascular endothelial cell growth factor inhibitors or vascular endothelial cell growth factor receptor; angiogenesis inhibitors); TNF-convertase inhibitors; anti-IL-12 antibodies; anti-IL-18 antibodies; interleukin-11 (see, for example, Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S296); interleukin-13 (see, e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S308); interleukin-17 (see, for example, Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S120); anti-thymocytic globulin; anti-CD4 antibodies; CD5 toxins; antisense phosphorothioate oligodeoxynucleotides ICAM-1 (ISIS 2302; Isis Pharmaceuticals, Inc.); soluble complementary receptor 1 (TP10; T Cell Sciences, Inc.); and anti-IL2R antibodies.

The pharmaceutical compositions may be loaded into the automatic injection device of the invention for delivery to the user. In one embodiment, antibodies, portions of antibodies, as well as other TNFα inhibitors, may be included in pharmaceutical compositions suitable for administration to a user using the device of the invention. Typically, a pharmaceutical composition includes an antibody, a portion of an antibody, or another TNFα inhibitor, and a pharmaceutically acceptable carrier. As used herein, the term “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, and combinations thereof. In many cases, it is preferable to include isotonic agents, for example sugars, polyalcohols, such as mannitol, sorbitol or sodium chloride, in combination. Pharmaceutically acceptable carriers may also include small amounts of additional substances, such as wetting or emulsifying agents, preservatives or buffers, which extend the shelf life or enhance the effectiveness of the antibody, part of the antibody, or other TNFα inhibitor.

Compositions for use in the methods and compositions of the invention can be presented in various forms, in accordance with the administration through the device of the invention, including, for example, liquid solutions (e.g., injectable and infused solutions), dispersions or suspensions. In a preferred embodiment, the antibody or other TNFα inhibitor is administered by subcutaneous injection using the device of the invention. In one embodiment, a user administers a TNFα inhibitor, including but not limited to a TNFα antibody, or an antigen binding portion thereof using the device of the invention.

Therapeutic compositions usually must be sterile and stable under the conditions of manufacture and storage. The composition may be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable for a high concentration of drug. Sterile injectable solutions can be prepared by incorporating the active compound (i.e., an antibody, part of an antibody or other TNFα inhibitor) in the required amount in an appropriate solvent, as required, with one or a combination of the ingredients listed above, followed by filtration sterilization. In general, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders to obtain sterile injectable solutions, the preferred methods of preparation are vacuum drying and lyophilization, which gives the powder of the active ingredient plus any desired ingredient from its previously sterilized by filtration solution. Appropriate fluidity of the solution can be maintained, for example, by using a coating such as lecithin, maintaining the desired particle size in the case of dispersion, and using surfactants. Prolonged absorption of the injectable compositions can be ensured by the inclusion in the composition of a substance that delays absorption, for example, monostearates and gelatin.

In one embodiment, the invention includes an automatic injection device, for example, an auto-injector handle, comprising an effective TNFα inhibitor and a pharmaceutically acceptable carrier. Thus, the invention provides a pre-filled automatic injection device comprising a TNFα inhibitor.

In one embodiment, an antibody or part of an antibody for use in the methods of the invention is included in a pharmaceutical formulation as described in PCT / IB03 / 04502 and US Patent Application No. 20040033228, incorporated herein by reference. This formulation includes an antibody of D2E7 (adalimumab) at a concentration of 50 mg / ml, where one auto-injection pen includes 40 mg of antibody for subcutaneous injection. In one embodiment, the automatic injection device of the invention (or more specifically, the syringe of the device) comprises an adalimumab formulation having the following composition: adalimumab, sodium chloride, monobasic sodium dihydrogen phosphate, dibasic sodium dihydrogen phosphate, sodium citrate, citric acid monohydrate, mannitol, polysorbate 80 and water, for example water for injection. In another embodiment, the automatic injection device comprises adalimumab in an amount of 40 mg, 4.93 mg of sodium chloride, 0.69 mg of monobasic sodium dihydrogen phosphate, 1.22 mg of dibasic sodium dihydrogen phosphate, 0.24 mg of sodium citrate, 1.04 mg of monohydrate citric acid, 9.6 mg of mannitol, 0.8 mg of polysorbate 80 and water, for example water for injection. In one embodiment, sodium hydroxide is added as needed to adjust pH.

The dose of a TNFα inhibitor in an automatic injection device may vary according to the disorder for which a TNFα inhibitor is used for treatment. In one embodiment, the invention includes an automatic injection device comprising a dose of adalimumab of about 20 mg; 40 mg adalimumab; 80 mg of adalimumab and 160 mg of adalimumab. It should be noted that for all ranges described herein, including dose ranges, all figures that are intermediate with respect to the given values are included in the invention, for example 36 mg of adalimumab, 48 mg of adalimumab, etc. In addition, the indicated intervals using the indicated numbers are also included, for example from 40 to 80 mg of adalimumab. The figures given in this document are not intended to limit the scope of the invention.

Antibodies and TNFα inhibitors used in the invention can also be administered in the form of protein crystalline formulations that include a combination of protein crystals encapsulated inside a polymer carrier to form coated particles. Coated particles of protein crystalline formulations may have a spherical morphology and may be microspheres with a diameter of up to 500 μm, or they may have some other morphology and be microparticles. The increased concentration of protein crystals allows subcutaneous delivery of the antibodies of the invention. In one embodiment, the TNFα antibodies of the invention are delivered via a protein delivery device, where one or more protein crystalline crystalline formulations or compositions are administered to a user having a disorder associated with TNFα. Compositions and methods for preparing stabilized formulations of whole antibody crystals or antibody fragment crystals are also described in WO 02/072636, which is incorporated herein by reference. In one embodiment, a formulation comprising crystallized antibody fragments described in PCT / IB03 / 04502 and US Patent Application No. 20040033228, incorporated herein by reference, is used to treat rheumatoid arthritis using the methods of the invention.

Additional active compounds may also be included in the composition. In certain embodiments, an antibody or antibody portion for use in the methods of the invention is co-formulated with one or more additional therapeutic agents, including a rheumatoid arthritis inhibitor or antagonist. For example, an anti-hTNFα antibody or part of an antibody can be co-formulated and / or co-introduced with one or more additional antibodies that bind to other targets associated with TNFα-related disorders (e.g., antibodies that bind other cytokines, or which bind cell surface molecules), one or more cytokines, a soluble TNFα receptor (see, for example, PCT publication No. WO 94/06476) and / or one or more chemical agents that inhibit production or activity hTNFα (such as cyclohexane-ylidene derivatives as described in PCT Publication No. WO 93/19751), or any combination thereof. In addition, one or more antibodies of the invention may be used in combination with two or more of the above therapeutic agents. In such combination therapies, it is possible to advantageously use lower dosages of the administered therapeutic agents, thus avoiding the possible side effects, complications or low level of patient response associated with various types of monotherapy. Additional agents that can be used in combination with a TNFα antibody or a portion of an antibody are described in US patent application No. 11/800531, which is fully incorporated herein.

An automatic injection device, for example, an autoinjection pen, according to the invention may comprise a “therapeutically effective amount” or a “prophylactically effective amount” of an antibody or part of an antibody of the invention. A “therapeutically effective amount” refers to an amount effective in dosage and over a period of time necessary to achieve the desired therapeutic result. A therapeutically effective amount of an antibody, part of an antibody or other TNFα inhibitor can vary according to factors such as the pathological condition, age, gender and weight of the individual, and the ability of the antibody, part of the antibody, other TNFα inhibitor to elicit the desired response in the individual. A therapeutically effective amount is also the amount at which any toxic or damaging effects of an antibody, part of an antibody, or other TNFα inhibitor are outweighed by therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective at dosages and for periods of time necessary to achieve the desired prophylactic result. Usually, since a prophylactic dose is used in patients before the disease or in its early stages, the prophylactically effective amount will be less than the therapeutically effective amount.

V. Manufactured products according to the invention

The invention also provides a manufactured article or kit comprising an automatic injection device according to the invention. In one embodiment, the kit includes an automatic injection device, for example, an auto-injection pen, such as a HUMIRA® pen containing a liquid drug, for example a TNFα inhibitor, such as an antibody, and instructions for administering a liquid drug. In one embodiment, the kit includes instructions for delivering a TNFα inhibitor for treating a disorder in which TNFα has a deleterious effect, such as rheumatoid arthritis, using an automatic injection device. The instructions may describe how, for example, subcutaneously, and when, for example, after 0 week, after 2 weeks, after 4 weeks, etc., a dose of a TNFα inhibitor should be administered to the patient for treatment.

A manufactured article, also referred to herein as a kit, refers to a packaged product comprising the automatic injection device of the invention. The kit preferably includes a box or container that contains the components of the kit, i.e. automatic injection device. In one embodiment, an automatic injection device, such as an auto-injection pen, is enclosed in a dose tray within a kit or article. The kit may also include instructions for administering to the patient a substance, such as a liquid drug, such as a TNFα antibody, using the automatic injection device of the invention. The term “package insert” is used to refer to the instructions usually included in the sold packaging of therapeutic products, including liquid medicines, which contain information about the indications, use, dosage, administration, contraindications and / or warnings regarding the use of such therapeutic products. In one embodiment, the package insert is a label for a therapeutic substance provided by the kit.

The kit or manufactured product may include a label or label containing information about the approval of the Administration of Food and Drug Administration, which provides a sequence of operations for the use of an automatic injection device for administration of a substance, such as a TNFα inhibitor. Thus, the invention also includes labels and tags, used alone or in combination with the manufactured product, which provide the patient with information regarding the automatic injection device, including information on how to use the device, which substance, for example a liquid dose, contains the device for administration to the patient, and how to remove the device after completion of the introduction. In one embodiment, the label is found on the package insert. In one embodiment, the label is a package insert that includes a patient information sheet providing the patient with information on how to use the automatic injection device of the invention.

A kit or manufactured product according to the invention may contain information about the automatic injection device in relation to how the device is packaged inside the kit or product. The kit may include a dose tray including an automatic injection device according to the invention, which contains a substance, such as a TNFα inhibitor. In one embodiment, the dose tray is for single use of the device for administering the agent. In another example, the kit may include 2 or more dose trays, each containing an automatic injection device, such as an auto-injection pen. The kit or manufactured product may also indicate related items needed to use the automatic injection device, for example, alcohol swabs for treating the skin, a package insert with the attached patient information leaflet and / or patient information leaflet. Such written material, such as a package insert with an attached patient information leaflet and / or patient information leaflet, can be used to provide the recipient with information regarding the administration methods, common side effects, information about removing the device, etc. In one embodiment, the kit or article of manufacture of the invention, visible from the outside of the package of the set or article, indicates that the kit or article contains 2 dose trays, 2 alcohol swabs for skin preparation, one package insert with an attached patient information sheet and one information leaflet for the patient.

The kit or manufactured product of the invention may contain information, for example on a label, regarding how a liquid dose of a preparation, such as a TNFα inhibitor (adalimumab), is packaged inside an automatic injection device, such as an auto-injection pen, according to the invention. For example, in one embodiment, the label of the invention may indicate that adalimumab is dispensed in a cardboard box containing 6 alcohol swabs for preparing the skin and 6 dose trays (initial packaging for treating Crohn’s disease). In one embodiment, the label may also indicate that each dose tray consists of a disposable pen, each pen containing a pre-filled 1 ml glass syringe with a 27 ½-inch fixed needle providing 40 mg (0.8 ml) of HUMIRA® .

In one embodiment, the kit or manufactured product of the invention includes information indicating that the automatic injection device provided within the kit includes a formulation comprising the human adalimumab antibody (adalimumab / HUMIRA® / D2E7) as described in PCT / IB03 / 04502 and U.S. Patent Application No. 10/222140, incorporated herein by reference to them.

In one embodiment, the kit or manufactured product of the invention may contain information, for example, on a label, that describes that HUMIRA® is supplied as a sterile, preservative-free adalimumab solution for subcutaneous administration. The label may also describe that the medicinal product is supplied either in the form of a 1 ml disposable glass syringe or a disposable pen (HUMIRA® pen). The label of the invention may indicate that a disposable, pre-filled 1 ml glass syringe is included inside the pen. The label of the invention may further indicate that the HUMIRA® solution is clear and colorless, with a pH of about 5.2. The label may also indicate that HUMIRA® (adalimumab) is supplied in pre-filled syringes or in pre-filled pens in the form of a preservative-free, sterile solution for subcutaneous administration. In one embodiment, the label indicates that the automatic injection device of the invention containing adalimumab is provided in a cardboard box with a HUMIRA® pen, where HUMIRA® is dispensed in a cardboard box containing 2 alcohol swabs for preparing the skin and 2 dose trays. The label may also determine that each dose tray consists of at least one disposable pen containing a pre-filled 1 ml glass syringe with a 27 ½-inch fixed needle providing 40 mg (0.8 ml) of HUMIRA ®.

The kit or manufactured product of the invention may contain information, for example, on a label, that provides information on how the automatic injection device should look in the kit and / or what the substance contained within the automatic injection device should look like, for example, a liquid medicine. Such information may be provided to ensure safety regarding the administration of the substance to the patient so that the patient knows whether the kit and / or the automatic injection device has been damaged and / or whether the substance is damaged, so that administration thereof should not be performed. In one embodiment, the label indicates that the solution in the HUMIRA® pen should be carefully inspected visually to detect particulate material and discoloration before subcutaneous administration.

The kit or manufactured product of the invention may contain information, for example on a label, that provides instructions on how to use the automatic injection device of the invention, including the administration of a substance, such as a liquid drug, contained within the device. In one embodiment, the label indicates that patients using the HUMIRA® pen should be instructed to inject the full amount of solution contained in the syringe (0.8 ml), which provides 40 mg of HUMIRA®, in accordance with the instructions provided in the leaflet for the patient.

The kit or manufactured product of the invention may contain information, for example, on a label that provides instructions for preparing to use the pen of the invention. For example, a label may provide assembly instructions for a pen injection. In one embodiment, the invention provides a pen filled with HUMIRA®, where a label for said pen may indicate that the patient will need the following items for each dose: one HUMIRA® pen and 1 alcohol swab for skin preparation (stick swab). The label may also indicate that the patient should find a clean, flat work surface. The label may also indicate that the pen should not be used if the seals on the top and bottom of the cardboard box are broken or missing, and also optionally indicate that the patient should contact the pharmacist if the seals are broken. The label may indicate to the patient that he should remove one dose tray containing, for example, a HUMIRA® pen, from the refrigerator (if the substance, such as a liquid medicine, requires cooling). In addition, a label containing instructions for using a pen filled with HUMIRA® may indicate that the patient should not use a pen that is frozen, or if it has been left in direct sunlight. The label may also indicate that if the patient does not have all the elements necessary for the injection, then a pharmacist should be called. The label may also indicate that the patient should only use items provided in the box in which the substance is delivered, such as HUMIRA®.

For labels of the invention relating to an autoinjection pen including adalimumab, the label may indicate that the patient should check and make sure that the name HUMIRA® is on the dose tray and handle label; that the patient should check the expiration date on the dose tray label and pen label in order to make sure that the expiration date has not expired, and in addition, the patient should not use the pen if the expiration date has expired; and that the patient should have a puncture-protected container nearby to remove the used pen.

The kit or product may also contain, either within the package, or through the accompanying information, material for use in treating the disorders described herein. In one embodiment, the package is specific for a disorder that is being treated with a TNFα antibody, such as adalimumab. The kit or manufactured product may also include a second agent (as described herein) packaged or jointly included with instructions for using the second agent with the first agent (as described herein).

Methods of using the automatic injection device according to the invention are described in more detail below in the examples. In addition, any of the methods described herein relating to an automatic injection device may be included in the label of the invention.

VI. Methods and compositions for use with an automatic injection device

Methods and compositions for delivering a substance using an automatic injection device

The invention also provides methods of using the automatic injection device of the invention to deliver a substance, for example a drug or a liquid dose of a drug, such as a TNFα inhibitor. In one embodiment, the automatic injection device is an auto-injection pen, such as a HUMIRA® pen.

The methods include preparation methods for the use of an automatic injection device, for example, an auto-injection pen according to the invention.

The use of an automatic injection device may require the patient to first select and prepare an injection site. For example, methods for selecting and preparing an injection site for administering an auto-injection pen, such as a HUMIRA® pen, include thoroughly washing the patient's hands first. In general, for an injection from an automatic injection device, a clean or healthy part of the patient’s body is selected. In one embodiment, the site is selected on the front surface of the thighs or abdomen of the patient. If the abdomen is selected, the patient should avoid the 2-inch area around the navel. For injection with an auto-injection pen, such as a HUMIRA® pen, a different area should be selected each time an injection is made. Each new injection should be made at least one inch from the previously used area. In general, areas where there is tender skin, hemorrhage, redness or hardness, or where there are scars or stretch marks should not be used as injection sites. Keeping records of the location of previous injection sites can help the patient.

After selecting the injection site, the patient generally clears this area. In one embodiment, the area to be injected with HUMIRA® is first wiped with an alcohol swab to prepare the skin surface. After cleaning, the injection site should not be touched again until the patient is ready for injection.

