저자는 레이 리 씨, HC 렁 씨와 월리스 소 씨에게 광원과 분말 인수프플레이터를 만드는 데 친절한 도움을 준 것에 대해 감사드립니다. 동물 화상 진찰에 대한 지원을위한 교수 핵심 시설. 이 작품은 홍콩 연구 보조금 위원회(17300319)의 지원을 받았습니다.

이 연구에서 수행 된 실험은 홍콩 대학 인 교육 및 연구를위한 살아있는 동물 사용위원회 (CULATR)의 승인을 받았습니다. 루시파라기 메신저 RNA(mRNA)의 0.5%를 함유한 스프레이 동결 건조(SFD)에 의해 제조된 건식 분말 제형은, 5% 합성 펩타이드 PEG12KL4 및 94.5%의 매니톨(w/w)을 함유하여 폐16에서mRNA 발현을 입증하기 위해 이 연구에서 사용된다. SFD 분말의 질량 중앙공기역학적 직경(MMAD)은 2.4 μm입니다. 분무 건조(SD) 매니톨 분말은 분말분산(16)에사용되는 공기 부피의 효과를 조사하는 데 사용된다. SD 분말의 MMAD는 1.5 μm입니다.
1. 건조 분말 인수프플랫터 의 제조 및 건조 분말의 적재
<ol><li>(선택 사항) 건식 분말(유리병)과 200 μL 비필터 라운드 젤 로딩 파이펫 팁의 정적 충전을 중화시합니다. 제조업체의 지시에 따라 정전기 방지 총 또는 탈이온화 기능과의 균형을 사용합니다.</li>
	<li>약 4cm x 4cm 크기의 계량 용지를 준비합니다. 용지를 대각선으로 반으로 접은 다음 전개합니다.</li>
	<li>계량 용지에 1-2 mg의 드라이 파우더를 계량합니다.</li>
	<li>팁의 넓은 개구부를 통해 분말로 젤 로딩 파이펫 팁을 채웁니다. 파우더가 팁의 좁은 끝 부근에서 느슨한 응집체가 형성될 때까지 분말을 부드럽게 포장하십시오(그림1A). 분말 분산을 방해할 수 있으므로 분말을 너무 단단히 포장하지 마십시오.</li>
	<li>3방향 스톱콕(도1B)을통해 분말로드 팁을 1mL 주사기에 연결합니다. 주사기의 크기는 분말을 분산하는 데 사용되는 공기의 부피에 따라 변경할 수 있습니다. 가루의 유출을 방지하기 위해 연결 중에 팁과 주사기를 수직으로 잡습니다. 즉시 투여가 수행되지 않으면 파라필름을 사용하여 팁의 개구부를 밀봉하고 투여 전까지 적절한 상태로 일시적으로 보관하십시오.</li>
</ol>2. 관착 장치의 제조
<ol><li>광원(그림 2)<ol>
<li>발광 다이오드(LED) 토치와 직경 0.8-1mm의 유연한 광섬유를 통해 맞춤형 광원을 준비합니다.</li>
		<li>광섬유가 간신히 통과할 수 있도록 LED 토치의 투명 렌즈에 핸드 드릴 또는 드릴 비트로 중앙 오리피스를 만듭니다.</li>
		<li>오리피스를 통해 광섬유를 삽입합니다. LED 토치를 켜서 광섬유의 다른 쪽 끝에서 최대 밝기를 위해 삽입의 위치와 깊이를 조정합니다.</li>
		<li>투명 에폭시 접착제로 광학 섬유를 제자리에 부착합니다.</li>
	</ol>
</li>
	<li>가이딩 캐뉼라(그림 3)<ol>
<li>1mL 플라스틱 파스퇴르 파이펫(그림3A)을가지고 파이펫을 양쪽 끝에 두십시오.</li>
		<li>알코올 램프(또는 분젠 버너와 같은 실험실내의 다른 열원)를 사용하여 피펫 의 중간을 화염 위 5-10cm(그림3B)에배치하여 가열합니다. 파이펫을 회전하여 균일하게 가열되었는지 확인합니다.</li>
		<li>플라스틱이 부드럽고 변형이 되면 파이펫을 화염에서 멀리 옮기고 파이펫을 부드럽게 펴십시오.</li>
		<li>파트 A와 파트 B(그림 3C-E)로가위 한 쌍으로 중간에 늘어난 파이펫을 잘라. 파트 A를 미세 팁 파이펫으로 사용하고 B파트를 안내 캐뉼라로 사용하십시오. 안내 캐뉼라와 성공적인 삽의 기회를 증가하려면, 파트 B(그림 3F)의끝에 bevel (너무 날카로운 동물을 다치게의 위험을 증가시킬 수 있습니다) 확인합니다. 200 μL 젤 로딩 파이펫 팁(분말 적재용)이 가이딩 캐뉼라에 삽입되면 캐뉼라를 1-2mm 돌출해야 합니다. 참고: 삽관을 위한 적절한 치수(내부 및 외부 직경)를 가진 안내 캐뉼라(Part B)는 17 게이지 바늘 내부에 들어갈 수 있는 동안 21게이지 바늘내부에 들어갈 수 있습니다. 적절한 치수를 달성하기 위해 파이펫을 스트레칭하는 데 여러 번 시도할 수 있습니다.</li>
		<li>(선택 사항): 가이딩 캐뉼라의 넓은 끝에서 작은 개구부를 잘라 서 광섬유(그림3F)를더 쉽게 보유할 수 있도록 보다 유연하게 만듭니다. 이 개방은 또한 액체 에어로졸의 투여를위한 마이크로 스프레이의 피팅을 허용합니다.</li>
	</ol>
</li>
</ol>3화 삽관
<ol><li>마우스 (BALB/c, 7-9 주) 케타민 (100 mg/kg) 및 자일라진 (10 mg/kg) 관면 주사에 의해 마취.</li>
	<li>플렉시글래스로 만든 플랫폼을 준비하고 클램프가 있는 스탠드에 장착합니다(도4A). 마취된 마우스를 플랫폼(약 60°의 경사)에 척추 위치에 놓습니다. 플랫폼의 높이와 경사각도는 스탠드의 클램프 위치에 의해 조정할 수 있습니다.</li>
	<li>나일론 치실(도 4B)에절개를 연결하여 마우스를 일시 중단합니다. 테이프 또는 고무 밴드로 마우스의 위치를 고정합니다.</li>
	<li>가이딩 캐뉼라의 개구부와 함께 섬유 레벨의 끝으로 관착하기 전에 가이딩 캐뉼라에 광섬유를 삽입합니다. LED 토치를 켜서 조명합니다.</li>
	<li>마우스의 혀를 집게 한 쌍으로 부드럽게 돌출하여 기관지노출을 합니다.</li>
	<li>다른 손으로 광학 섬유가 있는 가이딩 캐뉼라를 내부에 보관하십시오. 구강을 통해 삽입합니다. 광섬유의 조명으로 기관지의 개구부는 성대 사이의 오리피스로 시각화될 수 있다.</li>
	<li>개구부(그림5A)의중간선쪽으로 안내 캐뉼라의 경사를 정렬합니다. 기관 개구부에서 캐뉼라의 최고급 끝을 조준하여 광섬유로 가이딩 캐뉼라를 기관으로 부드럽게 삽관합니다.</li>
	<li>관관시, 광섬유를 신속하게 제거하고 기관 내부에 안내 캐뉼라를 둡니다(도5B). 정상적인 호흡을 관찰해야 합니다.</li>
	<li>안내 캐뉼라의 개구부에서 미세 팁 파이펫(파트 A)을 잡고 작은 공기 퍼프(약 0.2mL)를 마우스의 폐에 주입한다. 마우스 의 가슴에 약간의 인플레이션은 적절한 삽관을 나타냅니다. 분말 투여 전에 미세 팁 파이펫을 제거합니다.</li>
</ol>4. 분말 투여
<ol><li>1.5 단계에서 설명된 바와 같이 주사기에 연결된 분말 로드 팁을 누를 수 있습니다. 주사기와 팁 사이의 공기 흐름이 분리되었는지 확인합니다.</li>
	<li>주사기 플런저를 뒤로 당겨 0.6 mL의 공기를 인출하십시오. 참고: 분말을 분산하는 데 사용되는 공기의 양은 분말의 특성과 적재된 분말의 양에 따라 달라집니다. 이것은 결과 섹션에 더 설명됩니다.</li>
	<li>3방향 스톱콕의 밸브를 돌려 주사기와 분말로 적재된 팁 사이의 기류를 연결합니다.</li>
	<li>이미마우스(도 5C)의기관체에 배치된 가루 캐뉼라에 분말로드 팁을 삽입한다. 안내 캐뉼라를 잡고 주사기 플런저를 한 번의 연속 작용으로 강제로 밀어 에어로졸이 폐에 분말을 분산시보세요. 참고: 동물의 부상을 피하기 위해 장치의 전방 모션을 최소화해야 합니다.</li>
	<li>팁을 제거하고 팁 내부의 분말이 비워졌는지 확인합니다. 그렇지 않은 경우 4.1에서 4.4 단계를 반복합니다. 참고: 과도한 도청으로 인해 분말이 너무 단단히 포장되면 제대로 분산되지 않을 수 있습니다.</li>
	<li>투여가 완료되면 기관에서 안내 캐뉼라를 제거하십시오.</li>
	<li>마우스가 기도의 봉쇄를 피하기 위해 혀반이 튀어나온 척추 위치에 수평으로 배치하여 마우스를 복구할 수 있도록 합니다.</li>
</ol>