The methods of the invention also include preparing a dose of a substance to be injected inside an automatic injection device, such as an auto-injection pen. In one embodiment, the auto-injection handle is held with the first removable cap pointing up. The patient should examine the solution or substance, for example, a liquid drug, through the windows on the side of an automatic injection device, such as an auto-injection pen, in order to make sure, for example, that the liquid is clear and colorless. In general, an automatic injection device, such as an auto-injection pen, should not be used if the liquid is cloudy or has a discolored color, or contains flakes or particles. In addition, do not use an automatic injection device, such as an auto-injection pen, if it is frozen.

After determining that an automatic injection device, such as an auto-injection pen, is suitable for use and injection, the device can be held with the first removable cap pointing down. Such an action can serve to determine the level of a liquid drug inside an automatic injection device, for example, an auto-injection pen.

In one embodiment, a test should be performed prior to injection to verify that the amount of fluid in the automatic injection device, such as an auto-injection pen, is at or close to the line seen through the window. In one embodiment, this line represents the full dose of the product. The upper surface of the liquid may be curved. If an automatic injection device, such as an auto-injection pen, does not contain the right amount of liquid, then the auto-injection pen should not be used and, optionally, a pharmacist should be called.

Injection methods for delivering a substance, such as a liquid drug, using an automatic injection device, such as an auto-injection pen, according to the invention may include the following. An automatic injection device, such as an auto-injection pen, is held with one hand. With the other hand, the patient first removes and discards the removable cap. In one embodiment, the first removable cap should be removed directly and / or should not be twisted. After removing the first removable cap, the patient should check whether the sheath of the needle was removed along with the first removable cap. After removal, the inner coating of the needle is held in the cap. Do not touch the needle enclosed in the syringe barrel. The distal end of the casing with ledges will be exposed after removing the first removable cap. The first removable cap should not be put on again since the needle could be damaged. In addition, the patient must be careful to avoid dropping or crushing an automatic injection device, such as an auto-injection pen, because it contains a syringe.

After removing the first removable cap, the second removable cap (also called the protective cap) is removed to expose the start button on the top. The patient should remove the second removable cap by direct pulling. The second removable cap should not be twisted. After removing the first and second removable caps, the automatic injection device, such as the auto-injection pen, is now ready for use. The patient should understand that an automatic injection device, such as an auto-injection pen, is activated after the second removable cap is removed, and moreover, pressing the start button under the second removable cap will eject the drug. The patient should also understand that the start button should not be removed until the device is properly located. In addition, at this point, an automatic injection device, such as an auto-injection pen, should not be closed again with a cap, as this may cause the device to eject.

When the patient is ready to inject, an automatic injection device, such as an auto-injection pen, should be positioned so that a window is visible. The patient with his free hand can gently squeeze a limited area of the cleansed skin at the injection site, creating a flat surface on which an automatic injection device is placed, for example, an auto-injection pen. The proximal end of an automatic injection device, such as an auto-injection pen, can be placed at an angle of 90 degrees to the flat surface of the skin. An automatic injection device, such as an auto-injection pen, should be positioned so that it does not inject the needle into the patient's fingers. To start the injection, the start button is pressed. In one embodiment, the start button is pressed with a finger, such as the index finger of a patient, to start an injection. Alternatively, in another embodiment, the patient may also press the start button with the thumb of the hand to start the injection. During the injection, the patient should try not to close the window. In one embodiment, when you press the start button, an audible indicator will sound, such as a click. An audible indicator, such as a click, may indicate the start of an injection. In one embodiment, an autoinjection pen containing adalimumab produces noise when the start button is pressed. After pressing the start button, the pressure on the start button should be continued, and the patient can continue to hold the automatic injection device, such as the auto-injection handle, at constant pressure on the injection site until the end of the process. In one embodiment, the process of pushing the start button to complete the injection may take up to about 10 seconds. For injection, constant pressure on the injection site is maintained for the entire period of time.

When using an automatic injection device, such as an auto-injection pen, the patient will know that the injection has ended when an indicator appears in the window, occupies the entire visible field of view and stops. When the injection ends, an automatic injection device, such as an auto-injection pen, is removed from the user's skin. The cover will automatically advance over the tip of the needle. The patient can press a cotton ball to the injection site and hold it, for example, for 10 seconds. The patient should not rub the injection site, and should not be disturbed if there is a slight discharge of blood. After the injection, an automatic injection device, such as an auto-injection pen, should be removed so that the patient does not try to touch the needle. The needle sleeve prevents the patient from touching the needle.

It should be noted that any of the instructions given in the methods for using the automatic injection device according to the invention can be included in the label for an automatic injection device, for example, an auto-injection pen according to the invention.

Methods and compositions for training a recipient to use an automatic injection device

Another aspect of the invention relates to methods and compositions for training a recipient to use an automatic injection device. Based on the experience of using the device in clinical trials, certain important signs have been identified for the successful use of the device, and these signs can be included in working methods for training recipients to use an automatic injection device. Such training methods and compositions used in such methods are favorable for transmitting to the end user the device or company that will introduce, assign or sell the device to the end user, information about important features for the successful use of the device.

In addition, the use of a demonstration automatic injection device or preparatory device that mimics the appearance and tactile perception of a real automatic injection device, but which is unable to administer a substance or drug, is especially useful in preparing the recipient for the successful use of a real automatic injection device, as it allows the recipient test and manipulate and adjust the device without Necessary drug administration.

Accordingly, in one aspect, the invention provides a method for preparing a recipient for use of an automatic injection device, wherein the automatic injection device includes a needle and a medicament, the method comprising providing the recipient:

(a) a demonstration automatic injection device without a needle and a drug; and

(b) instructions for use of the automatic injection device.

In another aspect, the invention provides a kit for preparing a recipient for use of an automatic injection device, wherein the automatic injection device includes a needle and a medicament, the kit comprising:

(a) a demonstration automatic injection device in which there is no needle and drug; and

(b) instructions for use of the automatic injection device.

In a preferred embodiment, the recipient is a doctor who prescribes a drug contained within an automatic injection device. In another embodiment, the recipient is a patient who is taking a drug contained within an automatic injection device. Other examples of recipients include pharmacists who dispense the automatic injection device, family members or other categories of patients who take the drug, and representatives who train doctors or patients to use the automatic injection device.

In certain embodiments of the method, including the preparation methods described herein, instructions for using the automatic injection device are transmitted orally to the recipient. In other preferred embodiments, the instructions are transmitted to the recipient in writing (for example, through a printed document) or through an audiovisual device. In kits of the invention, instructions for using an automatic injection device are typically contained in a printed document or audiovisual device. Preferred audiovisual devices include VHS tapes and DVDs.

The automatic demonstration injection device is designed to have the appearance and tactile perception of a real automatic injection device, but which does not have at least one component necessary to ensure the successful administration of the drug by the end user, and most preferably at least at least, does not have a needle, which allows you to avoid accidental needle injections when using a demonstration automatic injection mouth oystva. Preferably, the demonstration automatic injection device is devoid of both the needle and the drug contained in the actual automatic injection device.

In another aspect, the invention provides a method of preparing a recipient for use of an automatic injection device, wherein the automatic injection device includes an actuation mechanism and a medicament, the method comprising transmitting to the recipient instructions:

(a) position the automatic injection device at the injection site;

(b) turn on the actuation mechanism to initiate drug injection;

(c) support the activation of the actuation mechanism for a designated period of time to continue the injection of the drug; and

(d) remove the automatic injection device from the injection site after passing the designated period of time.

The invention also provides an audiovisual device for preparing a recipient for use of an automatic injection device, wherein the automatic injection device includes an actuation mechanism and a medicament, the audiovisual device transmitting instructions to the recipient:

(a) position the automatic injection device at the injection site;

(b) turn on the actuation mechanism to initiate drug injection;

(c) support the activation of the actuation mechanism for a prescribed period of time to continue the injection of the drug; and

(d) remove the automatic injection device from the injection site after the expiration of the prescribed period of time.

Preferably, the audiovisual device is a VHS or DVD cassette.

In the preparation methods and audiovisual devices described above, the instructions may also transmit a message that the initial activation of the actuation mechanism is accompanied by an audible sound, such as a “click”. Other examples of audible sounds include a ringer, a buzzer, or a tone.

In other embodiments of the preparation methods and audiovisual devices described above, the instructions may also transmit a message indicating that the completion of the drug injection is accompanied by a visible indicator of completion of the injection and / or the instructions may further transmit a message indicating that the injection site should be sterilized before placement of the automatic injection device at the injection site.

Other examples of instructions that can be transmitted in the preparation methods and audiovisual devices described above are described in further detail in Example 4.

In yet another aspect, the invention provides a method for preparing a recipient for using an automatic injection device, wherein the automatic injection device includes an actuation mechanism and a medicament, the method comprising transmitting to the recipient instructions:

(a) position the automatic injection device at the injection site;

(b) turn on the actuation mechanism to initiate drug injection;

(c) maintain the activation mechanism to continue the drug injection until a visible indicator of completion of the injection is detected; and

(d) remove the automatic injection device from the injection site when a visible indicator of completion of the injection is detected.

The invention also provides an audiovisual device for preparing a recipient for use of an automatic injection device, wherein the automatic injection device includes an actuation mechanism and a medicament, the audiovisual device transmitting instructions to the recipient:

(a) position the automatic injection device at the injection site;

(b) turn on the actuation mechanism to initiate drug injection;

(c) maintain the activation mechanism to continue the drug injection until a visible indicator of completion of the injection is detected; and

(d) remove the automatic injection device from the injection site when a visible indicator of completion of the injection is detected.

Preferably, the automatic injection device includes an indicator window, and the visible indicator of completion of injection includes a color indicator that appears in the indicator window. The preferred indicator color is yellow. Other examples of suitable color indicators include red, orange, blue, green, pink, or magenta color indicators. Other examples of visible indicators of completion of an injection include the appearance of a symbol or image in the indicator window after completion of the injection and the appearance of a “depressed” button on the automatic injection device after completion of the injection.

In other embodiments of the preparation methods and audiovisual devices described above, instructions may also transmit a message stating that activation of the actuation mechanism should be maintained for a prescribed period of time to continue injecting the drug and / or instructions may also transmit the message that the injection site should be sterilized before the location of the automatic injection device in the injection site. Preferably, the prescribed time period is 10 seconds. Another preferred prescribed period of time is at least 10 seconds. In various other embodiments, the prescribed time period is 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, 11 seconds, 12 seconds, 13 seconds, 14 seconds, 15 seconds, 30 seconds, 45 seconds or 1 minute.

In another embodiment of the preparation methods and audiovisual devices described above, the instructions also send a message that the automatic injection device should be examined for the correct dosage and formulation of the drug before placing the automatic injection device in the injection site. Such an examination can be carried out, for example, by examining the drug through a window provided in the automatic injection device, which makes it possible to visualize the liquid drug contained in the device. Examples of screening for the correct dosage and formulation include screening to determine if the drug is clear and colorless (for example, that it is not clouded and does not contain particulate matter) and screening to see if the drug’s level is visible “fill line” display window or close to it.

Other examples of instructions that may be transmitted in the preparation methods and audiovisual means described above are described in further detail in Example 4.

VII. Methods and compositions for attracting the use of an automatic injection device

Another aspect of the invention relates to methods and compositions for attracting the use of an automatic injection device. Based on the results of clinical trials, the predominant features of an automatic injection device have now been discovered, and these signs can be included in working methods of attracting an automatic injection device to use. Such distribution promotion methods and compositions used in such methods are beneficial in informing the end user of the device or company that will introduce, designate or sell the device to the user about the advantageous features of the device.

Accordingly, in one aspect, the invention provides a method for attracting a patient to use an automatic injection device containing a substance, such as a drug, the method comprising transmitting to the recipient at least one message selected from the group consisting of messages that:

(a) using an automatic injection device is less painful than using a pre-filled syringe;

(b) the use of an automatic injection device by patients is preferred over a pre-filled syringe;

(c) it is easier for the patient to use an automatic injection device than a pre-filled syringe;

(d) it is more convenient for the patient to use an automatic injection device than a pre-filled syringe;

(e) an automatic injection device reduces anxiety in patients who are afraid of needles compared to a pre-filled syringe because the needle is not visible in the device; and

(f) an automatic injection device is designed for ease of use from the initial use of the device.

In a preferred embodiment, a message is sent to the recipient that using an automatic injection device is less painful than using a pre-filled syringe. For example, the recipient is informed that 80% of patients in a clinical trial rated the automatic injection device as less painful than a pre-filled syringe.

In another preferred embodiment, a message is sent to the recipient stating that patients prefer the use of an automatic injection device to the use of a pre-filled syringe. For example, a message is transmitted that 90% of patients in a clinical trial preferred an automatic injection device to a pre-filled syringe.

The recipient may also be notified of certain structural features of the automatic injection device. For example, the recipient may further receive a message that the automatic injection device contains a five-chamfered needle, compared with a three-chamfered needle for a pre-filled syringe. As another example, a message can be sent to the recipient that the needle is not visible in the device (i.e., it is not visible to the device user when the device is used in accordance with the instructions).

In a preferred embodiment, the recipient is a doctor who prescribes a drug contained within an automatic injection device. In another embodiment, the recipient is a patient who is taking a drug contained within an automatic injection device. Other examples of recipients include pharmacists who dispense the automatic injection device, family members or carers for patients who take the drug, and representatives who train doctors or patients to use the automatic injection device.

In a preferred embodiment, at least one message is transmitted to the recipient orally. In another preferred embodiment, at least one message is transmitted to said recipient in writing (for example, by means of a printed document, such as a package insert). In yet another preferred embodiment, at least one message is transmitted to the recipient via an audiovisual device.

In another aspect, the invention relates to an audiovisual device for attracting a recipient to use an automatic injection device comprising a medicament, where the device transmits to the recipient at least one message selected from the group consisting of messages that:

(a) using an automatic injection device is less painful than using a pre-filled syringe;

(b) the use of an automatic injection device by patients is preferred over a pre-filled syringe;

(c) it is easier for the patient to use an automatic injection device than a pre-filled syringe;

(d) it is more convenient for the patient to use an automatic injection device than a pre-filled syringe;

(e) an automatic injection device reduces anxiety in patients who are afraid of needles compared to a pre-filled syringe because the needle is not visible in the device; and

(f) an automatic injection device is designed for ease of use from the initial use of the device.

In a preferred embodiment, the audiovisual device is a home video system (VHS) cassette. In another preferred embodiment, the audiovisual device is either a digital video disc (DVD).

In a preferred embodiment, the audiovisual device transmits to the recipient a message that using an automatic injection device is less painful than using a pre-filled syringe. For example, an audiovisual device may convey a message that 80% of patients in a clinical trial rated the automatic injection device as less painful than a pre-filled syringe.

In another preferred embodiment, the audiovisual device transmits to the recipient a message that patients prefer the use of an automatic injection device to a pre-filled syringe. For example, an audiovisual device may convey to the recipient a message that 90% of patients in a clinical trial prefer an automatic injection device to a pre-filled syringe.

The audiovisual device may convey to the recipient a message about certain structural features of the automatic injection device. For example, an audiovisual device may transmit a message stating that the automatic injection device contains a five-chamfer needle compared to a three-chamfer needle for a prefilled syringe. As another example, an audiovisual device may transmit a message stating that the needle is not visible in the device (i.e., it is not visible to the device user when the device is used in accordance with the instructions).

In yet other embodiments, an automatic injection device previously described in this technical field is used in the methods and compositions of the invention relating to preparation for use and to attracting the use of an automatic injection device. Suitable automatic injection devices have been described in the art, including, but not limited to, the devices described in US Pat.

VII. Disorders in which TNFα activity has a damaging effect and which can be treated with a TNFα inhibitor using an automatic injection device

An automatic injection device, such as an auto-injection pen, of the invention can be used in methods for treating devices, including, in one embodiment, disorders associated with the damaging activity of TNFα. In one embodiment, an automatic injection device, such as an auto-injection pen, is used to deliver a substance, such as a TNFα inhibitor, to a patient for treatment, where the disorder includes, but is not limited to rheumatoid arthritis (including juvenile arthritis), Crohn's disease, psoriasis, psoriatic arthritis and ankylosing spondylitis .

As used herein, the term “disorder in which TNFα activity has a deleterious effect” is intended to include diseases and other disorders in which it has been shown that the presence of TNFα in a patient suffering from the disorder is either responsible or suspected of being responsible for the pathophysiology of the disorder, or it is a factor that contributes to the aggravation of the disorder. Accordingly, a disorder in which TNFα activity has a deleterious effect is a disorder in which inhibition of TNFα activity is expected to alleviate the symptoms and / or progression of the disorder. The presence of such disorders can be proved, for example, by an increase in the concentration of TNFα in the biological fluid of a patient suffering from a disorder (for example, an increase in the concentration of TNFα in the serum, plasma, synovial fluid, etc. of the patient), which can be detected, for example, using an anti-TNFα antibody as described above. There are numerous examples of disorders in which TNFα activity has a deleterious effect and are discussed below.