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S., Sarasija, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pulmonary+drug+delivery+strategies:+A+concise,+systematic+review.">Pulmonary drug delivery strategies: A concise, systematic review.</a> Lung India. 29 (1), 44-49 (2012).</li><li>Ihara, D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Histological+Quantification+of+Gene+Silencing+by+Intratracheal+Administration+of+Dry+Powdered+Small-Interfering+RNA/Chitosan+Complexes+in+the+Murine+Lung.">Histological Quantification of Gene Silencing by Intratracheal Administration of Dry Powdered Small-Interfering RNA/Chitosan Complexes in the Murine Lung.</a> Pharmaceutical Research. 32 (12), 3877-3885 (2015).</li><li>Qiu, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effective+mRNA+pulmonary+delivery+by+dry+powder+formulation+of+PEGylated+synthetic+KL4+peptide.">Effective mRNA pulmonary delivery by dry powder formulation of PEGylated synthetic KL4 peptide.</a> Journal of Controlled Release. 314, 102-115 (2019).</li><li>Pfeifer, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Dry+powder+aerosols+of+polyethylenimine+(PEI)-based+gene+vectors+mediate+efficient+gene+delivery+to+the+lung.">Dry powder aerosols of polyethylenimine (PEI)-based gene vectors mediate efficient gene delivery to the lung.</a> Journal of Controlled Release. 154 (1), 69-76 (2011).</li><li>Kim, I., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Doxorubicin-loaded+highly+porous+large+PLGA+microparticles+as+a+sustained-+release+inhalation+system+for+the+treatment+of+metastatic+lung+cancer.">Doxorubicin-loaded highly porous large PLGA microparticles as a sustained- release inhalation system for the treatment of metastatic lung cancer.</a> Biomaterials. 33 (22), 5574-5583 (2012).</li><li>Tonnis, W. F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+novel+aerosol+generator+for+homogenous+distribution+of+powder+over+the+lungs+after+pulmonary+administration+to+small+laboratory+animals.">A novel aerosol generator for homogenous distribution of powder over the lungs after pulmonary administration to small laboratory animals.</a> European Journal of Pharmaceutics and Biopharmaceutics. 88 (3), 1056-1063 (2014).</li><li>Hoppentocht, M., Hoste, C., Hagedoorn, P., Frijlink, H. W., de Boer, A. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=In+vitro+evaluation+of+the+DP-4M+PennCentury+insufflator.">In vitro evaluation of the DP-4M PennCentury insufflator.</a> European Journal of Pharmaceutics and Biopharmaceutics. 88 (1), 153-159 (2014).</li><li>Liao, Q., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Porous+and+highly+dispersible+voriconazole+dry+powders+produced+by+spray+freeze+drying+for+pulmonary+delivery+with+efficient+lung+deposition.">Porous and highly dispersible voriconazole dry powders produced by spray freeze drying for pulmonary delivery with efficient lung deposition.</a> International Journal of Pharmaceutics. 560, 144-154 (2019).</li><li>Ito, T., Okuda, T., Takashima, Y., Okamoto, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Naked+pDNA+Inhalation+Powder+Composed+of+Hyaluronic+Acid+Exhibits+High+Gene+Expression+in+the+Lungs.">Naked pDNA Inhalation Powder Composed of Hyaluronic Acid Exhibits High Gene Expression in the Lungs.</a> Molecular Pharmaceutics. 16 (2), 489-497 (2019).</li><li>Chaurasiya, B., Zhou, M., Tu, J., Sun, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Design+and+validation+of+a+simple+device+for+insufflation+of+dry+powders+in+a+mice+model.">Design and validation of a simple device for insufflation of dry powders in a mice model.</a> European Journal of Pharmaceutical Sciences. 123, 495-501 (2018).</li></ol>

저자는 공개 할 이해 상충이 없습니다.

이 논문에서는 건조 분말 부피 및 장내 삽관을 위한 맞춤형 장치가 제공됩니다. 분말 적재 단계에서, 건조 분말은 200 μL 젤 로딩 파이펫 팁에로드됩니다. 팁의 좁은 끝에 분말의 느슨한 포장을 허용 하기 위해 팁을 부드럽게 탭 하는 것이 중요 하다. 그러나 분말이 너무 단단히 포장되면 팁에 갇히고 제대로 분산 될 수 없습니다. 분말 로딩을 용이하게 하기 위해 분말 및 파이펫 팁의 정적 충전을 중...

투여의 폐 경로는 지역 및 조직 적 행동 모두에 대한 치료를 제공하는 다양한 혜택을 제공합니다. 폐 질환의 치료를 위해, 높은 국부 약물 농도는 폐 전달에 의해 달성 될 수있다, 따라서 필요한 용량을 감소시키고 전신 부작용의 발생률을 낮추는. 더욱이, 폐에서 상대적으로 낮은 효소 활동은 조기 약물 대사를 줄일 수 있습니다. 폐는 또한 크고 잘 퍼진 표면적, 매우 얇은 상피 세포 층 및 폐 모세혈관1의높은 혈액 부피로 인한 전신 작용에 대한 약물 흡수에 효율적입니다.
흡입건조분말제제는 천식, 만성폐쇄성 폐질환, 당뇨병 및 폐예방접종2,3,4등 다양한 질환의 예방 및 치료를 위해 널리 조사되고있다. 고체 상태의 약물은 일반적으로 액체 형태보다 더 안정하며, 건조 분말 흡입기는 분무기5,6보다휴대성이 뛰어나고 사용자 친화적이다. 흡입건조분말제형의 개발에서, 안전성, 약동성 프로파일 및 치료효능은 폐투여에 따른 전임상 동물모델에서 평가될 필요가있다 7. 건조 분말을 적극적으로 흡입할 수 있는 인간과 달리, 작은 동물에게 건조 분말을 폐로 전달하는 것은 어려운 일입니다. 동물의 폐에 건조 분말을 전달하는 효율적인 프로토콜을 확립 할 필요가있다.
마우스는 경제적이기 때문에 연구 동물 모델로 널리 사용되며 잘 번식합니다. 그들은 또한 취급하기 쉽고 많은 질병 모형이 잘 설치되어 있습니다. 마우스의 폐에 건조 분말을 관리 하는 두 가지 주요 접근 이 있다: 흡입 및 장 내 관리. 흡입을 위해 마우스는 건조 분말이 에어로졸화되고 동물이 체증 없이 에어로졸에서 호흡하는 전신 또는 코 전용챔버에배치됩니다8,9. 고가의 장비가 필요하며 약물 전달 효율이 낮습니다. 전신 챔버는 기술적으로 덜 어려울 수 있지만, 코 전용 노출 챔버는 신체 표면에 약물의 노출을 최소화 할 수 있습니다. 에 관계없이, 폐에 전달 된 복용량을 정확하게 제어하고 결정하는 것은 여전히 어렵습니다. 건조 분말은 주로 점막 간격이 눈에 띄는 비소하린스 지역에 증착된다10. 더욱이, 챔버 내부의 마우스는 식량 및급수(11)를제한하고 박탈당하기 때문에 투여 과정에서 상당한 스트레스를 받고 있다. 장내 투여를 위해, 일반적으로 기관내로 직접 물질의 도입을 의미한다. 이를 달성하기 위한 두 가지 기술이 있습니다: 기관 절제술과 오로트라세이션 삽관. 전자는 침입적이고 분말 투여에 거의 사용되지 않는 기관에서 절개를하는 수술 절차가 필요합니다. 두 번째 기술만 여기에 설명되어 있습니다. 흡입 방법에 비해, 내막 투여는 최소한의 약물 손실로 높은 전달 효율때문에 마우스내 폐 전달을 위해 보다 일반적으로 사용되는방법이다(12,13). 그것은 정확 하 게 마우스에 몇 밀리 그램 내에서 분말의 작은 금액을 제공 하는 간단 하 고 빠른 방법. 마우스는 해부학적으로 인간과 생리적으로 구별되지만, 관적 과정에서 마취가 요구되지만, 내내 투여는 상부 호흡기를 우회하고 폐 흡수, 생체 이용률 및 치료효과(14,15)와같은 건조 분말 제형의 생물학적 활성을 평가하는 보다 효과적인 방법을 제공한다.
건조 분말을 장내 관리하려면 마우스를 삽관해야 하므로 어려울 수 있습니다. 이 논문에서는 맞춤형 건조 분말 인수프플레이터 및 삽관 장치의 제조가 설명되어 있습니다. 마우스의 폐에 있는 건식 분말의 삽관 및 부당의 절차가 입증됩니다.

<table>
	<tbody>
		<tr>
			<td>BALB/c mouse</td>
			<td></td>
			<td></td>
			<td>Female; 7-9 weeks old; Body weight 20-25 g</td>
		</tr>
		<tr>
			<td>CleanCap Firefly Luciferase mRNA</td>
			<td>TriLink Biotechnology</td>
			<td>L-7602</td>
			<td></td>
		</tr>
		<tr>
			<td>Dry Powder Insufflator</td>
			<td>PennCentury</td>
			<td>Model DP-4M</td>
			<td></td>
		</tr>
		<tr>
			<td>Ketamine 10%</td>
			<td>Alfasan International B.V.</td>
			<td>NA</td>
			<td></td>
		</tr>
		<tr>
			<td>Light emitting diode (LED) torch</td>
			<td>Unilite Internation</td>
			<td>PS-K1</td>
			<td></td>
		</tr>
		<tr>
			<td>Mannitol (Pearlitol 160C)</td>
			<td>Roquette</td>
			<td>450001</td>
			<td></td>
		</tr>
		<tr>
			<td>Non-filter round gel loading pipette tip (200 &#181;L)</td>
			<td>Labcon</td>
			<td>1034-800-000</td>
			<td></td>
		</tr>
		<tr>
			<td>Nylon floss</td>
			<td>Reach</td>
			<td>30017050</td>
			<td></td>
		</tr>
		<tr>
			<td>One milliliter syringe without needle</td>
			<td>Terumo</td>
			<td>SS-01T</td>
			<td></td>
		</tr>
		<tr>
			<td>Optical fibre</td>
			<td>Fibre Data</td>
			<td>OMPF1000</td>
			<td></td>
		</tr>
		<tr>
			<td>PEG12KL4 peptide</td>
			<td>EZ Biolab</td>
			<td></td>
			<td>(PEG12)-KLLLLKLLLLKLLLLKLLLLK-NH2</td>
		</tr>
		<tr>
			<td>Plastic Pasteur fine tip pipette</td>
			<td>Alpha Labotatories</td>
			<td>LW4061</td>
			<td></td>
		</tr>
		<tr>
			<td>Three-way stopcock</td>
			<td>Braun</td>
			<td>D201</td>
			<td></td>
		</tr>
		<tr>
			<td>Xylazine 2%</td>
			<td>Alfasan International B.V.</td>
			<td>NA</td>
			<td></td>
		</tr>
		<tr>
			<td>Zerostat 3 anti-static gun</td>
			<td>MILTY</td>
			<td>5036694022153</td>
			<td></td>
		</tr>
	</tbody>
</table>