A. Autoimmune diseases

Считалось также, что TNFα способствует гибели островковых клеток и опосредовании устойчивости к инсулину при диабете (см., например, приведенный выше документ Tracey и Cerami; публикацию PCT No WO 94/08609). Считалось также, что TNFα опосредует цитотоксичность в отношении олигодендроцитов и индукцию воспалительных бляшек при рассеянном склерозе (см., например, приведенный выше документ Tracey и Cerami). Химерные и гуманизированные мышиные антитела против TNFα были подвергнуты клиническому испытанию для лечения ревматоидного артрита (см., например,

It was believed that the tumor necrosis factor plays a role in the pathophysiology of a variety of autoimmune diseases. For example, it was believed that TNFα is involved in the activation of tissue inflammation and causes joint destruction in rheumatoid arthritis (see, for example,

It was also believed that TNFα contributes to the death of islet cells and mediation of insulin resistance in diabetes (see, for example, Tracey and Cerami above; PCT publication No. WO 94/08609). It was also believed that TNFα mediates cytotoxicity against oligodendrocytes and the induction of inflammatory plaques in multiple sclerosis (see, for example, Tracey and Cerami, cited above). Chimeric and humanized murine anti-TNFα antibodies have been clinically tested to treat rheumatoid arthritis (see, for example,

TNFα antibodies, such as adalimumab, can be used to treat autoimmune diseases, in particular diseases associated with inflammation. Examples of such autoimmune conditions include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and gouty arthritis, allergies, multiple sclerosis, autoimmune diabetes, autoimmune uveitis and nephrotic syndrome. Other examples of autoimmune conditions include multisystem autoimmune diseases and autoimmune hearing loss.

In one embodiment, the TNFα inhibitor is used to treat autoimmune disorders such as lupus. Lupus has been shown to be associated with TNF activity (Shvidel et al. (2002) Hematol J. 3:32; Studnicka-Benke et al. (1996) Br J Rheumatol. 35: 1067). As used herein, the term "lupus" refers to a chronic, inflammatory autoimmune disorder called lupus erythematosus, which can affect many organ systems, including the skin, joints, and internal organs. Lupus is a general term that includes a number of specific types of lupus, including systemic lupus erythematosus, lupus nephritis, and lupus cerebritis. In systemic lupus erythematosus (SLE), the body’s natural defense mechanisms turn against the body, and evading forms of immune cells attack the body’s tissue. Antibodies can be produced that can react against blood cells, organs and body tissues. This reaction leads to the appearance of immune cells attacking the affected systems, causing chronic diseases. Lupus nephritis, also called lupus glomerular disease, is a kidney disorder that is usually a complication of SLE and is characterized by glomerular damage and progressive loss of renal function. Lupus erythematosus refers to another complication of SLE, which is inflammation of the brain and / or central nervous system.

Another autoimmune disease that can be treated using a TNFα antibody is Crohn's disease, which is described in more detail below in the section "Intestinal disorders"

B. Intestinal disorders

Tumor necrosis factor was believed to be involved in the pathophysiology of inflammatory intestinal disorders, including Crohn's disease (see, e.g., Tracy et al. (1986) Science 234: 470; Sun et al. (1988) J. Clin. Invest. 81: 1328 ; MacDonald et al. (1990) Clin. Exp. Immunol. 81: 301). Chimeric mouse antibodies against hTNFα have been clinically tested to treat Crohn's disease (van Dullemen et al. (1995) Gastroenterology 109: 129). The invention includes a treatment comprising administering a TNFα antibody obtained using the method of the invention for the treatment of intestinal disorders, such as idiopathic inflammatory bowel disease, using human antibodies or antigen binding fragments thereof. Idiopathic inflammatory bowel disease (IBD) includes two syndromes, Crohn's disease and ulcerative colitis. In one embodiment, an antibody obtained using the method of the invention is also used to treat disorders often associated with IBD and Crohn’s disease. The term “inflammatory bowel disorder (IBD) disorder” or “Crohn’s disease disorder”, used interchangeably herein, is used to describe conditions and complications commonly associated with IBD and Crohn’s disease.

The invention also includes a multiple variable dose regimen comprising administering a TNFα antibody to treat Crohn's disease. This treatment for Crohn's disease is based on the location, spread, and severity of the disease. Pharmacological interventions include anti-inflammatory drugs (aminosalicylates and corticosteroids) and immunomodulatory drugs (azathioprine and 6-mercaptopurine [6-MP], cyclosporine, methotrexate [MTX], antibiotic agents and biological agents). Levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) reflect the acute phase of non-specific reactions. Endoscopy is the primary diagnostic tool for Crohn's disease. X-ray signs of Crohn's disease, manifested by barium testing, include swelling of the mucosa, aphthous and linear ulcerations, asymmetric narrowing and strictures, and the separation of adjacent bowel loops caused by a thickening of the mesentery. Anomalies are focal and asymmetric. The primary histological lesion is an aphthous ulcer. The condition of subjects with Crohn’s disease can be assessed using the Crohn’s disease activity index (CDAI), which is a standard indicator of disease activity, with higher scores indicating a higher disease activity.

Examples of Crohn's disease-related disorders that can be treated using the methods of the invention include fistulas in the bladder, vagina and skin, intestinal obstruction; abscesses; nutritional dystrophy; complications from corticosteroids; joint inflammation; erythema nodosum; gangrenous pyoderma and eye lesions. Other disorders commonly associated with Crohn’s disease include arthralgia associated with Crohn’s disease, fistula formation due to Crohn’s disease, colitis of uncertain etiology, and diverticulitis.

C. Spondyloarthropathy

TNFα was believed to play a role in the pathophysiology of a wide variety of disorders, including inflammatory diseases such as spondylarthropathy (see, for example, Moeller et al. (1990) Cytokine 2: 162; US Patent No. 5231024; European Patent Publication No. 260610). The invention provides methods of using multiple variable doses to inhibit TNFα activity in a patient suffering from spondyloarthropathy, the method comprising administering to the patient an antibody, a portion of the antibody, so as to inhibit TNFα activity in a patient suffering from spondyloarthropathy.

As used herein, the term “spondyloarthropathy” or “spondyloarthropathy” is used to mean any of several diseases affecting the joints of the spine, and these diseases share common clinical, radiological and histological signs. A number of spondylarthropathies share genetic characteristics, i.e. they are linked to the HLA-B27 allele. In one embodiment, the term "spondyloarthropathy" is used to mean any of several diseases affecting the joints of the spine, excluding ankylosing spondylitis, and such diseases share common clinical, radiological and histological signs. Examples of spondylarthropathy include ankylosing spondylitis, psoriatic arthritis / spondylitis, enteropathic arthritis, reactive arthritis or Reiter's syndrome, and undifferentiated spondylarthropathies. Examples of experimental models used to study spondylarthropathy include ank / ank transgenic mice, HLA-B27 transgenic rats (see Taurog et al. (1998) The Spondyloarthritides. Oxford: Oxford University Press).

The automatic injection device of the invention can also be used to treat patients at risk of developing spondylarthropathy using multiple variable dose methods. Examples of patients at risk for developing spondylarthropathy include people with arthritis. Spondyloarthropathy may be associated with other forms of arthritis, including rheumatoid arthritis. In one embodiment, antibodies are used in multiple variable dose methods for treating a patient who suffers from spondyloarthropathy associated with rheumatoid arthritis. Examples of spondylarthropathies that can be treated with a TNFα antibody are described below.

1. Ankylosing Spondylitis (AS)

It was believed that the tumor necrosis factor plays a role in the pathophysiology of ankylosing spondylitis (see

Ankylosing spondylitis (AS) is an inflammatory disorder involving one or more vertebrae in the inflammatory process. AS is a chronic inflammatory disease that affects the axial skeleton and / or peripheral joints, including the joints between the vertebrae of the spine and the sacroiliac joints and the joints between the spine and pelvis. AS can ultimately cause fusion or fusion of the vertebrae. Spondylarthropathy, including AS, can be associated with psoriatic arthritis (PsA) and / or inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease.

Early manifestations of AS can be determined by x-ray tests, including computed tomography (CT) scans and magnetic resonance (MRI) scans. Early manifestations of AS often include sacroiliitis and changes in the sacroiliac joints, as evidenced by the vagueness of the cortical edges of the cartilage with subsequent erosion and sclerosis. Fatigue has also been noted as a common symptom of AS (Duffy et al. (2002) ACR 66 ^th Annual Scientific Meeting Abstract). Accordingly, methods using multiple variable doses, comprising administering an antibody or an antigen binding fragment thereof of the invention, can be used to treat AS.

In one embodiment, a multiple variable dose method of the invention is used to treat spondylarthropathy associated with IBD, including AS. AS is often treated with non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin or indomethacin. Accordingly, the TNFα antibody used in the multiple variable dose method of the invention can also be administered in combination with agents commonly used to reduce inflammation and pain, usually associated with ankylosing spondylitis.

2. Psoriatic arthritis

Tumor necrosis factor was thought to play a role in the pathophysiology of psoriatic arthritis (PsA) (Partsch et al. (1998) Ann Rheum Dis. 57: 691; Ritchlin et al. (1998) J Pheumatol. 25: 1544). As indicated herein, psoriatic arthritis or psoriasis associated with the skin refers to chronic inflammatory arthritis, which is associated with psoriasis, which is a common chronic skin disease that causes the appearance of red plaques on the body. About 1 in 20 people with psoriasis will develop arthritis along with skin lesions, and in about 75% of cases, psoriasis precedes arthritis. PsA appears in a variety of ways ranging from mild to severe arthritis, with arthritis usually affecting the fingers and spine. If the spine is affected, the symptoms are similar to those of ankylosing spondylitis, as described above. A TNFα antibody or antigen binding fragment thereof obtained using the invention can be used to treat PsA.

PsA is sometimes associated with crippling arthritis. Crippling arthritis refers to a disorder characterized by excessive bone erosion, resulting in a gross, erosive deformation that disfigures the joint. In one embodiment, antibodies produced using the method of the invention are used to treat crippling arthritis.

3. Reactive arthritis / Reiter syndrome

Tumor necrosis factor was thought to play a role in the pathophysiology of reactive arthritis, also referred to as Reiter’s syndrome (Braun et al. (1999) Arthritis Rheum. 42 (10): 2039. Reactive arthritis (ReA) refers to arthritis that complicates infection in others parts of the body, often after intestinal or genitourinary infections.ReA is often characterized by certain clinical symptoms, including inflammation of the joints (arthritis), urethritis, conjunctivitis, and lesions of the skin and mucous membranes.In addition, ReA can occur after an infection associated with a disease edavaemym sexually or dysenteric infection, including chlamydia, campylobacter, salmonella, or yersinia. Accordingly, antibodies obtained using the method of the invention can be used to treat ReA.

4. Undifferentiated spondyloarthropathy

In one embodiment, antibodies obtained using the methods of the invention are used to treat patients suffering from undifferentiated spondyloarthropathies (see Zeidler et al. (1992) Rheum Dis Clin North Am. 18: 187). Other terms used to describe undifferentiated spondyloarthropathy include seronegative oligoarthritis and undifferentiated oligoarthritis. As used herein, the term "undifferentiated spondyloarthropathy" refers to a disorder in which a patient exhibits only some of the symptoms associated with spondyloarthropathy. This condition is usually observed in young adults who do not have IBD, psoriasis, or the classic symptoms of AS or Reiter's syndrome. In some cases, undifferentiated spondyloarthropathy may be an early indicator of AS. In one embodiment, the invention includes the administration of a TNFα antibody or antigen binding fragment thereof, obtained using the claimed method, for the treatment of undifferentiated spondyloarthropathies.

D. Skin and nail lesions

It was believed that the tumor necrosis factor plays a role in the pathophysiology of skin and nail lesions. Interchangeably used herein, the term “skin disorder” or “skin disease” refers to skin abnormalities other than wounds resulting from damage that caused the condition of inflammation. In one embodiment, the skin disorder of the invention is an inflammatory skin disorder in which the skin is characterized by dilated capillaries, leukocyte infiltration, redness, fever and / or pain. Examples of skin disorders include, but are not limited to, psoriasis, pemphigus vulgaris, scleroderma, atopic dermatitis, sarcoidosis, erythema nodosum, purulent hydradenitis, lichen planus, Sweet syndrome, and vitiligo. As used herein, the term “skin disorder and nail damage in which TNFα activity has a damaging effect” is intended to include skin and / or nail lesions and other disorders in which the presence of TNFα has been shown or suspected in a patient suffering from this disorder, responsible for the pathophysiology of the disorder or a factor that contributes to the aggravation of the disorder, such as psoriasis. Accordingly, skin disorders and nail damage in which TNFα activity has a deleterious effect are disorders in which inhibition of TNFα activity is expected to alleviate the symptoms and / or progression of the disorder. The use of antibodies, antibody portions, and other TNFα inhibitors of the invention in the treatment of specific skin and nail disorders is discussed below. In certain embodiments, the treatment method of the invention is carried out in combination with another therapeutic agent, as described below. In one embodiment, antibodies obtained using the method of the invention comprising administering a TNFα antibody in combination with another therapeutic agent is used to treat psoriasis and treat psoriasis associated with arthritis.

1. Psoriasis

Tumor necrosis factor was thought to play a role in the pathophysiology of psoriasis.

As used herein, the term "psoriasis" refers to skin disorders associated with epidermal hyperplasia. Examples of psoriasis include, but are not limited to, chronic plaque-like psoriasis, teardrop-shaped psoriasis, inverted psoriasis, pustular psoriasis, simple psoriasis, and erythrodermic psoriasis. Psoriasis may also be associated with other inflammatory disorders, including inflammatory bowel disease (IBD) and rheumatoid arthritis (RA).

Psoriasis is described as an inflammation of the skin (irritation and redness), characterized by frequent episodes of redness, itching, and thick, dry, silver scales on the skin. In particular, lesions are formed that include primary and secondary changes in epidermal proliferation, inflammatory skin reactions, and expression of regulatory molecules such as lymphokines and inflammatory factors. Psoriatic skin is morphologically characterized by increased epidermal cell turnover, thickened epidermis, abnormal keratinization, inflammatory cell infiltrates in the epidermis and polymorphonuclear leukocyte and lymphocytic infiltration of the epidermal layers, leading to an increase in the basal cell cycle. Psoriasis often affects the nails, which is manifested by the formation of depressions, separation of the nail, thickening and discoloration. Psoriasis is often associated with other inflammatory disorders, such as arthritis, including rheumatoid arthritis, inflammatory bowel disease (IBD), and Crohn's disease. About one third of patients with psoriasis also have psoriatic arthritis (PsA), which, as described above, causes stiffness, joint swelling, pain, and a decrease in range of motion (Greaves et al. (1995) N. Eng. J. Med. 332: 581).

Psoriasis is most often indicated by lesions in the trunk, elbow joints, knee joints, scalp, skin folds or fingernails, but it can affect any or all parts of the skin. Usually, the advancement of new skin cells up from the lower layers to the surface takes about 1 month. In psoriasis, this process takes only a few days, leading to the accumulation of dead skin cells and the formation of thick scales. Symptoms of psoriasis include: dry or red skin plaques coated with silver scales; elevated plaques of the skin, accompanied by red borders that can crack and become painful, and which are usually localized on the elbows, knees, trunk, scalp and hands; skin lesions, including pustules, skin cracking and redness of the skin; acute or dull joint pain that may be associated with arthritis, such as psoriatic arthritis.

Treatment for psoriasis often includes topical corticosteroids, vitamin D analogues, and topically or orally retinoids, or combinations thereof. In one embodiment, the TNFα antibody of the invention is administered in combination with or in the presence of one of these conventional treatments. Additional therapeutic agents that can be combined with a TNFα antibody obtained using the methods of the invention for the treatment of psoriasis are described in more detail below.

Diagnosis of psoriasis is usually based on the appearance of the skin. In addition, a skin biopsy or scraping and culturing of skin plaques may be required to rule out other skin disorders. To detect psoriatic arthritis in the presence and persistent nature of joint pain, an X-ray study can be used.

Вкратце, этот показатель основан на оценке четырех анатомических участков, включая голову, верхние конечности, туловище и нижние конечности, на наличие эритемы, уплотнения и слущивания, с использование шкалы из 5 пунктов (0 = отсутствие симптомов; 1 = незначительные; 2 = умеренные; 3 = выраженные; 4 = очень выраженные). На основании степени поражений в данном анатомическом участке, пораженная область обозначается присвоенной ей цифровой величиной (0 = 0; 1 = <10%; 2 = 10-29%; 3 = 30-49%; 4 = 50-69%; 5 = 70-89%; 6 = 90-100%). Затем рассчитывают балльную оценку PASI, где возможный диапазон балльной оценки PASI составляет от 0,0 до 72,0, причем самая высокая балльная оценка представляет полную эритродермию самой тяжелой степени.Monitoring the improvement in psoriasis in a patient can be done by scoring the area and severity of psoriasis (PASI) in a patient. The method for determining PASI has been described in documents

In short, this indicator is based on an assessment of four anatomical sites, including the head, upper limbs, trunk and lower limbs, for erythema, compaction and desquamation, using a scale of 5 points (0 = no symptoms; 1 = minor; 2 = moderate; 3 = pronounced; 4 = very pronounced). Based on the degree of lesions in this anatomical site, the affected area is indicated by the digital value assigned to it (0 = 0; 1 = <10%; 2 = 10-29%; 3 = 30-49%; 4 = 50-69%; 5 = 70-89%; 6 = 90-100%). The PASI score is then calculated, where the possible range of the PASI score is from 0.0 to 72.0, with the highest score representing complete erythroderma of the most severe degree.

In one embodiment, the TNFα antibody is used to treat psoriasis, including chronic plaque-like psoriasis, teardrop-shaped psoriasis, inverted psoriasis, pustular psoriasis, simple psoriasis and erythroderma psoriasis, psoriasis may also be associated with other inflammatory disorders, including inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). In another embodiment, a TNFα antibody, such as adalimumab, is used to treat patients who have psoriasis in combination with PsA. The specific types of psoriasis included in the treatment methods of the invention are described in detail below:

a. Chronic plaque-like psoriasis

Tumor necrosis factor was thought to play a role in the pathophysiology of chronic plaque psoriasis (Asadullah et al. (1999) Br J Dermatol. 141: 94). Chronic plaque-like psoriasis (also called simple psoriasis) is the most common form of psoriasis. Chronic plaque-like psoriasis is characterized by elevated reddened skin plaques in the size range from coins to much larger ones. In chronic plaque-like psoriasis, plaques can be single or multiple, they can vary in size from a few millimeters to several centimeters. Plaques are usually red with a flaky surface and reflect light when carefully scraped off, creating a “silver” effect. Lesions in chronic plaque-like psoriasis (which are often symmetrical) occur throughout the body, but mainly on the extensor surfaces, including the knee, elbow, lumbosacral, scalp and nails. Chronic plaque-like psoriasis can sometimes occur on the penis, vulva and bends of the skin, but peeling is usually absent. Diagnosis in patients with chronic plaque-like psoriasis is usually based on the clinical signs described above. In particular, the distribution, color, and typical silvery flaking of the lesion in chronic plaque psoriasis are characteristic of chronic plaque psoriasis.

b. Teardrop-shaped psoriasis

Teardrop-shaped psoriasis refers to a form of psoriasis with characteristic scaly plaques in the form of drops of water. Inflammatory hyperemia of guttate psoriasis generally occurs after infection, especially streptococcal throat infection. Diagnosis of guttate psoriasis is usually based on the appearance of the skin and the fact that there is often a recent history of angina.

c. Inverted psoriasis

Inverted psoriasis is a form of psoriasis in which the patient has smooth, usually moist areas of the skin that are red and inflamed, which are different from peeling associated with plaque psoriasis. Inverted psoriasis is also called intertriginous psoriasis or flexural psoriasis. Inverted psoriasis occurs mainly in the axillary fossa, groin, under the mammary glands and in other skin folds around the genitals and buttocks, and, as a result of the localization of manifestations, friction and sweating can irritate the affected areas.

d. Pustular psoriasis

Pustular psoriasis, also called palmar-plantar psoriasis, is a form of psoriasis that causes pus-filled blisters that vary in size and location, but often occur on the hands and feet. Blisters can be localized or spread over large areas of the body. Pustular psoriasis can cause pain when pressed or constant pain, it can cause fever.

e. Other psoriatic disorders

Other examples of psoriatic disorders that can be treated with TNFα antibody delivered using the methods of the invention include erythrodermic psoriasis, simple psoriasis, psoriasis associated with IBD, and psoriasis associated with arthritis, including rheumatoid arthritis.

2. Pemphigus vulgaris

Pemphigus vulgaris is a severe autoimmune systemic dermatological disease that often affects the oral mucosa and skin. It is believed that the pathogenesis of ordinary pemphigus is an autoimmune process that is directed to dermatosomes of the skin and oral mucosa. Subsequently, the cells do not adhere to each other. The disorder manifests itself in the form of large, fluid-filled, prone to bursting bubbles, and has a distinct histological appearance. Anti-inflammatory drugs are the only effective therapeutic agent for this disease, in which there is a high mortality rate. Complications that arise in patients suffering from pemphigus vulgaris are non-relieving pain, malnutrition, and loss of fluid and infection.

3. Atopic dermatitis / eczema

Atopic dermatitis (also called eczema) is a chronic skin disorder characterized by flaky and itchy plaques. People with eczema often have a family history of allergic conditions like asthma, hay fever, or eczema. Atopic dermatitis is a hypersensitivity reaction (similar to an allergy) that occurs in the skin, causing chronic inflammation. Inflammation causes itching and peeling of the skin. Chronic irritation and combing can cause thickening of the skin, and it can acquire a texture similar to the skin. Exposure to environmental irritants can exacerbate symptoms, as well as dry skin, exposure to water, temperature changes, and stress.

Subjects with atopic dermatitis can be identified by certain symptoms, which often include intense itching, blisters with fluid and scabs, redness of the skin or inflammation around the blisters, rash, areas of dry, thickened skin, bleeding areas of the skin as a result of scratching and bleeding / bleeding from ears.

4. Sarcoidosis

Sarcoidosis is a disease in which granulomatous inflammation occurs in the lymph nodes, lungs, liver, eyes, skin, and / or other tissues. Sarcoidosis includes cutaneous sarcoidosis (sarcoidosis of the skin) and nodular sarcoidosis (sarcoidosis of the lymph nodes). Patients with sarcoidosis can be identified by symptoms, which often include general discomfort, anxiety, or malaise; fever skin lesions.

5. Nodular erythema

Erythema nodosum refers to an inflammatory disorder that is characterized by painful pressure, red nodules under the skin, usually on the front surface of the lower legs. Lesions associated with erythema nodosum often begin as flat, but dense, hot, red, painful, bulky lesions (approximately 1 inch across). Within a few days, the lesions may turn purple and then gradually turn into a brownish, flat plaque over the course of several weeks.

In some cases, erythema nodosum may be associated with infections, including streptococcal infection, coccidioidomycosis, tuberculosis, hepatitis B, syphilis, feline scratch disease, tularemia, yersinia infection, leptospirosis, psittacosis, histoplasmosis, mononucleosis (EBV). In other cases, erythema nodosum may be associated with sensitivity to certain drugs, including oral contraceptives, penicillin, sulfonamides, sulfones, barbiturates, hydantoin, phenacetin, salicylates, iodides and progestin. Erythema nodosum is often associated with other disorders, including leukemia, sarcoidosis, rheumatism, and ulcerative colitis.

Symptoms of erythema nodosum usually appear on the legs, but lesions can also occur on other areas of the body, including the buttocks, calves, ankles, hips, and upper limbs. Other symptoms in patients with erythema nodosum may also include fever and malaise.

6. Purulent hydradenitis

Purulent hydradenitis refers to a skin disorder in which swollen, painful, inflamed lesions or swelling develop in the inguinal region and sometimes in the armpits and under the mammary glands. Purulent hydradenitis occurs when the outlet ducts of the apocrine glands are blocked by sweat or are unable to drain properly due to incomplete development of the glands. The secretions trapped in the glands force sweat and bacteria to enter the surrounding tissue, causing subcutaneous tightening, inflammation, and infection. Purulent hydradenitis is limited to areas of the body that contain apocrine glands. These areas are the axillary, areolar, nipple, inguinal, crotch, perianal, and umbilical region.

7. Flat lichen

Tumor necrosis factor was believed to play a role in lichen planophysiology (Sklavounou et al. (2000) J Oral Pathol Med. 29: 370). Lichen planus is a disorder of the skin and mucous membranes that leads to inflammation, itching, and distinct skin lesions. Lichen planus may be associated with hepatitis C or certain medicines.

8. Sweet Syndrome

Inflammatory cytokines, including tumor necrosis factor, were thought to play a role in the pathophysiology of Sweet syndrome (Reuss-Borst et al. (1993) Br J Haematol. 84: 356). Sweet Syndrome, which was described by R.D. Sweet in 1964, is characterized by a sudden onset of fever, leukocytosis and skin rash. The rash consists of painful pressure, erythematous, clearly defined papules and plaques, which microscopically appear as dense neutrophilic infiltrates. These lesions can appear anywhere, but mainly develop in the upper body, including the face. Individual lesions are often described as pseudovesicular or pseudopustular, but can be clearly pustular, bullous, or ulcerative. In patients with Sweet Syndrome, damage to the oral cavity and eyes (conjunctivitis or episiscleritis) was also often noted. Leukemia has also been linked to Sweet Syndrome.

9. Vitiligo

Vitiligo refers to a skin condition in which there is a loss of pigment from areas of the skin, leading to white spots of irregular shape with a normal skin texture. Lesions characteristic of vitiligo have the appearance of flat depigmented areas. The edges of the lesions are sharply limited, but have an irregular shape. Often, affected areas in vitiligo patients include the face, elbows and knees, hands and feet, and genitals.

10. Scleroderma

Склеродермия относится к диффузному заболеванию соединительной ткани, характеризуемому изменениями в коже, кровеносных сосудах, скелетных мышцах и внутренних органах. Склеродермия также именуется синдромом CREST или прогрессирующим системным склерозом, и обычно поражает людей в возрасте 30-50 лет. Женщины поражаются чаще, чем мужчины.Tumor necrosis factor was believed to play a role in the pathophysiology of scleroderma.

Scleroderma refers to a diffuse disease of the connective tissue, characterized by changes in the skin, blood vessels, skeletal muscles and internal organs. Scleroderma is also called CREST syndrome or progressive systemic sclerosis, and usually affects people between the ages of 30-50. Women are affected more often than men.

The cause of scleroderma is unknown. The disease can cause local or systemic symptoms. The course and severity of the disease in affected individuals varies widely. Excessive deposition of collagen in the skin and other organs causes the development of symptoms. Damage to small blood vessels inside the skin and affected organs also occurs. In the skin, ulceration, calcification and changes in pigmentation may occur. Systemic symptoms may include fibrosis and degenerative changes in the heart, lungs, kidneys, and gastrointestinal tract.

Patients with scleroderma exhibit certain clinical signs, including whitening, blueness, or redness of the fingers and toes in response to the effects of heat and cold (Raynaud's phenomenon), pain, stiffness, and swelling of the fingers and joints, thickening of the skin, and shiny hands and forehead, esophageal reflux or heartburn, difficulty swallowing and shortness of breath. Other clinical symptoms used to diagnose scleroderma include an increased erythrocyte sedimentation rate (ESR), an increased rheumatoid factor (RF), a positive antinuclear antibody test, a urine test that detects protein and microscopic blood, a chest x-ray that can detect fibrosis, and pulmonary function tests that detect restrictive pulmonary disease.

11. Nail damage

Nail lesions include any abnormality of the nails. As used herein, the term “nail damage” or “nail disease” refers to conditions in which the nails of the fingers or toes of the hands acquire an abnormal color, shape, texture or thickness. Specific nail lesions include, but are not limited to, indentations, coilonychia, Beau lines, spoon-shaped nails, onycholysis, yellow nails, nail pterygium (observed in lichen planus), and leukonychia. The formation of depressions is characterized by the presence of small depressions on the nail surface. Combs or linear elevations can develop along the nail, occurring "in the longitudinal" or "transverse" direction. Beau lines are linear recesses that occur in the “transverse” direction (transverse) on the nails of the hands. Leukonychia describes white streaks or spots on the nails. Koylonikhia is an abnormal shape of the nails of the hands, where the nail has raised ridges and is thin and concave. Coylonichia is often associated with iron deficiency.

Nail lesions that can be treated with TNFα antibody of the invention also include psoriatic nail lesions. Psoriatic nail lesions include nail changes that can be associated with psoriasis. In some cases, psoriasis can occur only in the nails and nowhere else on the body. Psoriatic changes in the nails range from mild to severe, generally reflecting the degree of psoriatic lesion of the nail plate, the nail matrix, i.e. the tissue from which the nail grows, the nail bed, i.e. tissue under the nail, and skin at the base of the nail. Damage to the nail bed with a purulent type of psoriasis can lead to loss of the nail. Nail changes in psoriasis fall into general categories that can occur individually or all together. In one category of psoriatic nails, the nail plate has deep fossae, probably due to defects in nail growth caused by psoriasis. In another category, the nail has a color changed to yellow or yellow-pink, possibly due to psoriatic lesions of the nail bed. The third subtype of psoriatic nails is characterized by white areas that appear under the nail plate. The white areas are actually air bubbles, where the nail plate becomes detached from the nail bed. There may also be reddened skin around the nail. The fourth category is indicated by the destruction of the nail plate into yellowish plaques, i.e. onychodystrophy, probably due to psoriatic lesions of the nail matrix. The fifth category is characterized by complete loss of the nail due to psoriatic lesions of the nail matrix and the nail bed.

Antibodies obtained using the methods of the invention can also be used to treat nail lesions, often associated with lichen planus. Nails in patients with lichen planus often exhibit thinning and surface roughness of the nail plate with longitudinal ridges or nail pterygium.

Antibodies obtained using the invention can be used to treat nail lesions, such as the lesions described herein. Often, nail damage is associated with skin disorders. In one embodiment, the invention includes treatment for nail lesions using a TNFα antibody and the methods and compositions of the invention. In another embodiment, nail damage is associated with another disorder, including a skin disorder such as psoriasis. In another embodiment, the lesion associated with a nail lesion is arthritis, including psoriatic arthritis.

12. Other disorders of the skin and nails

Antibodies obtained using the method of the invention can be used to treat other skin and nail disorders, such as chronic actinic dermatitis, bullous pseudo-bladderwort and alopecia areata. Chronic actinic dermatitis (CAD) is also referred to as dermatitis due to photosensitivity / actinic reticuloid syndrome (PD / AR). CAD is a condition in which the skin becomes inflamed, in particular in areas that have been exposed to sunlight or artificial light. CAD patients are usually allergic to certain substances that come in contact with their skin, in particular various colors, trees, perfumes, sunscreens and rubber compounds. Bullous pseudo-pemphigus refers to a skin disorder characterized by the formation of large blisters on the trunk and extremities. Alopecia areata refers to hair loss, characterized by round spots of complete baldness on the scalp or beard.

E. Other disorders related to TNFα

In one embodiment, the invention provides a method of administering multiple variable doses for the treatment of TNFα-related disorders in which TNFα activity has a deleterious effect, the method comprising administering to a patient a TNFα antibody to treat said TNFα-related disorder. Examples of disorders associated with TNFα in which TNFα activity has a deleterious effect are discussed below.

1. Juvenile Arthritis

В одном варианте осуществления, TNFα антитело используется для лечения ювенильного ревматоидного артрита с использованием способов и композиций по изобретению.Tumor necrosis factor was thought to play a role in the pathophysiology of juvenile arthritis, including juvenile rheumatoid arthritis.

In one embodiment, a TNFα antibody is used to treat juvenile rheumatoid arthritis using the methods and compositions of the invention.

As used herein, the term “juvenile rheumatoid arthritis” or “JRA” refers to a chronic, inflammatory disease that occurs before the age of 16 years that can cause damage to the joint or connective tissue. JRA is also referred to as juvenile chronic polyarthritis and Still disease.

JRA causes inflammation and stiffness of joints for more than 6 weeks in a child aged 16 years or less. Inflammation causes redness, swelling, warmth and soreness in the joints. Any joint can be affected, and inflammation can limit the mobility of the affected joints. One type of JRA can also affect internal organs.

JRAs are often classified into 3 groups according to the number of affected joints, symptoms, and the presence or absence of certain antibodies detected by a blood test. These classifications help the doctor determine how the disease will progress and whether internal organs or skin are affected. JRA classifications include the following:

but. JRA with a small number of joints, in which four or fewer joints are affected. JRA with a small number of joints is the most common form of JRA and usually affects large joints, such as the knee.

b. A multi-joint JRA in which five or more joints are affected. Small joints, such as the joints of the hands and feet, are most often affected, but the disease can also affect large joints.

C. Systemic JRA is characterized by joint swelling, fever, mild skin rash, and can also affect internal organs such as the heart, liver, spleen, and lymph nodes. Systemic JRA is also referred to as Still disease. A small percentage of these children develop arthritis in many joints, and they can have severe arthritis, which continues into adulthood.

2. Endometriosis

В одном варианте осуществления, TNFα антитело можно использовать для лечения эндометриоза. Используемый в настоящем документе термин «эндометриоз» относится к состоянию, при котором ткань, в норме выстилающая матку (эндометрий) растет в других областях тела, вызывая боль, нерегулярные менструации и часто бесплодие.Tumor necrosis factor was thought to play a role in the pathophysiology of endometriosis, as women with endometriosis have increased peritoneal levels of TNF

In one embodiment, a TNFα antibody can be used to treat endometriosis. As used herein, the term "endometriosis" refers to a condition in which tissue normally lining the uterus (endometrium) grows in other areas of the body, causing pain, irregular menstruation, and often infertility.

3. Prostatitis

. Кроме того, на крысиной модели простатита, уровни TNF были также повышены, по сравнению с контролями

В одном варианте осуществления, TNFα антитело по изобретению используется для лечения простатита.Tumor necrosis factor was believed to play a role in the pathophysiology of prostatitis, as men with chronic prostatitis and chronic pelvic pain have significantly higher levels of TNF and IL-1 in seminal fluid compared to controls

. In addition, in the rat prostatitis model, TNF levels were also elevated compared to controls

In one embodiment, the TNFα antibody of the invention is used to treat prostatitis.