intratracheal administration of dry powder formulation in mice

흡입 할 수없는 건조 분말 제제의 개발에서, 전임상 동물 모델에서 자신의 생물학적 활동을 평가하는 것이 필수적이다. 본 논문은 마우스에서 건식 분말 제형의 비침습적 전달 방법을 소개합니다. 3방향 스톱콕을 통해 1mL 주사기에 연결된 200 μL 젤 로딩 파이펫 팁으로 구성된 드라이 파우더 로딩 장치가 제시됩니다. 소량의 건조 분말(1-2 mg)이 파이펫 팁에 적재되어 주사기에 0.6mL의 공기가 분산됩니다. 파이펫 팁은 일회용이고 저렴하기 때문에 다른 건조 분말 제형은 사전에 다른 팁으로 로드 할 수 있습니다. 다양한 제형은 장치 세척 및 용량 리필 없이 동일한 동물 실험에서 평가될 수 있으므로 시간을 절약하고 잔류 분말로부터 의 교차 오염의 위험을 제거합니다. 분말 분산의 정도는 파이펫 팁에 남아있는 분말의 양에 의해 검사 될 수있다. 사용자 정의 광원과 안내 캐뉼라가있는 마우스에 삽관 프로토콜이 포함되어 있습니다. 적절한 관착은 마우스의 깊은 폐 부위에 건조 분말 제형의 장내 전달에 영향을 미치는 주요 요인 중 하나입니다.

건조 분말 insufflator동물의 폐에 분말 에어로졸을 전달하는 데 사용되는 경우, 사용되는 공기의 양은 분말 분산 효율뿐만 아니라 안전에 영향을 미치기 때문에 매우 중요합니다. 이를 최적화하기 위해, 다양한 공기량(0.3mL, 0.6mL 및 1.0mL)을 사용하여 건조 분말(1 mg의 분무 건조 매니톨)을 분산시키고 마우스의 무게를 투여 후 48시간 동안 모니터링하였다(도6). 0.3 mL 및 0.6 mL의 공?...

Watch this Scientific Journal Video about Intratracheal Administration of Dry Powder Formulation in Mice at JoVE.com

Intratracheal Administration of Dry Powder Formulation in Mice

흡입을 위한 건식 분말 제형은 호흡기 질환 치료에 큰 잠재력을 가지고 있습니다. 인간 연구에 들어가기 전에, 전임상 연구에서 건식 분말 제형의 효능을 평가할 필요가 있다. 간 내 막 경로를 통해 마우스에서 건조 분말을 투여하는 간단하고 비침습적 방법이 제시된다.

쥐에서 건조 분말 제형의 장내 투여

In the development of inhalable dry powder formulations, it is essential to evaluate their biological activities in preclinical animal models. This paper ...

intratracheal-administration-of-dry-powder-formulation-in-mice

Research

JoVE Journal

Medicine

9.7K 조회수.  The University of Hong Kong. 흡입을 위한 건식 분말 제형은 호흡기 질환 치료에 큰 잠재력을 가지고 있습니다. 인간 연구에 들어가기 전에, 전임상 연구에서 건식 분말 제형의 효능을 평가할 필요가 있다. 간 내 막 경로를 통해 마우스에서 건조 분말을 투여하는 간단하고 비침습적 방법이 제시된다.

비디오: Intratracheal Administration of Dry Powder Formulation in Mice

A Novel Surgical Approach for Intratracheal Administration of Bioactive Agents in a Fetal Mouse Model

Prenatal pulmonary delivery of cells, genes or pharmacologic agents could provide the basis for new therapeutic strategies for a variety of genetic and acquired diseases. Apart from congenital or inherited abnormalities with the requirement for long-term expression of the delivered gene, several non-inherited perinatal conditions, where short-term gene expression or pharmacological intervention is sufficient to achieve therapeutic effects, are considered as potential future indications for this kind of approach. Candidate diseases for the application of short-term prenatal therapy could be the transient neonatal deficiency of surfactant protein B causing neonatal respiratory distress syndrome1,2 or hyperoxic injuries of the neonatal lung3. Candidate diseases for permanent therapeutic correction are Cystic Fibrosis (CF)4, genetic variants of surfactant deficiencies5 and &alpha;1-antitrypsin deficiency6.
Generally, an important advantage of prenatal gene therapy is the ability to start therapeutic intervention early in development, at or even prior to clinical manifestations in the patient, thus preventing irreparable damage to the individual. In addition, fetal organs have an increased cell proliferation rate as compared to adult organs, which could allow a more efficient gene or stem cell transfer into the fetus. Furthermore, in utero gene delivery is performed when the individual's immune system is not completely mature. Therefore, transplantation of heterologous cells or supplementation of a non-functional or absent protein with a correct version should not cause immune sensitization to the cell, vector or transgene product, which has recently been proven to be the case with both cellular and genetic therapies7.
In the present study, we investigated the potential to directly target the fetal trachea in a mouse model. This procedure is in use in larger animal models such as rabbits and sheep8, and even in a clinical setting9, but has to date not been performed before in a mouse model. When studying the potential of fetal gene therapy for genetic diseases such as CF, the mouse model is very useful as a first proof-of-concept because of the wide availability of different transgenic mouse strains, the well documented embryogenesis and fetal development, less stringent ethical regulations, short gestation and the large litter size.
Different access routes have been described to target the fetal rodent lung, including intra-amniotic injection10-12, (ultrasound-guided) intrapulmonary injection13,14 and intravenous administration into the yolk sac vessels15,16 or umbilical vein17. Our novel surgical procedure enables researchers to inject the agent of choice directly into the fetal mouse trachea which allows for a more efficient delivery to the airways than existing techniques18.