As used herein, the term "prostatitis" refers to inflammation of the prostate gland. Prostatitis is also referred to as pelvic pain syndrome. Prostatitis manifests itself in a variety of forms, including non-bacterial prostatitis, bacterial prostatitis and acute prostatitis. Acute prostatitis refers to inflammation of the prostate gland, which develops suddenly. Acute prostatitis is usually caused by a bacterial infection of the prostate gland. Chronic prostatitis is an inflammation of the prostate gland that develops gradually, continues over an extended period, and usually has mild symptoms. Chronic prostatitis is also commonly caused by a bacterial infection.

4. Choroidal neovascularization

It was believed that the tumor necrosis factor plays a role in the pathophysiology of choroidal neovascularization. For example, in surgically excised choroidal neovascular membranes, neovascular vessels stained positively for both TNF and IL-1 (Oh H et al. (1999) Invest Ophthalmol Vis Sci 40: 1891). In one embodiment, a TNFα antibody is used to treat choroidal neovascularization. As used herein, the term “choroidal neovascularization” refers to the growth of new blood vessels that originate from the choroid of the eye through the destruction of the Bruch membrane into the subcellular pigment epithelium (sub-RPE) or the subcellular space. Choroidal neovascularization (CNV) is the main cause of vision loss in patients with this condition.

5. Sciatica

Tumor necrosis factor was thought to play a role in the pathophysiology of sciatica (Ozaktay et al. (2002) Eur Spine J. 11: 467; Brisby et al. (2002) Eur Spine J. 11:62). In one embodiment, a TNFα antibody is used to treat sciatica. As used herein, the term sciatica refers to a condition that includes impaired movement and / or sensation in the lower limb caused by damage to the sciatic nerve. Sciatica is also commonly referred to as sciatic nerve neuropathy and sciatic nerve dysfunction. Sciatica is a form of peripheral neuropathy. It occurs when there is damage to the sciatic nerve located in the back of the lower limb. The sciatic nerve controls the muscles of the back of the knee joint and lower leg and provides sensitivity to the back of the thigh, part of the lower leg and sole of the foot. Sciatica can be an indicator of another disorder, including hernial protrusion of the lumbar intervertebral disc, spinal stenosis, degenerative disc disease, isthmus spondylitis and pineal syndrome.

6. Sjogren's syndrome

Tumor necrosis factor was thought to play a role in the pathophysiology of Sjogren's syndrome (Koski et al. (2001) Clin Exp Rheumatol. 19: 131). In one embodiment, the TNFα antibody of the invention is used to treat Sjogren's syndrome. As used herein, the term "Sjogren's syndrome" refers to a systemic inflammatory disorder characterized by dry mouth, decreased lacrimal formation, and dryness of other mucous membranes, and it is often associated with autoimmune rheumatic disorders such as rheumatoid arthritis. Dry eyes and mouth are the most common symptoms of this syndrome. Symptoms may occur alone or with symptoms associated with rheumatoid arthritis or other connective tissue diseases. An increase in the salivary glands associated with the syndrome may be observed. Damage to other organs may occur. The syndrome can be associated with rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis and other diseases.

7. Uveitis

Tumor necrosis factor was thought to play a role in the pathophysiology of uveitis (Wakefield and Lloyd (1992) Cytokine 4: 1; Woon et al. (1998) Curr Eye Res. 17: 955). In one embodiment, the TNFα antibody of the invention is used to treat uveitis. As used herein, the term “uveitis” refers to inflammation of the choroid of the eyeball, which is the layer between the sclera and the retina and includes the iris, ciliary body and the choroid itself. Uveitis is also commonly referred to as iritis, parsite, choroiditis, chorioretinitis, anterior uveitis and posterior uveitis. The most common form of uveitis is anterior uveitis, which involves inflammation of the front of the eye, which is usually isolated from the iris. This condition is often called iritis. In one embodiment, the term uveitis refers to inflammation of the choroid of the eyeball, which excludes inflammation associated with an autoimmune disease, i.e. excludes autoimmune uveitis.

8. Wet macular degeneration

It was believed that tumor necrosis factor plays a role in the pathophysiology of wet macular degeneration. In one embodiment, the TNFα antibody of the invention is used to treat wet macular degeneration. As used herein, the term “macular degeneration” refers to a disorder that affects the macula (central part of the retina) and causes a decrease in visual acuity and possible loss of central vision. Patients with wet macular degeneration develop new blood vessels under the retina, which causes hemorrhage, edema, and scar tissue.

9. Osteoporosis

Tumor necrosis factor was thought to play a role in the pathophysiology of osteoporosis (Tsutsumimoto et al. (1999) J Bone Miner Res. 14: 1751). The term “osteoporosis” is used to refer to a disorder characterized by progressive loss of bone density and thinning of bone tissue. Osteoporosis occurs when the body cannot form enough new bone, or when too much old bone is reabsorbed by the body, or both of these processes occur. The TNFα antibody or antigen binding fragment thereof of the invention can be used to treat osteoporosis.

10. Osteoarthritis

Остеоартрит (ОА) также именуется гипертрофическим остеоартритом, остеоартрозом и дегенеративным заболеванием суставов. ОА представляет собой дегенеративное заболевание суставов скелета, которое поражает определенные суставы, обычно коленные суставы, тазобедренные суставы, суставы кистей рук и позвоночника у взрослых людей всех возрастов. ОА характеризуется рядом следующих проявлений, включая дегенерацию и истончение суставного хряща, с ассоциированным развитием «язв» или кратеров, образованием остеофитов, гипертрофией кости по краям и изменения синовиальной оболочки и увеличение пораженных суставов. Кроме того, остеоартрит сопровождается болью и тугоподвижностью, в частности, после продолжительной активности. Антитело или его связывающий антиген фрагмент по изобретению можно использовать для лечения остеоартрита. Характерные рентгенологические признаки остеоартрита включают сужение суставного пространства, подхрящевой склероз, остеофитоз, образование подхрящевых кист, свободное костное тело (или «суставная мышь»).It was believed that tumor necrosis factor plays a role in the pathophysiology of osteoarthritis,

Osteoarthritis (OA) is also referred to as hypertrophic osteoarthritis, osteoarthritis and degenerative joint disease. OA is a degenerative disease of the joints of the skeleton that affects certain joints, usually the knee joints, hip joints, joints of the hands and spine in adults of all ages. OA is characterized by a number of the following manifestations, including degeneration and thinning of the articular cartilage, with the associated development of “ulcers” or craters, the formation of osteophytes, bone hypertrophy along the edges and changes in the synovial membrane and an increase in the affected joints. In addition, osteoarthritis is accompanied by pain and stiffness, in particular, after prolonged activity. An antibody or antigen binding fragment thereof of the invention can be used to treat osteoarthritis. Typical radiological signs of osteoarthritis include narrowing of the joint space, cartilage sclerosis, osteophytosis, the formation of cartilage cysts, a free bone body (or “articular mouse”).

Medicines used to treat osteoarthritis include a variety of non-steroidal anti-inflammatory drugs (NSAIDs). In addition, COX2 inhibitors, including celebrex, vioxx and backstra, and etoricoxib are also used to treat OA. Steroids that are injected directly into the joint can also be used to reduce inflammation and pain. In one embodiment, the TNFα antibodies of the invention are administered in combination with an NSAID, a COX2 inhibitor, and / or steroids.

11. Other diseases

The methods of the invention can also be used to treat various other disorders in which TNFα activity has a deleterious effect. Examples of other diseases and disorders in which TNFα activity was believed to play a role in pathophysiology and thus can be treated using the antibody or part of an antibody of the invention include inflammatory bone lesions, bone resorption disease, coagulation disorders, burns, reperfusion damage, keloid formation, scar tissue formation, pyrexia, periodontal disease, obesity, radiation toxicity, age-related cachexia, Alzheimer's disease, cerebral edema, inflammatory damage brain waiting, cancer, chronic fatigue syndrome, dermatomyositis, drug reactions such as Stevens-Johnson syndrome and Jarisch-Herkshainer reaction, edema in and around the spinal cord, familial periodic fevers, Felty's syndrome, fibrosis, glomerulonephritis (e.g. post-streptococcal glomerulonephritis or IgA nephropathy), weakened prosthesis fixation, microscopic polyangiitis, mixed connective tissue disorder, multiple myeloma, cancer and cachexia, multiple organ disorder, myelodysplastic syndrome , orchitis, osteolysis, pancreatitis, including acute, chronic pancreatitis and pancreatic abscess, polymyositis, progressive renal failure, pseudogout, gangrenous pyoderma, recurrent polychondritis, rheumatic heart disease, sarcoidosis, sclerocorticitis, inciso-pulmonary arteriosis, sclerosing, incisional cholangiopancreatitis TAAA), periodic TNF receptor-related syndrome (TRAPS), symptoms associated with yellow fever vaccination, inflammatory diseases associated with ami, chronic ear inflammation, chronic otitis media with or without cholesteatoma, ear inflammation, myotosis, ovarian cancer, colorectal cancer, treatment-related therapy, induced inflammatory syndrome (e.g., syndromes after administration of IL-2) and a disorder, associated with reperfusion injury.

The methods of the invention can also be used to treat the following diseases: acquired immunodeficiency syndrome, acquired immunodeficiency diseases, acquired pernicious anemia, acute coronary syndromes, acute and chronic pain (various forms of pain), acute idiopathic polyneuritis, acute immune disease associated with organ transplantation, an acute or chronic immune disease associated with organ transplantation, acute inflammatory demyelinating polyradiculoneuropath i, acute ischemia, acute liver disease, acute rheumatism, acute transverse myelitis, Addison's disease, (acute) adult respiratory distress syndrome, adult Still's disease, alcoholic cirrhosis, alcohol-induced liver damage, allergic diseases, allergies, baldness, nude alopecia, disease Alzheimer's, anaphylaxis, ankylosing spondylitis, pulmonary disease associated with ankylosing spondylitis, antibody syndrome against phospholipids, aplastic anemia, arteriosclerosis, arthropathy, asthma, atheromatosis Disease / arteriosclerosis, arteriosclerosis, atopic allergy, atopic eczema, atopic dermatitis, atopic autoimmune hypothyroidism, autoimmune bullous disease, autoimmune dermatitis, autoimmune diabetes, autoimmune hematoma, autoimmune lymphoma, streptocemtimucoimmut lymphoma, autoimmune lymphoma autoimmune hearing loss, autoimmune lymphoproliferative syndrome (ALPS), hypoglycemia mediated by autoimmune processes autoimmune myocarditis, autoimmune neutropenia, autoimmune premature ovarian insufficiency, autoimmune thrombocytopenia (AITP), autoimmune thyroid disease, autoimmune uveitis, bronchitis obliterans, pseudo-ulcer disease, bronchitis pulmonary disease , cervical spondylosis, chlamydial infection, cholestasis, chronic active hepatitis, fatty liver, chronic eosinophil pneumonia, chronic fatigue syndrome, chronic immune disease associated with organ transplantation, chronic ischemia, chronic liver disease, chronic muscular-skin candidiasis, cicatricial pseudobenzemia, clinically isolated syndrome (CIS) with the risk of multiple sclerosis, common varying immune deficiency (common variable hypogamma) , connective tissue disease associated with interstitial pulmonary disease, conjunctivitis, hemolytic anemia with positive re Coombs campaign, childhood-onset psychiatric disorder, chronic obstructive pulmonary disease (COPD), Crohn’s disease, cryptogenic autoimmune hepatitis, cryptogenic fibrosing alveolitis, dacryocystitis, depression, scleroderma dermatitis, dermatomyositis, pulmonary disease, retinal disease, , diabetes mellitus, dilated myocardiopathy, discoid lupus erythematosus, hernial protrusion of the intervertebral disc, prolapse of the intervertebral disc, disseminated intravascular coagulation, drug hepatitis, drug interstitial pulmonary disease, drug immune hemolytic anemia, endocarditis, endometriosis, endophthalmitis, enteropathic synovitis, episcleritis, polymorphic erythema, large polymorphic erythema, female infertility, pulmonary fibrosis, pulmonary fibrosis, pulmonary fibrosis, pulmonary fibrosis, pulmonary fibrosis, pulmonary fibrosis, and pulmonary fibrosis , glomerulonephritis, goiter autoimmune hypothyroidism (Hashimoto's disease), Goodpass syndrome, gouty arthritis, graft versus host disease (GVHD), Graves' disease, Group B streptococcus infection (GBS), Jullen-Barré syndrome (GBS), hemosiderosis-related pulmonary disease, hay fever, heart failure, hemolytic anemia, Genoch-Shenlein purpura, hepatitis B, hepatitis C, Hughes syndrome, Huntington’s chorea, hyperthyroidism, hypoparathyroidism, idiopathic leukopenia, idiopathic thrombocytopenia, idiopathic Parkinson’s disease, idiopathic interstitial pneumonia, idiosyncratic liver disease, allergy, IgE mediated, immune hemoliti erythema, myositis with inclusion bodies, infectious diseases, infectious eye inflammatory disease, inflammatory bowel disease, inflammatory demyelinating disease, inflammatory heart disease, inflammatory renal disease, insulin-dependent diabetes mellitus, interstitial pneumonitis, IPF / UIP (idiopathic pneumosclerosis pneumonia), iritis, juvenile chronic arthritis, juvenile pernicious anemia, juvenile rheumatoid arthritis, Kawasaki disease, keratitis, dry keratoconjunctivitis, Kussmaul’s disease or Kussmaul-Meyer’s disease, Landry’s paralysis, Langerhans cell histiocytosis, linear IgA disease, marble vasculitis, Lyme arthritis, lymphocytic infiltrative pulmonary disease, macular degeneration, male infertility - idiopathic diagnosis, microscopic renal vasculitis, microscopic polyangiitis, pulmonary disease associated with mixed connective tissue disease, ankylosing spondylitis, motor disorders x neurons, pseudo-pemphigus of the mucous membranes, multiple sclerosis (all subtypes: primary progressive, secondary progressive, relapsing remitting, etc.), multiple organ failure, myalgic encephalitis / Ryal Free disease, severe myasthenia gravis, myelodysplastic syndrome, myocardial infarction, myocarditis nephrotic syndrome, nerve root disorders, neuropathy, non-alcoholic steatohepatitis, non-A non-B hepatitis, optic neuritis, organ transplant rejection, osteoarthritis, osteolysis, ovarian cancer Cove, ovarian failure, pancreatitis, parasitic diseases, Parkinson's disease, JRA with lesions of a small number of joints, pemphigus pemphigus, Pemphigus vulgaris, peripheral arterial occlusive disease (PAOD), peripheral vascular disease (PVD), peripheral artery disease (PAD), phacogenic uveitis , phlebitis, polyarteritis nodosa (or periarteritis nodosa), polychondritis, polymyalgia rheumatism, polyosis, polyarticular JRA, polyendocrine insufficiency syndrome, polymyositis, multiple type I glands and insufficiency of multiple type II glands, polymyalgia rheumatoid polymialgia (PMR), post-infection interstitial pulmonary disease, post-inflammatory interstitial pulmonary disease, cardiopulmonary disorders, premature ovarian failure, primary biliary cirrhosis, pulmonary myxedema, primary parkinsonism, primary skinsonitisism primary sclerosing hepatitis, primary vasculitis, cancer of the prostate and rectum and hematopoietic evil quality diseases (leukemia and lymphoma), prostatitis, psoriasis, type 1 psoriasis, type 2 psoriasis, psoriatic arthritis, psoriatic arthropathy, pulmonary hypertension caused by connective tissue disease, pulmonary polyarteritis manifestation of lung, pure erythrocytic aplasia, primary adrenal fibrosis, reactive arthritis, Reiter’s disease, recurrent optic neuromyelitis, kidney disease with an unknown diagnosis, restenosis, rheumatoid arthritis, interstitial le full-time rheumatoid arthritis disease, rheumatic heart disease, SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis), sarcoidosis, schizophrenia, Schmidt syndrome, scleroderma, secondary amyloidosis, shock lung, scleritis, sciatica, secondary adrenal gland syndrome , septic arthritis, septic shock, seronegative arthropathy, silicone-related connective tissue disease, Sjögren’s syndrome lung disease, Sjögren’s syndrome, Fekddon-Wilkinson dermatosis, autoimmunity to perme, spondylarthropathy, ankylosing spondylitis, sporadic Stevens-Johnson syndrome (SJS), Still's disease, stroke, sympathetic ophthalmia, systemic inflammatory response syndrome, systemic lupus erythematosus, pulmonary disease associated with systemic lupus erythematosus, systemic sclerosis, interstitial pulmonary disease with systemic sclerosis, Takayasu’s disease / arteritis, temporal artery arteritis, diseases mediated by Th2 type and Th1 type, thyroiditis, toxic shock syndrome, toxoplasmic retinitis, toxic epidermal necrolysis, transverse myelitis, TRAPS (tumor necrosis factor receptor, type B insulin resistance with blackening acanthosis, type 1 allergic reaction, type 1 autoimmune hepatitis (classic autoimmune or lupoid hepatitis), autoimmune type 1 hepatitis (hepatitis 2) LKM (liver / kidney microsomes), type II diabetes, arthropathy with ulcerative colitis, ulcerative colitis, rash, common interstitial pneumonia (UIP), uveitis, diffuse pulmonary vasculitis, vasculitis, spring conjunct vit, Viral retinitis, Vitiligo, Vogt-Koyanagi-Harada syndrome (VKH syndrome), Wegener's granulomatosis, Wet macular degeneration, wound healing, arthropathy related to infection yersisnia and salmonella.

Other examples of disorders that can be treated using the methods and compositions of the invention are found in US Publication No. 2004-0126372.

It is understood that all of the above TNFα-related disorders, where appropriate, include both adult and juvenile forms of the disease. It is also understood that all of the above disorders include both chronic and acute forms of the disease. In addition, methods using multiple variable doses according to the invention can be used to treat each of the above TNFα-related disorders, alone or in combination with each other, for example, a patient suffering from uveitis and lupus.

The invention also includes a manufactured product, including packaging material; an automatic injection device, for example, an auto-injection pen containing a syringe filled with a TNFα inhibitor such as adalimumab, and a package insert inside the packaging material indicating that in studies of a TNFα inhibitor using the automatic injection device of the invention for treating rheumatoid arthritis, the most common side effects the phenomena (AE) were bronchitis, hypersensitivity, arthritic pain, cough and rhinitis.

Other examples of biological agents that can be administered to a user using an automatic injection device, such as an auto-injection pen, according to the invention include, without limitation, antibodies or antagonists of human cytokines or growth factors, for example, TNF, LT, IL-1, IL-2, IL- 3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-15, IL-16, 1L-18, 1L-21, IL-23, interferons, EMAP-II, GM- CSF, FGF and PDGF; antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands, including CD154 (gp39 or CD40L); actemra (tocilizumab) humanized MAb against interleukin 6 receptor (IL-6); TNFα converting enzyme inhibitors (TACE); IL-1 inhibitors (inhibitors of the enzyme converting interleukin-1, IL-1RA, etc.); interleukin 11; IL-18 antagonists, including IL-18 antibodies or soluble IL-18 receptors, or IL-18 binding proteins; non-depleting anti-CD4 inhibitors; CD80 (B7.1) or CD86 (B7.2) co-stimulatory pathway antagonists, including antibodies, soluble receptors or antagonistic ligands; agents that inhibit signaling by pro-inflammatory cytokines, such as TNFα or IL-1 (for example, IRAK, NIK, IKK, p38 or MAP kinase inhibitors); IL-1β converting enzyme inhibitors (ICE); T cell signaling inhibitors, such as kinase inhibitors; metalloproteinase inhibitors; angiotensin converting enzyme inhibitors; soluble cytokine receptors and their derivatives (for example, soluble TNF p55 or p75 receptors and p75TNFRIgG derivatives (Enbrel ^TM and p75TNFRIgG (Lenercept)), sIL-1RI, sIL-1RII, sIL-6R); anti-inflammatory cytokines (e.g., Il-4, IL-10, IL-11, IL-13 and TGFb); rituximab; IL-1 TRAP; MRA; CTLA4-Ig; IL-18 BP; anti-IL-18; anti-IL15; IDEC-CE9.1 / SB 210396 (non-depleting, primatized anti-CD4 antibody; IDEC / SmithKline; see, for example, Arthritis & Rheumatism (1995) Vol. 38, S185); DAB 486-IL-2 and / or DAB 389-IL-2 (fusion proteins of IL-2; Seragen; see, for example, Arthritis & Rheumatism (1993) Vol. 36, 1223); anti-Tac (humanized anti-IL-2Ra; Protein Design Labs / Roche); IL-4 (anti-inflammatory cytokine; DNAX / Schering); IL-10 (SCH 52000; recombinant IL-10, anti-inflammatory cytokine; DNAX / Schering); agonists of IL-10 and / or IL-4 (e.g., agonistic antibodies); IL-1RA (IL-1 receptor antagonist; Synergen / Amgen); Anakinra (Kineret® / Amgen); TNF-bp / s-TNF (soluble TNF binding protein; see, for example, Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S284; Amer. J. Physiol. - Hearst and Circulatory Physiology (1995 ) Vol. 268, pp. 37-42); R973401 (type IV phosphodiesterase inhibitor; see, for example, Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S282); MK-966 (COX-2 inhibitor; see, for example, Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S81); iloprost (see, for example, Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S82); zap-70 and / or 1ck inhibitor (zap-70 and / or 1ck tyrosine kinase inhibitor); VEGF inhibitor and / or VEGF-R inhibitor (vascular endothelial cell growth factor inhibitors or vascular endothelial cell growth factor receptor; angiogenesis inhibitors); TNF-convertase inhibitors; anti-IL-12 antibodies; anti-IL-18 antibodies; interleukin-11 (see, for example, Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S296); interleukin-13 (see, e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S308); interleukin-17 (see, for example, Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S120); anti-thymocytic globulin; anti-CD4 antibodies; CD5 toxins; antisense phosphorothioate oligodeoxynucleotides ICAM-1 (ISIS 2302; Isis Pharmaceuticals, Inc.); soluble complementary receptor 1 (TP10; T Cell Sciences, Inc.), efalizumab, and anti-IL2R antibodies, including anti-IL12 antibody (ABT 874); anti-IL18 antibody (ABT 325); small molecule inhibitor of LCK; small molecule COT inhibitor; anti-IL1 antibody; small molecule inhibitor MK2; anti-CD19 antibody; small molecule inhibitor of CXCR3; small molecule inhibitor of CCR5; small molecule CCR11 inhibitor, anti-E / L selectin antibody; small molecule P2X7 inhibitor; small molecule inhibitor of IRAK-4; small molecule glucocorticoid receptor agonist; anti-C5a receptor antibody; small molecule inhibitor of the C5a receptor; anti-CD32 antibody; and CD32 as a therapeutic protein.

Other examples of biological agents that can be administered to a user using an automatic injection device, such as an auto-injection pen, on request include, but are not limited to, a small molecular weight inhibitor KDR (ABT-123), a small molecular weight inhibitor Tie-2; methotrexate; prednisone; celecoxib; folic acid; hydroxychloroquine sulfate; rofecoxib; etanercept; infliximab; Anakinru (Kineret® / Amgen); leflunomide; naproxen; valdecoxib; sulfasalazine; ibuprofen; methylprednisolone; meloxicam; methylprednisolone acetate; gold sodium thiomalate; aspirin; azathioprine; triamsinolone acetonide; propoxyphene napsilate / acetyl paraminophenol; folate; nabumeton; diclofenac; piroxicam; etodolac; diclofenac sodium; oxaprozin; oxycodone hydrochloride; hydrocodone bitartrate / acetyl paraminophenol; diclofenac sodium / misoprozole; fentanyl; Anakinra, a human recombinant; tramadol hydrochloride; salsalate; sulindac; cyanocobalamin / free acid / pyridoxine; acetaminophen; alendronate sodium; prednisone; morphine sulfate; lidocaine hydrochloride; indomethacin; glucosamine sulfate / chondroitin; cyclosporine; sulfadiazine; amitriptyline gel; oxycodone gel / acetaminophen; olopatadine gel; misoprostol; naproxen sodium; omeprazole; mycophenolate mofetil; cyclophosphamide; rituximab; IL-1 TRAP; MRA; CTLA4-IG; IL-18 BP; ABT-874; ABT-325 (anti-IL 18); anti-IL 15; BIRB-796; SCIO-469; VX-702; AMG-548; VX-740; roflumilast; IC-485; CDC-801; and mesopram, antibiotics, including clarithromycin (Biaxin®), ciprofloxacin (Cipro®) and metronidazole (Flagyl®), mesalamine, prednisone, azathioprine, mercaptopurine, infliximab, budesonide, souflasalazine, methylprednisolonium sulfofludenocide dopropenocin, lidrofenocin dimerfenucide, luprodinuchendinuchenonide sulfonuchenoside, methotrexate, omeprazole, folate, ciprofloxacin / dextrose-water, hydrocodone bitartrate / acetyl paraminophenol, tetracycline hydrochloride, fluocinonide, metronidazole, thimerosal / boric acid, hyoscyamine sulfate, cholestyramine / sucrose, cipheroclide ohlorid, midazolam hydrochloride, oxycodone hydrochloride / acetaminophen, promethazine hydrochloride, sodium phosphate, sulfamethoxazole / trimethoprim, celecoxib, polycarbophil, propoxyphene napsylate, hydrocortisone, multivitamins, balsalazide disodium, codeine phosphate / atsetilparaminofenol gel colesevelam, cyanocobalamin, folic acid, levofloxacin, natalizumab , methylprednisolone, interferon-gamma, sargramostim (GM-CSF), non-steroidal anti-inflammatory drugs (NSAIDs), COX2 inhibitors including Cerebrex®, Vioxx® and Bextra®, etoricoxib, ibuprofen, diclofenac and isoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, prednisone, methotrexate, azathioprine, minocycline, prednisone, etanercept, and infliximab; rofecoxib; celecoxib; folic acid; sulfasalazine; naproxen; leflunomide; methylprednisolone acetate; indomethacin; hydroxychloroquine sulfate; sulindac; prednisone; reinforced betamethasone dipropionate; infliximab; methotrexate; folate; triamsinolone acetonide; dicofenac; dimethyl sulfoxide; piroxicam; dicolfenac sodium; ketoprofen; meloxicam; prednisone; methylprednisolone; nabumeton; tolmetin sodium; calcipotriene; cyclosporine; dicolfenac; sodium / misoprostol; fluocinonide; glucosamine sulfate; gold sodium thiomalate; hydrocodone; bitartrate / acetyl paraminophenol; ibuprofen; sodium residronate; sulfadiazine; thioguanine; valdecoxib; Alefacept; RAPTIVA® (efalizumab), a small molecule inhibitor of KDR (ABT-123), a small molecule inhibitor of Tie-2, calcipotriene, clobetasol propionate, triamsinolone acetonide, halobetazole propionate, tazarotene, methotrexate, fluocinone azinone dione, aminotropinfenone dimethinone dione phosphonetinone dimethinone dione phosphonetinone dimethinone donone , betamethasone valerate, mometasone furoate, ketoconazole, pramoxin / fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate / emollient, fluticasone propionate, azithromycin, hydrocortisone, moisturizing hydrochloric acid, desonide, coal tar resin, diflorazone diacetate, etanercept, folate, lactic acid, methoxalen, bismuth hydrochloride / bismuth subgallate / zinc oxide / resorcinol, methylprednisolone acetate, prednisone, sunscreen agent, salicylic acid, galcinonate, eqrotalin, anthralinum, anthralinolite, anthralinum, anthralinum, anthralinolite, anthralinolite, anthralinolite, anthralone, , coal tar / salicylic acid, coal tar / salicylic acid / sulfur, deoxymethasone, diazepam, emollient, emollient pimecrolimus, fluocinonide / emollient, mineral oil / castor oil / l sodium actate, mineral oil / peanut butter, petrolatum / isopropyl myristate, psoralen, salicylic acid, soap / tribromsalan, thimerosal / boric acid, celecoxib, alefacept, RAPTIVA® (efalizumab), tacrolimus, pimecrolimus, PUVAz.

The invention is further illustrated by the following examples, which should not be construed as limiting. The contents of all references, patents and published patent applications cited throughout this application are incorporated herein by reference.

The following examples describe studies using an illustrative automatic injection device, such as an auto-injection pen, according to the invention. The illustrative auto-injection pen described in the following examples contains a human TNFα antibody, for example, adalimumab (HUMIRA®), and is often referred to below as the HUMIRA® pen.

Example 1 : Use of an automatic injection device for administration of a TNFα inhibitor

Survey Overview / Summary

Adalimumab is a therapeutic monoclonal antibody for subcutaneous administration with 2 bioequivalent, disposable injection devices: ready-to-use, pre-filled syringe and integrated, disposable delivery system, auto-injection pen. Although it has been shown that patients requiring prolonged subcutaneous administration of drugs prefer pens to syringes, there is no data on preference and pain when using biological substances in patients with chronic inflammatory diseases. Thus, the goal of the next study (TOUCH study) was to evaluate the pain at the injection site, the safety and patient preference for the two adalimumab delivery devices.

The aim of the TOUCH study (to test the applicability of the HUMIRA autoinjector in clinical settings compared to a pre-filled syringe) was to evaluate which delivery method rheumatoid arthritis patients preferred: a pre-filled HUMIRA syringe or a new HUMIRA pen.

Briefly, patients with rheumatoid arthritis (RA) were included in phase II of a multicenter, open, single-arm sequential trial. Patients subcutaneously injected themselves with a standard dose of adalimumab once every 2 weeks at each of 3 controlled clinical visits: visit 1 (syringe), visits 2 and 3 (pen). At each visit, patients scored their pain at 2 points in time and expressed their impressions and preferences of each delivery device. Safety was evaluated throughout the study and 70 days after the introduction of the final dose of the study.

Overall, 52 patients were included in the trial and they completed all 3 visits. 40 patients (76.9%) reported that using a pen was less painful than a syringe, 4 patients (7.7%) thought that using a syringe was less painful, and 8 patients (15.4%) did not have a preference. In visits 2 and 3, patients had a significant average reduction in pain at the injection site immediately after injection (respectively -1.4 and -1.6, p <0.01) and 15-30 minutes after injection (-0.6 at both time points, p <0.01). ≈90% of patients considered the use of a pen more convenient and easier. Patients had statistically significant reductions in pain scores from visit 1 to visit 2 and from visit 1 to visit 3. The types and cumulative frequency of adverse events during the 2-week period after injection with a syringe and the 4-week period after 2 injection with pens were comparable. 5 patients (9.6%) reported adverse events, including bronchitis, hypersensitivity, arthritic pain, cough and rhinitis after injection with a syringe, and 8 (15.4%) after injection with a pen. There were no side effects that led to the cessation of injection. Thus, both delivery devices were safe, and there were no significant differences in side effects noted for each of the delivery devices. In addition, 46 patients (88.5%) preferred a pen, 3 (5.8%) preferred a syringe, and 3 (5.8%) did not have a preference. Overall, patients rated the use of a pen as lighter, more convenient, requiring less time for injection, and safer.

In conclusion, patients experienced less pain with self-administration of adalimumab using a pen and preferred it to a syringe. In addition, patients perceived the use of a pen as lighter and more convenient. There were no differences in safety phenomena between the two bioequivalent delivery devices.

Detailed study

The following study was performed to evaluate whether patients (also referred to in this document as users) preferred a delivery method — a prefilled HUMIRA® syringe (PFS) (also called adalimumab) or a new HUMIRA® pen. The following study was also performed to compare two routes of administration, including the level of pain at the injection site caused by these two delivery devices.

The study structure included phase II of a multicenter, open-label study involving patients who had previous experience administering adalimumab using a pre-filled syringe. Subjects included in the study were patients who were ≥18 years old, who had RA, diagnosed in accordance with the criteria of the American College of Rheumatology, revised in 1987, and they independently administered 40 mg of adalimumab subcutaneously 1 time in 2 weeks with a pre-filled syringe for at least 3 months. The main exclusion criteria included patients with a history of malignant diseases, patients with impaired immunity or a history of infection with the immunodeficiency virus, demyelinating diseases or untreated chronic diseases; patients with active infections requiring treatment; patients with active tuberculosis or a positive test with purified protein derivative for at least 6 months; patients who received active research drugs within 30 days or 5 elimination half-lives; patients who regularly used any medication administered by subcutaneous injection, with the exception of adalimumab; and women who were pregnant or breastfeeding. Patients in this study were allowed to continue taking standard antirheumatic drugs at the dosage in which they took them before the study.

Patients (n = 52) injected themselves with a pre-filled HUMIRA® syringe at 0 weeks followed by injections with a HUMIRA® pen after 2 and 4 weeks when filling out questionnaires at all 3 time points. Patients rated their injection preference for several characteristics, including general preference, ease of use, convenience, time to complete the injection, perceived safety, and pain.

The study included 3 study visits to self-administration of adalimumab by patients once every 2 weeks. Each injection at each visit was carried out under the supervision of a medical professional. At the first visit, patients independently injected themselves subcutaneously with 40 mg of adalimumab using a pre-filled syringe held at an angle of 45 degrees to the surface of the skin. At the second visit, the study staff instructed patients how to correctly administer adalimumab using a pen, and explained to the patients the characteristic features of the pen (Fig. 25), including a window for examining the drug solution before injection and a yellow bar to indicate the completion of the injection; sequential opening of the protective caps to prevent accidental erroneous starting; and the correct location, capture, and actuation of the device with the click of a button. At the 2nd and 3rd visits, patients independently administered adalimumab using a pen held at an angle of 90 degrees to the skin surface. Patients at the first visit chose either the thigh or abdominal region for self-injection and were monitored to ensure that they used the same body area for injection at the 2nd and 3rd visits, making each injection at a distance of at least at least 2 inches from the previous injection site.

Patients used the pen in accordance with the following sequence of operations: first, before the injection using the pen, patients were introduced to the pen device by watching the video and reading the brochure that describes 5 steps. Patients also used a demonstration pen to practice using the pen before injecting the pen. The steps for using the HUMIRA® pen included adjusting the pen at which the pen was removed from the box and allowed to adapt to room temperature, leaving it for 15-20 minutes. The patient then wipes the skin with an alcohol swab before injection. An injection site is selected and prepared. HUMIRA® injection was performed using the pen by pressing the start button of the patient. After an audible “click” injection began, which lasted about 10 seconds. After 10 seconds, or when the yellow bar stopped moving in the window, the injection was completed.