We developed a novel surgical approach for intratracheal administration of bioactive agents into the mouse fetus. The delivery route is more efficient in targeting the fetal mouse lungs than the commonly used intra-amniotic injection. This procedure has to date not been described in a mouse model.

태아 마우스 모델에서 Bioactive 에이전트의 Intratracheal 관리를위한 소설 외과 접근

Prenatal pulmonary delivery of cells, genes or pharmacologic agents could provide the basis for new therapeutic strategies for a variety of genetic and ...

연구

의학

Intranasal Administration of CNS Therapeutics to Awake Mice

Intranasal administration is a method of delivering therapeutic agents to the central nervous system (CNS). It is non-invasive and allows large molecules that do not cross the blood-brain barrier access to the CNS. Drugs are directly targeted to the CNS with intranasal delivery, reducing systemic exposure and thus unwanted systemic side effects1. Delivery from the nose to the CNS occurs within minutes along both the olfactory and trigeminal neural pathways via an extracellular route and does not require drug to bind to any receptor or axonal transport2. Intranasal delivery is a widely publicized method and is currently being used in human clinical trials3.
Intranasal delivery of drugs in animal models allows for initial evaluation of pharmacokinetic distribution and efficacy. With mice, it is possible to administer drugs to awake (non-anesthetized) animals on a regular basis using a specialized intranasal grip. Awake delivery is beneficial because it allows for long-term chronic dosing without anesthesia, it takes less time than with anesthesia, and can be learned and done by many people so that teams of technicians can dose large numbers of mice in short periods. Efficacy of therapeutics administered intranasally in this way to mice has been demonstrated in a number of studies including insulin in diabetic mouse models 4-6 and deferoxamine in Alzheimer's mouse models. 7,8
The intranasal grip for mice can be learned, but is not easy and requires practice, skill, and a precise grip to effectively deliver drug to the brain and avoid drainage to the lung and stomach. Mice are restrained by hand using a modified scruff in the non-dominant hand with the neck held parallel to the floor, while drug is delivered with a pipettor using the dominant hand. It usually takes 3-4 weeks of acclimating to handling before mice can be held with this grip without a stress response. We have prepared this JoVE video to make this intranasal delivery technique more accessible.

A method to intranasally administer drugs to awake mice for the purpose of targeting the brain is described. This method allows for repeat dosing over long periods using intranasal administration of drug without anesthesia, and nose-to-brain delivery with minimal systemic exposure.

깨어 마우스로 CNS의 치료학의 비강 관리

Intranasal administration is a method of delivering  therapeutic agents to the central nervous system (CNS). It is  non-invasive and allows large ...

Dry Powder and Nebulized Aerosol Inhalation of Pharmaceuticals Delivered to Mice Using a Nose-only Exposure System

Obstructive respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD) are currently treated by inhaled anti-inflammatory and bronchodilator drugs. Despite the availability of multiple treatments, both diseases are growing public health concerns. The majority of asthma patients are well controlled on current inhaled therapies but a substantial number of patients with severe asthma are not. Asthma affects an estimated 300 million people worldwide and approximately 20 percent have a severe form of the disease. In contrast to asthma, there are few effective therapies for COPD. An estimated 10% of the population has COPD and the trend in death rates is increasing for COPD while decreasing for other major diseases. Although developing drugs for inhaled delivery is challenging, the nose-only inhalation unit enables direct delivery of novel drugs to the lung of rodents for pre-clinical efficacy and safety/toxicology studies. Inhaled drug delivery has multiple advantages for respiratory diseases, where high concentration in the lung improves efficacy and minimizes systemic side effects. Inhaled corticosteroids and bronchodilators benefit from these advantages and inhaled delivery may also hold potential for future biologic therapies. The inhalation unit described herein can generate, sample for characterization, and uniformly deposit a drug aerosol in the lungs of rodents. This enables the pre-clinical determination of the efficacy and safety of drug doses deposited in the lungs of rodents, key data required before initiating clinical development.

The inhalation unit described herein can generate, sample for characterization, and uniformly deposit a drug aerosol in the lungs of rodents. This enables the pre-clinical determination of the efficacy and safety of drug doses deposited in the lungs; key data enabling clinical inhaled drug development.

Obstructive respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD) are currently treated by inhaled anti-inflammatory and ...

A Pleural Effusion Model in Rats by Intratracheal Instillation of Polyacrylate/Nanosilica

Pleural effusion is a prevalent clinical finding of many pulmonary diseases. Having a useful animal pleural effusion model is very important to study these pulmonary diseases. Previous pleural effusion models paid more attention to biological factors rather than nanoparticles in the environment. Here, we introduce a model to make pleural effusion in rats by intratracheal instillation of polyacrylate/nanosilica, and a method of nanoparticle isolation in the pleural effusion. By intratracheal instillation of polyacrylate/nanosilica with concentrations of 3.125, 6.25 and 12.5 mg/kg&#8729;mL, the pleural effusion in rats presented on day 3, peaked at days 7-10 in 6.25 and 12.5 mg/kg&#8729;mL groups, then slowly decreased and disappeared on day 14. When the concentration of polyacrylate/nanosilica increased, the pleural effusion is produced more and faster. This pleural fluid was detected by ultrasound examination or CT chest scanning and confirmed by dissection of rats. Silica nanoparticles were observed in the rats' pleural effusion by transmission electron microscope. These results showed that the exposure to polyacrylate/nanosilica leads to the induction of pleural effusion, which was consistent with our previous report in humans. Additionally, this model is beneficial for the further study of nanotoxicology and the pleural effusion diseases.

Here, we present a protocol to construct a pleural effusion model in rats by intratracheal instillation of polyacrylate/nanosilica.

Polyacrylate/Nanosilica의 Intratracheal 주입에 의해 쥐에서 흉 막 유출 모델

Pleural effusion is a prevalent clinical finding of many pulmonary diseases. Having a useful animal pleural effusion model is very important to study ...

Inducing Acute Lung Injury in Mice by Direct Intratracheal Lipopolysaccharide Instillation

Airway administration of lipopolysaccharide (LPS) is a common way to study pulmonary inflammation and acute lung injury (ALI) in small animal models. Various approaches have been described, such as the inhalation of aerosolized LPS as well as nasal or intratracheal instillation. The presented protocol describes a detailed step-by-step procedure to induce ALI in mice by direct intratracheal LPS instillation and perform FACS analysis of blood samples, bronchoalveolar lavage (BAL) fluid, and lung tissue. After intraperitoneal sedation, the trachea is exposed and LPS is administered via a 22 G venous catheter. A robust and reproducible inflammatory reaction with leukocyte invasion, upregulation of proinflammatory cytokines, and disruption of the alveolo-capillary barrier is induced within hours to days, depending on the LPS dosage used. Collection of blood samples, BAL fluid, and lung harvesting, as well as the processing for FACS analysis, are described in detail in the protocol. Although the use of the sterile LPS is not suitable to study pharmacologic interventions in infectious diseases, the described approach offers minimal invasiveness, simple handling, and good reproducibility to answer mechanistic immunological questions. Furthermore, dose titration as well as the use of alternative LPS preparations or mouse strains allow modulation of the clinical effects, which can exhibit different degrees of ALI severity or early vs. late onset of disease symptoms.

Presented here is a step-by-step procedure to induce acute lung injury in mice by direct intratracheal lipopolysaccharide instillation and to perform FACS analysis of blood samples, bronchoalveolar lavage fluid, and lung tissue. Minimal invasiveness, simple handling, good reproducibility, and titration of disease severity are advantages of this approach.

직접 경포당증 주입에 의해 마우스에 있는 심각한 폐 상해를 유도하는

Airway administration of lipopolysaccharide (LPS) is a common way to study pulmonary inflammation and acute lung injury (ALI) in small animal models. ...

Establishment of a Severe Dry Eye Model Using Complete Dacryoadenectomy in Rabbits

Dry eye disease (DED) is a complex disease with multiple etiologies and variable symptoms, having ocular surface inflammation as its key pathophysiologic step. Despite advances in our understanding of DED, significant knowledge gaps remain. Advances are limited in part due to the lack of informative animal models. The authors recently reported on a method of DED induced by injecting all orbital lacrimal gland (LG) tissues with the lectin concanavalin A. Here, we report a novel model of aqueous-deficient DED based on the surgical resection of all orbital LG (dacryoadenectomy) tissues. Both methods use rabbits because of their similarity to human eyes in terms of the size and structure of the ocular surface. One week after removal of the nictitating membrane, the orbital superior LG was surgically removed under anesthesia, followed by removal of the palpebral superior LG, and finally removal of the inferior LG. Dacryoadenectomy induced severe DED, evidenced by a marked reduction in the tear break up time test and the Schirmer&#39;s tear test, and significantly increased tear osmolarity and rose bengal staining. Dacryoadenectomy-induced DED lasted at least eight weeks. There were no complications and animals tolerated the procedure well. The technique can be mastered relatively easily by those with adequate surgical experience and appreciation of the relevant rabbit anatomy. Since this model recapitulates the features of human aqueous-deficient DED, it is suitable for studies of ocular surface homeostasis, DED, and candidate therapeutics.

A novel approach is presented to induce chronic dry eye disease in rabbits by surgically removing all orbital lacrimal glands. This method, distinct from those previously reported, produces a stable, reproducible model of aqueous deficient dry eye well suited to study tear physiology and pathophysiology and ocular therapeutics.

토끼의 완전한 다크레오아데네절제술을 이용한 중증 안구건조증 모델 구축

Dry eye disease (DED) is a complex disease with multiple etiologies and variable symptoms, having ocular surface inflammation as its key pathophysiologic ...