После каждой инъекции пациенты также проводили рейтинг своих общих впечатлений от шприца в сравнении с ручкой как «крайне неблагоприятные», «неблагоприятные», «нейтральные», «благоприятные» или «крайне благоприятные».Initial demographic data for the study were obtained in patients who used HUMIRA® PFS from 3 to 32 months, with an average duration of use of 15.4 months. Patients reported that self-injection of PFS lasted from <1 minute to 5 minutes with an average duration of <1 minute. Initial estimates included the duration of adalimumab treatment, the duration of self-administration of adalimumab, the usual injection site, the duration of the injection time, and the overall impression of administering adalimumab via a syringe. The pain in the injection site was scored on an 11-point digital rating scale ranging from 0 (no pain) to 10 (as much as possible severe pain) at 2 points in time after injection: immediately after injection and 15-30 minutes after injection

After each injection, patients also rated their overall syringe impressions compared to the pen as “extremely unfavorable”, “unfavorable”, “neutral”, “favorable” or “extremely favorable”.

At week 0, patients were questioned to obtain the following information: the amount of time they received HUMIRA®, their typical injection site, their typical injection time, and overall impression of the syringe. The most common injection sites were the abdomen (25/52) and the thigh (22/52).

Analysis of patient preferences was performed after the last visit or after a premature exit from the study. During the analysis, patients were asked to rate their general preferences (syringe, pen, or lack of preference) and justify their preferences. We also rated patients' preferences (syringe, pen, or lack of preference) for each of the following categories: ease of use, convenience, time for an injection, safety, and pain reduction. Patients were also asked to rate the likelihood of their switching to the pen if it is available at the same price (“highly probable”, “not probable”, “neutral”, “probable” or “highly probable”) and the likelihood that they will recommend the pen to another patient receiving adalimumab (same ratings as described above).

At the first and third injections (2 and 4 weeks), patients were asked to rate the immediate pain when using the pen (scale 0-10, where 0 = no pain and 10 = as much pain as possible), severity of pain after 15-30 minutes (scale 0-10), evaluate their overall impression, their injection site, whether they experienced a wet or normal injection, whether they followed the instructions for using the pen and any additional comments.

At the end of the study, patients were given a final preference questionnaire to determine the following characteristics: general preference, as well as its causes; specific preference related to ease of use, convenience, injection time, safety, pain reduction; whether the patient would probably have switched from PFD to the handle; and whether it would be likely that the patient recommended a pen to other patients taking adalimumab.

Safety was evaluated in the initial state (for comparison) and throughout the study using clinical laboratory data and physical examination data. Patients were monitored to detect treatment-related adverse events (AE) reported spontaneously by the patient or presented by the investigator. Severe AE was defined in accordance with the Medical Dictionary of Regulatory Activities (MedDRA, version 9.0) as AE that was fatal or life-threatening; requiring prolonged hospitalization; leading to significant disability, congenital malformations, birth defects, miscarriage or planned termination of pregnancy; or required medication / surgery to prevent another serious outcome. The number and percentage of the studied patients with AE was reported on the signed informed consent forms up to 70 days after the last visit during the study (time 5 times the certain half-life of adalimumab). Safety and tolerability assessments also compared 2- and 4-week periods after administration using a syringe and pen, respectively. Routine hematological analysis, serum biochemical analysis and serology, as well as urinalysis were performed in a certified clinical laboratory. Laboratory reference ranges were obtained before the start of the study, and the researcher analyzed them for screening purposes.

To demonstrate the equivalence between the scores of pain after administration of a pre-filled syringe compared with a pen at 80% statistical strength, a sample size of approximately 50 patients was required with an tolerance of the equivalence limit of ± 5, a standard deviation (differences) of 1.25, and a one-sided error rate of type I 0.025. Assessments of preference and pain at the injection site covered all participants who received 1 injection with a syringe and at least 1 pen injection. Baseline characteristics, preferences, and other category data were summarized using averages and percentages. An “accurate” 95% confidence interval (CI) was calculated to compare patients who either preferred a pen or did not have a preference with patients who preferred a pre-filled syringe. Changes from the initial pain level at the injection site were analyzed using paired Student's t test and a calculation of 95% CI. Safety analyzes covered all patients who received at least 1 injection. AE frequencies for each device were compared using the McNemar test. All statistical studies were performed at a statistical significance level of 0.05. Statistical analysis was performed using SAS® software, Release 8.2 (SAS Institute, Inc., Cary, North Carolina) with UNIX operating system version 11.0.

Interim Results

Interim study 1

In an intermediate study, a statistical and descriptive analysis of the information obtained from 17 patients was performed; 11 had all 3 visits, and 6 had 2 visits. The study also examined data in the initial state and at the first visit in another 7 patients.

Overall excellent results indicated that a pen over a syringe was preferred. The pain during injection was comparable when using a pen or syringe, although there was a difference in pain in the area after the injection, mainly in favor of the pen:

- Most patients reported either no or minimal pain during the injection with both devices.

- Most patients reported less pain in the area after the injection when using a pen than a syringe (average values on a scale of 0-10: 3.6 (syringe); 2.4 (pen 1); 1.9 (pen 2)).

Preference: almost all patients considered the pen superior to the syringe in all rating characteristics, such as general preference, less pain, ease of use, convenience and safety. A pen was preferred in 63 of 66 answers (6 questions about preference for 11 patients).

All 11 patients considered probable (4) or highly probable (7) switching to a pen and recommending the pen to others.

Additional details of Interim Study 1 included the following:

Pain data: (17 patients using pen 1; 11 patients using pen 2) are shown below in table 1.1, where the pain during injection (scale 0-10; average values) - when using the pen, the pain is always either the same or less than pain when using a syringe.

Table 1.1 Injection pain (scale 0-10; average values) - when using a pen, the pain is always either the same or less than the pain when using a syringe Syringe 0.8 Pen 1 0.2 Pen 2 0.1

Table 1.2 below shows the details of Study 1 based on another patient population described in Table 1.1. Pain in the area after the injection (scale 0-10, average values) - 11 patients reported that the pain when using the pen was the same or less, in 6 patients the pen increased the pain sensation from 1 to 3-5.

Pain at the injection site (scale 0-10; average values) Syringe 3.6 Pen 1 2,4 Pen 2 1.9

Preference data (EF: extremely favorable; F: favorable; N: neutral; U: unfavorable; EU: extremely unfavorable)

Handle 1: The overall impression was mainly EF (7) or F (6).

Knob 2: It was mainly EF (6) or F (4). Patient 904, when using pen 2, had the EU, although he had EF when using pen 1, but he was also “very likely” to switch to the pen and recommend it to others.

Interim study 2

In an intermediate study (time after intermediate study 1) examined 19 patients with 3 injections. A summary of Interim Study 1 included exclusively preference results based on descriptive analyzes obtained in 31 patients: 19 had all 3 visits, 5 had 2 visits, and 7 had only the first visit.

Overall excellent results confirmed that a pen is definitely preferable to a syringe. Almost all patients believed that the pen exceeded the syringe in all rating characteristics, such as general preference, less pain, ease of use, convenience or safety. The pen was preferred in 106 of 114 answers (6 questions about preference for 19 patients).

18 out of 19 patients preferred the pen and considered switching to the pen and recommending its use to others to be highly probable or probable. One patient preferred a syringe, considered switching to a pen unlikely, and was neutral about recommending the use of a pen to others. Additional details included the following:

Subjective impression of a syringe:

n = 31

Extremely favorable = 2 (6.5%)

Favorable = 8 (26%)

Neutral = 11 (35%)

Adverse = 8 (26%)

Extremely unfavorable = 2 (6.5%)

Subjective impression after visit 2 - the first injection with a pen:

n = 24

Extremely favorable = 12 (50%)

Favorable = 8 (33.3%)

Neutral = 2 (8.3%)

Adverse = 1 (4.2%)

Extremely unfavorable = 1 (4.2%)

Subjective impression after visiting 3 - the second injection with a pen:

n = 19

Extremely favorable = 11 (57.9%)

Favorable = 6 (31.6%)

Neutral = 1 (5.3%)

Extremely unfavorable = 1 (5.3%)

Subjective impression after visiting 3 - the second injection with a pen:

n = 19

When asked about their general preference based on experience with the HUMIRA® syringe and pen, 18 out of 19 people preferred the pen. One subject preferred a syringe.

When patients were asked which HUMIRA® injection method was preferred in terms of:

Ease of use - All 19 persons preferred the pen

Amenities - 18 people preferred a pen; 1 subject did not note preference

Time required to complete the injection - 17 out of 19 people preferred a pen; 2 subjects had no preference

Security - 17 out of 19 people preferred a pen; 2 subjects had no preference

Less painful - 16 out of 19 people preferred a pen; 1 subject preferred syringe; and 2 subjects had no preference

When patients were asked: “What is the likelihood that you would use a pen if it had the same cost as a syringe?”, 12 people said: “Extremely likely”; 6 individuals reported “Probably,” and 1 subject reported “unlikely.”

When asked: “What is the likelihood that you would recommend the pen to another HUMIRA® user?”, 11 users said: “Very likely”; 7 users reported “Probably,” and 1 user reported a “neutral” rating.

Some comments from users who prefer a pen :

“The use of a pen is lighter, faster, and less painful.”

“Safer, faster, and easier to administer in the absence of fear factor”

"Because I don't like the needle that I can really see."

“Easier to hold / insert”

“Less painful, quick and easy to administer”

“It suits you”

“It facilitates tracking of my actions + injection control during the method. And he did not seem as painful as before. ”

“It wasn't as painful as before.”

"Convenient way".

"The pain is not so strong and lasts less."

Some user comments on why they were not chosen as the preferred syringe injection device:

"Painfully"

“More preparation time, physical and psychological”

“The syringe requires more time, with more stages.”

“Harder to use.”

"Slower, Sore"

“Harder to Hold / Insert”

“When injected, burning may be felt, the injection is more painful.”

“When using a syringe, you need to push the piston to the end, while when using the pen you press the button once and observe when the yellow mark stops”

“It’s easier for me to use a pen, while my chance of making a mistake is less

“Because the pen is easier to use, and the pain after using it is less”

“The longer the injection time, the more painful it is.”

“With slow administration, burning is felt”

Information from the subject who preferred the syringe

With regard to ease of use, convenience and time spent on the injection and safety, a pen is preferred; less pain - when using a syringe; how likely it is to use a pen is unlikely; how likely a pen recommendation is a neutral attitude.

Comments - “It seems to me that I have better control of the injection needle. The second injection was more painful than using a syringe. ”

Interim study 3

In an intermediate study, when examining 35 patients, the following responses were received:

- Which injection method of HUMIRA® would you prefer in terms of the time it takes to inject? Handle (n = 29); syringe (n = 2); no preference (n = 4)

- Which injection method of HUMIRA® would you prefer in terms of safety? Handle (n = 31); syringe (n = 0); no preference (n = 4)

Finished Study Results

Propensity and baseline characteristics of patients

A total of 52 patients were included in the study, who completed all 3 visits during the study. During the study, no patient discontinued treatment. Initial demographic and baseline survey results are included in table 1.3. Patients included in the study were treated with adalimumab for an average treatment period of 15.4 months, and they themselves administered adalimumab with a syringe during their treatment periods (average duration of self-administration was 14.9 months). In addition, approximately 655 patients received concomitant treatment with methotrexate, and 35% received concomitant treatment with steroids. Patients were practically equally divided into groups that usually injected doses of adalimumab into the abdomen or thigh, while a small percentage of patients alternated injection sites. During the study, 29 patients (55.8%) chose the abdomen as the injection site, and 23 patients (44.2%) chose the thigh area as the injection site.

Table 1.3
Baseline demographic data, clinical characteristics, and survey responses Characteristic General population (N = 52) Middle Age (SD) 53.8 (12.1) The average duration of rheumatoid arthritis (SD) 8 (7.5) Gender, n (%) Female 32 (61.5) Male 20 (38.5) Race, n (%) White 46 (88.5) Black 6 (11.5) Other 0 (0) Medicines for RA over the past 12 months, n (%) Adalimumab 52 (100) Etanercept 2 (3.8) Infliximab 2 (3.8) Other 1 (1.9) Source analysis N = 52 Duration of adalimumab treatment (months) Medium (SD) 15.4 (9.8) Median 12.0 Range 3.0-40.0 Duration of self-injection of adalimumab (months) Medium (SD) 14.9 (10.0) Median 12.0 Range 2.0-40.0 Duration of injection (min) Medium (SD) 1.6 (4.1) Median 0.8 Range 0.2-30.1 Normal injection site, n (%) Stomach 25 (48.1) Hip 22 (42.3) Both belly and hip 5 (9.6) RA = Rheumatoid Arthritis

Injection pain

The ratings of pain at the injection site are included in Table 2. At the first visit, immediately after injection with a syringe, the average pain rating at the injection site was 3.7. The average pain ratings decreased by 37% to 2.3 at the second visit and by 46% to 2.0 at the third visit immediately after the pen injection. The average intragroup changes in pain at the injection site immediately after the injection at the second visit (pen) and the third visit (pen) were statistically significantly reduced (P = 0.002 and P <0.001, respectively) compared with the first visit (syringe) (table 2). The average pain ratings 15-30 minutes after injection were 0.8 at the first visit; 0.2 on the second visit; and 0.2 on the third visit. Similarly, the average intragroup changes in pain at the injection site 15-30 minutes after injection at the second visit (pen) and the third visit (pen) were statistically significantly reduced (P = 0.004 and P = 0.001, respectively) compared with the first visit ( syringe) (table 2).

General impressions

At the first visit, patients were evenly divided according to the rating of their overall impressions of their first syringe injections. Approximately one third of the patients rated their overall impression of the syringe injection as “favorable” or “extremely favorable”, approximately one third rated their impressions as “neutral”, and approximately one third rated them as “unfavorable” or “extremely unfavorable” (table 3 ) After using the pen, more than 80% of patients at the second visit rated their general impressions of the pen as “favorable” or “extremely favorable” at the second visit (86.5%) and the third visit (88.5%).

Table 3
General impressions of the syringe pre-filled with adalimumab and the auto-injection pen Reaction Syringe, n (%) Pen, n (%) 1st visit 2nd visit 3rd visit N = 52 N = 52 N = 52 Extremely favorable 2 (3.8) 26 (50.0) 33 (63.5) Favorable 15 (28.8) 19 (36.5) 13 (25.0) Neutral 18 (34.6) 3 (5.8) 3 (5.8) Unfavorable 14 (26.9) 1 (1.9) 2 (3.8) Extremely unfavorable 3 (5.8) 3 (5.8) 1 (1.9)

Patient preference

The final review of patient preferences, which was prescribed after the third visit, showed that overall, 88.5% (95% CI 84.1, 98.8) preferred the pen, 5.8% (95% CI 1.2, 15.9) preferred a syringe and 5.8% had no preference (Fig. 26). Patients were asked to list some reasons for their preferences. Most patients who chose the pen as their preferred delivery device said it was easier to use with less pain than using a syringe. Other reasons why patients preferred a pen included the following: lack of hematomas at the injection site; shorter injection time; shorter preparation times and fewer steps to follow; Better device control less effort required; there is no need to push the syringe to insert the needle into the skin; the needle is not visible; less worries associated with storing and removing the needle; and no need to pull the syringe plunger back to check for blood. Patients who chose the syringe as their preferred delivery device gave the following reasons: fame of the syringe / lack of need for replacement; difficulty removing the handle cap; Better control of the injection needle and less soreness than using a pen.

When patients were asked to rate specific reasons for their preferences, more patients preferred a pen over a syringe (in order from the largest to the smallest percentage) for the following reasons: ease of use; convenience; general safety and general characteristics (equal percentage); less time to complete the injection and less pain (figure 2). More than 94% of patients said they would probably or very likely use a pen if it were available at the same price as a syringe (Fig. 27). Similarly, more than 94% of patients said they would recommend a pen to another patient who is taking adalimumab (Fig. 27).

Adherence to prescribed treatment

At each visit, the healthcare provider evaluated the injection techniques used by patients to help determine the effectiveness of the training procedure. In general, for each component evaluated (i.e., the injection site prepared by alcohol, the tested level and quality of the preparation, caps removed in order, the prepared flat skin surface, the flat skin held during the injection, the correct position of the handle, the correct start of the handle, maintenance constant pressure without delay, continuation of the injection until completion and the observed yellow stopper in the window at the end of the injection), the execution rating of the patient preparation and injection methods was 98-100% phenomenon). Approximately 90% of patients indicated that instructional devices (videos or brochures) used by health care providers provided adequate training.