Intratracheal Instillation of Stem Cells in Term Neonatal Rats

Prolonged exposure to high concentrations of oxygen leads to inflammation and acute lung injury, which is similar to human bronchopulmonary dysplasia (BPD). In premature infants, BPD is a major complication despite early use of surfactant therapy, optimal ventilation strategies, and noninvasive positive pressure ventilation. Because pulmonary inflammation plays a crucial role in the pathogenesis of BPD, corticosteroid use is one potential treatment to prevent it. Nevertheless, systemic corticosteroid treatment is not usually recommended for preterm infants due to long-term adverse effects. Preclinical studies and human phase I clinical trials demonstrated that use of mesenchymal stromal cells (MSCs) in hyperoxia-induced lung injuries and in preterm infants is safe and feasible. Intratracheal and intravenous MSC transplantation has been shown to protect against neonatal hyperoxic lung injury. Therefore, intratracheal administration of stem cells and combined surfactant and glucocorticoid treatment has emerged as a new strategy to treat newborns with respiratory disorders. The developmental stage of rat lungs at birth is equivalent to that in human lungs at 26&#8722;28 week of gestation. Hence, newborn rats are appropriate for studying intratracheal administration to preterm infants with respiratory distress to evaluate its efficacy. This intratracheal instillation technique is a clinically viable option for delivery of stem cells and drugs into the lungs.

Described is a protocol for performing intratracheal transplantation of mesenchymal stromal cells (MSCs) through intratracheal injection in term neonatal rats. This technique is a clinically viable option for delivery of stem cells and drugs into neonatal rat lungs to evaluate their efficacy.

신생아 쥐 기간에 줄기 세포의 내 치 통 주입

Prolonged exposure to high concentrations of oxygen leads to inflammation and acute lung injury, which is similar to human bronchopulmonary dysplasia ...

A Minimally Invasive Method for Intratracheal Instillation of Drugs in Neonatal Rodents to Treat Lung Disease

Treatment of neonatal rodent with drugs instilled directly into the trachea could serve as a valuable tool to study the impact of a locally administered drug. This has direct translational impact because surfactant and drugs are administered locally into the lungs. Though the literature has many publications describing minimally invasive transoral intubation of adult mice and rats in therapeutic experiments, this approach in neonatal rat pups is lacking. The small size of orotracheal region/pharynx in the pups makes visualization of laryngeal lumen (vocal cords) difficult, contributing to the variable success rate of intratracheal drug delivery. We hereby demonstrate effective oral intubation of neonatal rat pup - a technique that is non-traumatic and minimally-invasive, so that it can be used for serial administration of drugs. We used an operating otoscope with an illumination system and a magnifying lens to visualize the tracheal opening of the rat neonates. The drug is then instilled using a 1 mL syringe connected to a pipette tip. The accuracy of the delivery method was demonstrated using Evans blue dye administration. This method is easy to get trained in and could serve as an effective way to instill drugs into trachea. This method could also be used for administration of inoculum or agents to simulate disease conditions in animals and, also, for cell-based treatment strategies for various lung diseases.

This technique of instilling drugs directly into the trachea of neonatal rodents is important in studying the impact of locally administered drugs or biologicals on neonatal lung diseases. Additionally, this method can also be used for inducing lung injury in animal models.

Treatment of neonatal rodent with drugs instilled directly into the trachea could serve as a valuable tool to study the impact of a locally administered ...

건조 분말 에어로졸 약물을 마우스에 전달하기 위한 맞춤형 일회용 투여기

Disposable Dosators Intended for Dry Powder Delivery to Mice

Dry powder inhalers offer numerous advantages for delivering drugs to the lungs, including stable solid-state drug formulations, device portability, bolus metering and dosing, and a propellant-free dispersal mechanism. To develop pharmaceutical dry powder aerosol products, robust in vivo testing is essential. Typically, initial studies involve using a murine model for preliminary evaluation before conducting formal studies in larger animal species. However, a significant limitation in this approach is the lack of suitable device technology to accurately and reproducibly deliver dry powders to small animals, hindering such models&#39; utility. To address these challenges, disposable syringe dosators were developed specifically for intrapulmonary delivery of dry powders in doses appropriate for mice. These dosators load and deliver a predetermined amount of powder obtained from a uniform bulk density powder bed. This discrete control is achieved by inserting a blunt needle to a fixed depth (tamping) into the powder bed, removing a fixed quantity each time. Notably, this dosing pattern has proven effective for a range of spray-dried powders. In experiments involving four different model spray-dried powders, the dosators demonstrated the ability to achieve doses within the range of 30 to 1100 &#181;g. The achieved dose was influenced by factors such as the number of tamps, the size of the dosator needle, and the specific formulation used. One of the key benefits of these dosators is their ease of manufacturing, making them accessible and cost-effective for delivering dry powders to mice during initial proof-of-concept studies. The disposable nature of the dosators facilitates use in animal procedure rooms, where cleaning and refilling reusable systems and weighing materials is inconvenient. Thus, developing disposable syringe dosators has addressed a significant hurdle in murine dry powder delivery for proof-of-concept studies, enabling researchers to conduct more accurate and reproducible preliminary studies in small animal models for pulmonary drug delivery.

저자 스포트라이트: 소동물 모델에서 건조 분말 흡입기의 전임상 테스트를 위한 일회용 투여제 개발 

Pharmaceutical dry powder development necessitates reliable in vivo testing, often using a murine model. Device technology for accurately and reproducibly delivering dry powder aerosols to mice is restricted. This study presents disposable dosators for pulmonary drug delivery at mouse-relevant doses, aiding initial proof-of-concept research.

생쥐에 건조 분말을 전달하기 위한 일회용 투여제

Dry powder inhalers offer numerous advantages for delivering drugs to the lungs, including stable solid-state drug formulations, device portability, bolus ...

Methods Article

쥐에서 건조 분말 제형의 장내 투여