Safety ratings

No new safety signals were observed during this study. Adalimumab has been shown to be generally safe and well tolerated, regardless of delivery by syringe or pen. No statistically significant differences were observed between AEs noted during syringe use compared to the use of a pen or the point of view of all AEs, or the individual preferred term MedDRA. A total of 13 patients reported treatment-related AE: 5 using a pre-filled syringe (9.6%) and 10 (19.2%) after 2 pen injections. Two patients reported AE during use of both the syringe and pen. Most AEs were mild to moderate and included bronchitis, hypersensitivity, arthritic pain, cough, and rhinitis. 3 infections and 1 drug hypersensitivity reaction were noted. Two patients had severe AE when using a pen. Of these, a 69-year-old white man with a history of hypertension and coronary heart disease, which led to triple coronary artery bypass grafting, required hospitalization due to exacerbation of congestive heart failure, a diagnosis first established in 1989. This patient received a second dose of adalimumab by pen after stabilizing his condition and recovery. Another patient was a 51-year-old white man who required hospitalization for pneumonia approximately 71 days after the start of the study treatment. No other phenomena of interest related to the TNF antagonist were noted during this study, including malignant neoplasms, demyelinating events (including multiple sclerosis), or reactions like lupus. None of the patients stopped participating in the study in response to treatment-related AE, and device failures were noted.

The final results of the study show that 46 of 52 patients preferred a pen (88.5%), while 5.8% (n = 3) did not have a preference and 5.8% preferred PFS (n = 3). In addition, 40 of 52 patients considered the pen less painful (76.9%), although 15.4% did not have a preference. Only 7.7% thought PFS was less painful. In addition, patient responses indicated that the pen was easier to use, as 49 out of 52 patients thought the pen was easier to use (94.2%). Finally, the pen was considered more comfortable, since 48 out of 52 patients considered the pen more comfortable (92.3%). 61.5% (n = 32) of patients said they would probably recommend the pen to another HUMIRA® user, although 32.7% (n = 17) said they would probably not recommend it and 5.8% (n = 3) neutralized the problem. Additional research results are shown below in tables 4-6.

Table 4
Results of filling out a questionnaire regarding “How painful was the HUMIRA® injection that you just injected?” (And immediately after the injection and after 15-30 minutes) Visit N 1st week (syringe) Average Visit Average Immediately after injection
3rd week (pen)
5th week (pen) 52 3,7 2.3 ^@ 52 3,7 2.0 * 15-30 min after injection
3rd week (pen)
5th week (pen) 52
52 0.8
0.8 0.2 ^&
0.2 ^# * P value <0.001
^# P value 0.001
^@ P value 0.002
^& P value 0.004

Table 5
Subjective impression: general impression Impression Week 1 (syringe)
(N = 52)
n (%) Week 3 (pen)
(N = 52)
n (%) Week 5 (pen)
(N = 52)
n (%) Extremely unfavorable 3 (5.8) 3 (5.8) 1 (1.9) Unfavorable 14 (26.9) 1 (1.9) 2 (3.8) Neutral 18 (34.6) 3 (5.8) 3 (5.8) Favorable 15 (28.8) 19 (36.5) 13 (25.0) Extremely favorable 2 (3.8) 26 (50.0) 33 (63.5)

The types and cumulative incidence of adverse events (AE) during the 2-week period after injection with a syringe and the 4-week period after 2 injections with a pen were comparable. 5 patients (9.6%) reported AE, including bronchitis, hypersensitivity, arthritic pain, cough and rhinitis after injection with a syringe and 8 (15.4%) after injection with a pen. There were no AEs leading to discontinuation of treatment.

Although the pen was designed to provide patients with greater convenience, it was unclear which characteristics, such as less soreness, would trigger patient preferences. This study showed that all of the individual characteristics — less pain during injection, safety, ease of use, convenience, and time to complete the injection — were in favor of the pen relative to the syringe. In this study, the pen showed a statistically significant advantage in relation to pain during injection, which was reduced by 46% immediately after injection and by 75% 15-30 minutes after injection.

Regarding preference, patients were equally divided according to their general impressions of the syringe with respect to 5 predefined categories (ie, “extremely favorable”, “favorable”, “neutral”, “unfavorable”, “extremely unfavorable”). However, after switching to the pen, the rating of the general impression of patients significantly shifted to either “favorable” or “extremely favorable”. In addition, only after 2 pen injections did most patients say that they would “probably” or “extremely likely” switch to the pen and would recommend the pen to another patient who was receiving adalimumab treatment, indicating that patients quickly accepted the pen and its properties.

These results can have important therapeutic consequences for patients who require long-term use of a TNF inhibitor or other types of biological therapy. Due to the association of patient preference with the prescribed treatment (Schwartzman et al. Arthritis Research & Therapy. 2004; 6 (Suppl 2): S19-S23), the preference for a particular route of administration may be a significant factor in the choice of biological therapy by the physician. In addition, adherence to treatment is considered to be one of the most important factors in maintaining the long-term benefits of treatment with a TNF antagonist, and therefore a lack of adherence to treatment can dramatically decrease treatment efficacy (Schwartzman et al. (2004)).

As a result, patients determined that it was easier to use a pen than a pre-filled syringe. In addition, patients found that the pen was more comfortable than a syringe and less painful than a pre-filled syringe. Patients preferred the HUMIRA® PFS HUMIRA® pen for all rating parameters. Approximately 90% of patients reported a general pen preference over a pre-filled syringe. 8 out of 10 patients would also recommend a pen to other patients using adalimumab. Finally, 80% of patients rated the pen as less painful than PFS.

This study shows that patients believed that the pen with adalimumab caused significantly less pain than a traditional pre-filled syringe. In addition, patients with RA who received adalimumab preferred subcutaneous injection of adalimumab with an auto-injection pen over a pre-filled syringe. Patients thought the pen was easier to use, more comfortable, and required less time for injection. Regarding the security profile, there were no visible differences between the two delivery devices. The general patient preference for a device in the form of an auto-injection pen can lead to improved adherence to the prescribed treatment, and, in turn, to improved clinical outcomes during long-term therapy by self-administration of biological agents.

Example 2 : Assessment of the relative bioavailability, safety, and tolerability of single doses of adalimumab administered via an auto-injection pen and a pre-filled syringe

Rheumatoid arthritis (RA) is a chronic, disabling disease that requires long-term treatment that is safe and effective. Modern biological drug delivery tools, pre-filled syringes, are painful and burdensome. Pre-filled, single-use, auto-injection pens, such as those described in the example below, provide more convenient insertion.

The purpose of the following example was to compare the bioavailability, safety, and tolerability of adalimumab administered subcutaneously with an auto-injection pen compared to a pre-filled syringe.

Study Structure

Adalimumab was injected with a pen or pre-filled syringe into the abdomen or thigh in healthy, adult volunteers in this multicenter, open, parallel, group I phase study. Scheme A included a 40-mg subcutaneous dose of adalimumab using an auto-injection pen, while Scheme B included a 40-mg subcutaneous dose of adalimumab using a pre-filled syringe.

Blood samples were taken by puncture of a vein before administration (hour 0); and after 4, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 288, 336 and 360 hours; and 3, 4, 5, 6, 7, and 8 weeks after administration. Serum adalimumab concentration was determined using an approved dual antigen immunoassay. The assay had a lower limit of quantification of 3.125 ng / ml in diluted serum.

The main inclusion criteria were: age 18-55 years and overall good condition of patients. The main exclusion criteria were: pregnancy and a positive skin test PPD (tuberculin purified from protein).

Pharmacokinetic analysis included the analysis of pharmacokinetic (PK) parameters, which represented the estimated use of non-compartmental methods. The included PK parameters were: maximum serum concentration observed (Cmax); time to reach Cmax (Tmax); the area under the curve of the dynamics in time of concentration in serum (AUC) from 0 to 360 hours (AUC0-360); and AUC from 0 to 1344 hours (AUC0-1344).

Statistical analysis was performed using the following considerations. A four-way analysis of covariance (ANCOVA) was performed for Tmax and the logarithms of AUC and Cmax using the scheme, injection site, study center and gender as factors. Covariate was body weight. To evaluate the bioequivalence of the circuits, 2 one-way testing procedures were performed for AUC and Cmax through a 90% confidence interval for the ratio of the central values of the circuits. The ratio of the central values of the circuits corresponds to the difference between the main effects of the circuits on the ANCOVA model.

Safety was determined based on side effects (AE) scores, physical examinations, vital signs, and laboratory tests.

The study included a total of 295 healthy volunteers of men and women. Of these, 146 volunteers received a dose of 40 mg of adalimumab using an auto-injection pen and 149 individuals received a dose of 40 mg of adalimumab using a pre-filled syringe. Table 7 contains the summary statistics of demographic parameters.

Table 7
Source demographic variables Characteristics All randomized volunteers (N = 295) Age 37.5 ± 10.6 Weight (kg) 72.4 ± 10.9 Height (cm) 168.9 ± 9.8 Body mass index 25.3 ± 2.7 % of men 49 % white 81 All values are Mean ± SD (standard deviation), excluding percentages

The temporal dynamics profiles of mean serum adalimumab concentrations were the same for the two regimens. The pharmacokinetic profiles of the pen and prefilled syringe were also comparable between the two injection sites, the thigh and the abdomen.

The pharmacokinetic parameters of adalimumab after administration in each of the two regimens were the same (table 8). The central values of Tmax, logarithmically transformed by Cmax, AUC0-360, AUC0-1344 for the pen did not statistically significantly differ from the values for the pre-filled syringe (Table 8).

Table 8
Pharmacokinetic parameters of adalimumab when using an auto-injection pen and a pre-filled syringe Scheme Pharmacokinetic parameters Adalimumab administration via autoinjection pen (N = 146) Adalimumab administration via pre-filled syringe (N = 147) * Tmax (hours) 142.3 ± 76.2 151.4 ± 88.5 Cmax (μg / ml) 4.8 ± 1.5 4.8 ± 1.5 AUC0-360 (mcg · h / ml) 1260 ± 352 1276 ± 373 AUC0-1344 (mcg / h / ml) 2454 ± 815 2544 ± 952 * N = 146 for AUC0-360 and AUC0-1344
In both schemes, a single dose of 40 mg of adalimumab is administered subcutaneously.
All values are Mean ± SD.

90% confidence intervals for logarithmically transformed AUC0-360, AUC0-1344 and Cmax were within the range of 0.80 to 1.25, indicating that Scheme A using the auto-injection pen was bioequivalent to Comparative Scheme B using pre-filled syringe in both injection sites, thigh and abdomen (table 9).

In this study, the auto-injector was well tolerated with a safety profile comparable to that of a pre-filled syringe (table 10)

Table 10
Adverse events ≥2% in the population Auto Injection Pen Pre-filled syringe N = 146 N = 149 n (%) n (%) Any AE 70 (48) 60 (40) Headache 29 (20) 28 (19) Upper respiratory tract infection 9 (6) 13 (9) Stasis in the nasal mucosa 9 (6) 7 (5) Pain (in the limbs) 2 (1) 7 (5) Constipation 7 (5) 2 (1)

During the study, there were no deaths or discontinuation of injections due to side effects. One volunteer reported a severe side effect of appendicitis, which required surgery and hospitalization on the 20th day of the study. This subject asked to continue participating in the study after being discharged from the hospital, and was allowed to continue participating after a full medical examination. Researchers rated most of the side effects that occurred during treatment as unrelated or possibly drug related studies and easily expressed.

In conclusion, the auto-injection pen was bioequivalent to a pre-filled syringe. Both courses were also bioequivalent in each injection site, abdomen and thigh. The pen's safety profile was comparable to that of a pre-filled syringe.

Example 3 : Introduction of the HUMIRA® automatic injection device compared to the pre-filled HUMIRA® delivery syringe

A HUMIRA® representative visits a doctor who has previously prescribed HUMIRA® PFS to patients. The representative provides an oral presentation to the doctor in which the TOUCH study and its results are described for the doctor (the TOUCH study is presented, for example, in Example 1 above). In particular, the representative tells the doctor that 90% of patients reported a general preference for the HUMIRA® pen over PFS, 8 out of 10 would recommend the pen to other patients who received HUMIRA®, and 80% of the patients rated the pen as less painful than PFS. In addition, the representative gives the doctor a flip chart and a DVD, each of which describes a TOUCH study, and reports that 90% of patients reported a general preference for HUMIRA® bundles over PFS, 8 out of 10 would recommend a pen to other patients who received HUMIRA® , and 80% of patients rated the pen as less painful than PFS.

Example 4 : Ways to prepare for the use of an automatic injection device HUMIRA®

A HUMIRA® representative visits a doctor who has previously prescribed HUMIRA® PFS to patients. The representative provides an oral presentation to the doctor describing how the HUMIRA® pen is used to deliver the dose of HUMIRA® to the patient. This presentation includes instructions for the following steps:

(i) remove the HUMIRA® handle from the refrigerator 15-20 minutes before the injection;

(ii) select the injection site on the thigh or abdomen (where the site should be at least 1 inch from the previous injection site and at least 2 inches from the navel) and wipe the injection site with an alcohol swab;

(iii) examine the HUMIRA® solution in the HUMIRA® pen through the window in the pen in order to ensure that the liquid is clear and colorless. Also, while holding the knob so that the end of the needle is pointing down, check to make sure that the fluid level is the same or close to the line visible through the window (in order to make sure that the correct dosage is present);

(iv) remove the caps from the needle end and from the end of the handle start button. Gently squeeze the area of the cleansed skin of sufficient size and place the handle at an angle of 90 degrees with focus on the skin. Press the start button, firmly pressing the handle to the skin, and listen until a “click” appears. Continue pushing the start button and count up to 10 seconds. Make sure that the yellow indicator completely appears and stops in the display window; and

(v) throw the pen into an appropriate container (e.g. Sharps container).

In addition, the representative provides the doctor with a flip chart and DVDs that transmit instructions for steps (i) to (v) as described above. In addition, the representative provides the doctor with a training kit, the kit including (1) a demonstration automatic injection device that simulates a HUMIRA® pen but does not contain a needle and a dose of HUMIRA®, (2) a brochure that gives instructions for steps (i) - ( v) as described above, and (3) an audiovisual device (VHS or DVD cassette) that transmits instructions to carry out steps (i) to (v) as described above.

Equivalents

Those skilled in the art will understand or will, using nothing more than ordinary experimentation, be able to determine the many equivalents of certain embodiments of the invention described herein. Such equivalents are covered by the following claims. The contents of all references, patents, patent applications and published patent applications cited throughout the application are hereby incorporated by reference.

Claims (12)

1. An automatic injection device for providing subcutaneous injection of a substance to a user, including:
a housing having an open first end, a second end, a window located in the side wall for viewing the interior of the housing, and an indicator that aligns with the window when the substance is introduced to the user;
a syringe movably located in the housing, the syringe comprising a sleeve portion for containing the substance, a hollow needle in fluid communication with the sleeve portion for expelling the substance from the syringe, and a plug for sealing the sleeve portion and selectively applying pressure to the substance to force it to move through cannula;
a syringe drive component for the first movement of the syringe towards the first end of the housing so that the needle protrudes from the first end and for subsequent pressure is applied to the plug, the syringe drive component comprising:
a core part having: an upper solid part, a lower solid part having one end, which can be actuated to move the cork and transmit pushing forces to it; a protruding part that protrudes from the rod along at least a portion of the length of the rod, the protruding part comprising one or more flexible elbows on each side of the central cavity located between the upper and lower solid parts, the protruding part having a first extended position before entering a sleeve portion of the syringe in which the flexible elbows extend radially outward to form a central cavity, and the protruding portion has a second compressed position for leading the supercharger to the plug, in which the e knee compressed radially inwardly toward the central cavity, and a flange disposed between the second end of the syringe drive component and the protruding portion;
a first biasing mechanism for biasing the syringe drive component toward the first open end of the housing, the first biasing mechanism being located between the flange of the syringe drive component and the second end of the housing;
a second biasing mechanism for holding the syringe in a retracted position in the housing until the first biasing mechanism is released; and
and a first removable cap to cover the first end or second end of the housing. 2. The automatic injection device according to claim 1, wherein the central cavity is a longitudinally extending gap. 3. The automatic injection device according to claim 1, wherein the body is fixed relative to the syringe. 4. The automatic injection device according to claim 1, further comprising a start button connected to the housing for actuating the syringe drive component. 5. The automatic injection device according to claim 4, further comprising a latch for locking the syringe drive component in the retracted position before being actuated by the start button. 6. The automatic injection device according to claim 1, wherein the syringe contains a dose of a TNFα inhibitor to be injected to a user. 7. The automatic injection device according to claim 1, further comprising a dose of a TNFα inhibitor placed in the sleeve portion of the syringe. 8. The automatic injection device according to claim 1, further comprising a sheath of a needle that advances along the needle protruding through the first end of the body after expelling the substance from the syringe. 9. An automatic injection device for providing subcutaneous injection of a substance to a user, including:
a housing having an open first end and a second end;
a plunger comprising a rod that is configured to connect to or fit onto the syringe plug at the first end of the housing, a compressible portion protruding from the rod at least along a portion of the length of the rod, the compressible portion having a first expanded inactivated position and a second compressed activated position for bringing the supercharger to the plug, and a flange between the second end of the rod and the compressible part; and
a biasing mechanism for biasing the plunger toward the first open end of the housing, the biasing mechanism being located near the second end of the shaft between the flange and the second end of the housing. 10. The automatic injection device according to claim 9, further comprising a start button connected to the housing for actuating the plunger. 11. The automatic injection device according to claim 10, further comprising a latch for locking the plunger in the retracted position before being actuated by the start button. 12. The automatic injection device according to claim 9, further comprising a window on the housing for viewing the interior of the housing.

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